ILMN_1779234 CXCL6 2.176765229
ILMN_2161577 CXCL6 1.772099149
ILMN_1682636 CXCL2 1.421599429
ILMN_1787897 CXCL1 1.001257032
ILMN_1791447 CXCL12 0.452343235
ILMN_1689111 CXCL12 0.424927863
ILMN_1728478 CXCL16 0.298548249
ILMN_1791759 CXCL10 0.291211017
ILMN_1752562 CXCL5 0.212344214
ILMN_1803825 CXCL12 0.205825531
ILMN_2171384 CXCL5 0.118066746
simplified:
CXCL6:
Ascorbic Acid deficiency results in increased expression of CXCL6 mRNA
Ascorbic Acid results in decreased expression of CXCL6 mRNA
CXCL2:
Estradiol affects the expression of CXCL2 mRNA
Estradiol inhibits the reaction [Halothane results in increased expression of CXCL2 mRNA]
Estradiol results in decreased expression of CXCL2 mRNA
fulvestrant inhibits the reaction [Estradiol inhibits the reaction [Halothane results in increased expression of CXCL2 mRNA]
butyraldehyde results in increased expression of CXCL2 mRNA
CXCL16:
lysophosphatidic acid results in increased expression of CXCL16 protein https://en.wikipedia.org/wiki/LPAR6
Valproic Acid results in increased expression of CXCL16 mRNA
CXCL10:
tofacitinib inhibits the reaction [IFNG protein results in increased expression of CXCL10 mRNA]
tofacitinib results in decreased expression of CXCL10 mRNA
tofacitinib results in decreased secretion of CXCL10 protein <== I have already trialled Tofacitinib 2 years back. It doesnt work and made my scalp very itchy. a possible reason could be that the Th response was swifted to Th2.
Valproic Acid results in increased expression of CXCL10 mRNA
Quercetin results in decreased expression of CXCL10 mRNA <== same goes for Quecertin and Resveratrol- they are double-edged swords.
Quercetin results in decreased secretion of CXCL10 protein
resveratrol results in decreased expression of CXCL10 mRNA
resveratrol results in decreased expression of CXCL10 protein
Ethanol results in increased expression of CXCL10 mRNA
butyraldehyde results in increased expression of CXCL10 mRNA
Estradiol results in increased expression of CXCL10 mRNA
Estradiol results in increased expression of CXCL10 protein
Ascorbic Acid deficiency results in increased expression of CXCL10 mRNA
Ascorbic Acid results in decreased expression of CXCL10 mRNA
CXCL5:
Antirheumatic Agents results in decreased expression of CXCL5 mRNA <== Sulfasalazine and Cox2 inhibitors are some examples. Thus, they are double-edged swords becos they down both pro-hair growth and pro-hair loss chemokine ligands.
Estradiol results in increased expression of CXCL5 mRNA
butyraldehyde results in increased expression of CXCL5 mRNA
Valproic Acid results in decreased expression of CXCL5 mRNA
Valproic Acid results in increased expression of CXCL5 mRNA
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Another ROS scavenger and FoxO target gene is SOD2. There are three SOD2 transcripts, and all three are underexpressed in balding DPCs (47.2%, 28.7%, and 27.0% expression compared to non-balding DPCs in untreated cells).
ILMN_2336781 SOD2 0.472452155
ILMN_2406501 SOD2 0.286869356
ILMN_1792922 SOD2 0.269849418
BAB-A shows an interesting periodic expression pattern when treated with DHT, which would be expected based on the mechanism I described earlier. There's also a slow overall reduction over time.
BAB-B also oscillates, but with a longer and uneven period:
BAB-C drops precipitously at the start and has no clear oscillation pattern (but perhaps a pattern would be apparent with more frequent measurements?):
The non-balding DPCs also fluctuate. For example, here's BAN-A:
The steep drop-off in SOD2 in each case happens within 15-30 minutes, which suggests that AR is acting through a non-genomic pathway, I suppose? So maybe the pathway shown here which acts through the Akt/mTOR/FoxO axis:
Another things is that AR binding to beta-catenin might also inhibit FoxO-mediated transcription, since FoxO uses beta-catenin as a co-activator when cells are under stress.Leave a comment:
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It's from the Chew/Philpott study (accession GSE66663 for untreated cells, GSE66664 for DHT-treated cells).
Really cool site, thanks. And about mTOR...I forgot to mention in my last post that since mTORC1 inhibits autophagy, overactivation of mTORC1 could cause mitochondrial damage and consequent oxidative stress over time. So perhaps mTORC1 and mTORC2 are both implicated in AGA.
One of the interesting thing about estrogen is that it has specific effects on different types of hair follicles -- it suppressed facial hair growth but promotes head hair growth. This is different from say Minoxidil, which promotes hair growth everywhere.
I would say that the most likely barrier to regrowing hair would be degeneration and senescence of dermal papilla cells, and possibly increased androgen sensitivity due to AR upregulation, increased activity of co-activators like HSP27, and post-translational modifications.
Yeah, the intricate systems of cross-talk between different pathways in hair follicles (and other systems) are fascinating. And I remember some people talking about how, if you want to induce new follicles, you need Jak-Stat pathway (and therefore not to use Jak inhibitors when trying to do that).Estrogenic signalling involves oxidation. Perhaps while Estradiol is(likely) part of the solution to AGA- there's still another half that is required to regrow hair- and this requires a certain factor to neutralise the oxidation brought on by estrogenic and androgenic signalling.
Without oxidative elements in the first place(like STAT3 involving il-6 in NFKB)- hair growth cannot happen- yet without anti-oxidative elements to neutralise that oxidative element - hair cannot grow further and die off.
Here's the entire list of expression levels of CXCLs in balding DPCs.
ILMN_1779234 CXCL6 2.176765229
ILMN_2161577 CXCL6 1.772099149
ILMN_1682636 CXCL2 1.421599429
ILMN_1787897 CXCL1 1.001257032
ILMN_1791447 CXCL12 0.452343235
ILMN_1689111 CXCL12 0.424927863
ILMN_1728478 CXCL16 0.298548249
ILMN_1791759 CXCL10 0.291211017
ILMN_1752562 CXCL5 0.212344214
ILMN_1803825 CXCL12 0.205825531
ILMN_2171384 CXCL5 0.118066746
So CXCL6 and CXCL2 are upregulated, CXCL1 is unchanged, while CXCL12, CXCL16, CXCL10, and CXCL5 are downregulated. But I get lost when it comes to the complex details and interactions of several thousand genes -- that's why I'm playing with computational approaches to analyzing these networks.
Leave a comment:
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inbeforethecure:
If we were to look@ page 21 of the study- the only https://en.wikipedia.org/wiki/Chemokine gene that we can see that appears in the ENTIRE list of downregulated genes in balding scalp(when compared to non-balding scalp) for vasculature- is https://en.wikipedia.org/wiki/Stroma...rived_factor_1 aka CXCL12. This means this gene is extremely crucial for promoting hair growth.
Dihydrotestosterone results in decreased expression of CXCL12 mRNA
Dihydrotestosterone results in decreased expression of CXCL12 protein
Estradiol results in increased expression of CXCL12 mRNA
Estradiol results in increased expression of CXCL12 protein
Estrogens results in increased expression of CXCL12 mRNA
Oxygen deficiency results in increased expression of CXCL12 mRNA
Oxygen deficiency results in increased expression of CXCL12 protein
Valproic Acid results in decreased expression of CXCL12 mRNA
Valproic Acid results in increased expression of CXCL12 mRNA
butyraldehyde results in increased expression of CXCL12 mRNALeave a comment:
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IMO, I have come to the conclusion that we have 2 factors causing AGA:
1)The prominence of androgenic factors instead of estrogenic 1s in the balding scalp(likely involving some androgen pathway-independent factors as well)
2)Oxidative stress
Estrogenic signalling involves oxidation. Perhaps while Estradiol is(likely) part of the solution to AGA- there's still another half that is required to regrow hair- and this requires a certain factor to neutralise the oxidation brought on by estrogenic and androgenic signalling.
Without oxidative elements in the first place(like STAT3 involving il-6 in NFKB)- hair growth cannot happen- yet without anti-oxidative elements to neutralise that oxidative element - hair cannot grow further and die off.Leave a comment:
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Inbeforethecure:
This is the holy bible.
http://ctdbase.org/detail.go?type=ge...=2475&view=ixn for mTOR(and all other genes)Leave a comment:
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From where was the 'top 1000 genes in balding DPCs' from?Unfortunately, it looks like I can't access my inbox...? I get the following message:
That sucks. Facial hair develops in a pattern too, of course, so it would be interesting to know.
Actually, the interesting thing is that the expression of anti-oxidation genes are not necessarily "upregulated". In fact, they fluctuate over time. For example...
GPX4 expression vs. hours of DHT exposure, for Balding DPCs of Subject A:
Subject B:
Subject C:
Now, you probably know about FoxO genes and mTOR, right?
Link to pathway diagram: mTOR signaling at a glance
Here are the most upregulated genes in balding DPCs with 100 nM DHT added from that study by Kwack et. al that focused on DKK1:
DHT induces expression of SLC3A2 and SLC7A5, which you can see in the mTOR pathway diagram. These are amino acid transporters that act upstream of mTORC1-mediated anabolic processes. Also, SGK is 4.53x upregulated, which you can also see in the diagram is a substrate of mTORC2. SGK is similar in structure and function to Akt. FoxO1/FoxO3 enforce quiescence of cells and play a critical role in homeostasis and stress resistance -- they transcribe a lot of ROS scavenger genes, for example.
So Akt/SGK, to promote cell proliferation, phosphorylate FoxO. This allows a protein called 14-3-3 to bind it and move it from the nucleus into the cytoplasm where it undergoes proteasomal degradation. It's also important to note that in response to ROS, MST1 and JNK phosphorylate FoxO to keep it in the nucleus, and this signal overrides the Akt/SGK-induced nuclear exclusion signal.
Now imagine what would happen if you were to take this system in its "ground state" (low ROS, low Akt/SGK). Add DHT and you induce FoxO nuclear exclusion and proteasomal degradation through mTORC2 -> Akt + highly upregulated SGK. ROS start to accumulate, but since FoxO protein levels are low, the cells are unable to respond despite the MST1/JNK override signal. Then there's a lag time while new FoxO mRNA are being transcribed and then translated while ROS accumulate, and the newly produced nuclear FoxOs transcribe ROS scavenger genes and the ROS levels drop. Now it's in the ground state once more, and the process repeats itself. If it's an oscillating system like this, static measurements might be misleading and give contradictory results between different experiments.
BTW, here's a nice review paper on FoxOs from Nature: https://www.dropbox.com/s/fpwoka8h9n...m2013.pdf?dl=0
PAX1 has been shown to interact directly with FOXO1, especially under hypoxic stress, while an interaction between PAX9 (a PAX1 paralog) was not detected (see Section 3.6). But maybe PAX1 could play in a role in coordinating homeobox genes as well. Speaking of that, I ran another quick analysis with oPossum on the top 1000 upregulated genes in balding DPCs. What this does is search for enriched transcription factor binding motifs in a list of genes, which gives clues as to which TFs may be differentially regulated. These were the results:
Interesting that lots of homeobox genes show up. Also, SRY (a Y-chromosomal gene responsible for male sex determination). AR is there, lots of FOX genes, AP1, STATs, NF-kB, and more.Code:TF JASPAR ID Class Family Tax Group IC GC Content Target gene hits Target gene non-hits Background gene hits Background gene non-hits Target TFBS hits Target TFBS nucleotide rate Background TFBS hits Background TFBS nucleotide rate Z-score Fisher score HOXA5 MA0158.1 Helix-Turn-Helix Homeo vertebrates 8.759 0.315 673 129 17629 7123 12090 0.0525 205993 0.0458 43.625 36.952 Nkx2-5 MA0063.1 Helix-Turn-Helix Homeo vertebrates 8.27 0.218 663 139 16973 7779 11546 0.0439 197210 0.0384 39.008 42.733 SRY MA0084.1 Other Alpha-Helix High Mobility Group vertebrates 9.193 0.238 603 199 14714 10038 6056 0.0296 101929 0.0255 35.306 45.351 Pdx1 MA0132.1 Helix-Turn-Helix Homeo vertebrates 9.04 0.194 618 184 15507 9245 8348 0.0272 140973 0.0235 33.057 39.832 ARID3A MA0151.1 Helix-Turn-Helix Arid vertebrates 9.896 0.062 619 183 16086 8666 9711 0.0316 166235 0.0277 32.395 29.867 FOXA1 MA0148.1 Winged Helix-Turn-Helix Forkhead vertebrates 12.533 0.332 550 252 13355 11397 3731 0.0223 63112 0.0193 29.512 37.245 Foxd3 MA0041.1 Winged Helix-Turn-Helix Forkhead vertebrates 12.945 0.223 491 311 11354 13398 2950 0.0192 49535 0.0165 28.77 39.588 FOXI1 MA0042.1 Winged Helix-Turn-Helix Forkhead vertebrates 13.183 0.263 505 297 11680 13072 2917 0.019 49366 0.0165 27.126 41.788 FOXO3 MA0157.1 Winged Helix-Turn-Helix Forkhead vertebrates 11.734 0.298 561 241 13611 11141 4116 0.0179 69410 0.0154 26.948 39.221 Foxa2 MA0047.2 Winged Helix-Turn-Helix Forkhead vertebrates 13.268 0.315 493 309 11656 13096 2581 0.0168 43535 0.0145 26.08 35.049 CEBPA MA0102.2 Zipper-Type Leucine Zipper vertebrates 8.712 0.358 543 259 12828 11924 3306 0.0162 55606 0.0139 26.048 43.054 Sox5 MA0087.1 Other Alpha-Helix High Mobility Group vertebrates 10.831 0.199 541 261 13087 11665 4272 0.0162 72042 0.014 25.659 36.79 Nobox MA0125.1 Helix-Turn-Helix Homeo vertebrates 9.573 0.26 556 246 13558 11194 4512 0.0196 77190 0.0172 25.477 37.118 AP1 MA0099.2 Zipper-Type Leucine Zipper vertebrates 9.193 0.405 640 162 16390 8362 6497 0.0247 113253 0.022 24.617 37.724 Prrx2 MA0075.1 Helix-Turn-Helix Homeo vertebrates 9.063 0.027 595 207 15063 9689 7172 0.0195 123270 0.0171 24.5 33.384 ELF5 MA0136.1 Winged Helix-Turn-Helix Ets vertebrates 8.693 0.429 644 158 16547 8205 6604 0.0323 117435 0.0294 23.311 37.45 FOXD1 MA0031.1 Winged Helix-Turn-Helix Forkhead vertebrates 11.926 0.275 551 251 13087 11665 3680 0.016 62921 0.014 23.068 43.075 NKX3-1 MA0124.1 Helix-Turn-Helix Homeo vertebrates 11.127 0.179 524 278 12654 12098 4026 0.0153 68823 0.0134 22.597 34.707 NFATC2 MA0152.1 Ig-fold Rel vertebrates 9.859 0.346 618 184 15176 9576 5597 0.0213 97757 0.019 22.418 46.546 TBP MA0108.2 Beta-sheet TATA-binding vertebrates 10.086 0.377 447 355 10389 14363 1966 0.016 33775 0.0141 22.265 32.386 Gfi MA0038.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 9.47 0.391 576 226 13731 11021 3747 0.0203 65844 0.0183 20.727 46.787 SPIB MA0081.1 Winged Helix-Turn-Helix Ets vertebrates 9.06 0.466 677 125 17547 7205 9699 0.0369 175639 0.0342 20.147 41.641 SOX9 MA0077.1 Other Alpha-Helix High Mobility Group vertebrates 9.079 0.358 491 311 11417 13335 2415 0.0118 41403 0.0104 19.385 38.365 Foxq1 MA0040.1 Winged Helix-Turn-Helix Forkhead vertebrates 14.07 0.202 372 430 8007 16745 1308 0.00781 22088 0.00675 17.565 35.701 Gata1 MA0035.2 Zinc-coordinating GATA vertebrates 10.878 0.373 583 219 14350 10402 4194 0.025 75905 0.0232 16.64 39.077 SPI1 MA0080.2 Winged Helix-Turn-Helix Ets vertebrates 9.64 0.435 622 180 15792 8960 5329 0.0203 95792 0.0186 16.257 37.032 Sox17 MA0078.1 Other Alpha-Helix High Mobility Group vertebrates 10.502 0.384 584 218 13879 10873 3668 0.0179 65883 0.0165 15.419 49.338 TAL1::TCF3 MA0091.1 Zipper-Type Helix-Loop-Helix vertebrates 14.07 0.453 367 435 7491 17261 873 0.00569 14681 0.0049 15.401 43.825 RUNX1 MA0002.2 Ig-fold Runt vertebrates 10.401 0.502 557 245 13641 11111 3248 0.0194 58648 0.0179 15.045 36.189 YY1 MA0095.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.101 0.51 679 123 17190 7562 9001 0.0293 165054 0.0275 14.953 51.067 Pou5f1 MA0142.1 Helix-Turn-Helix Homeo vertebrates 14.808 0.308 187 615 3402 21350 329 0.00268 5205 0.00217 14.863 28.176 MEF2A MA0052.1 Other Alpha-Helix MADS vertebrates 15.709 0.179 328 474 7006 17746 930 0.00505 15631 0.00434 14.559 30.883 HLF MA0043.1 Zipper-Type Leucine Zipper vertebrates 11.147 0.394 263 539 5508 19244 604 0.00394 9969 0.00332 14.399 25.267 NFIL3 MA0025.1 Zipper-Type Leucine Zipper vertebrates 14.139 0.265 301 501 6731 18021 933 0.00557 15828 0.00484 14.352 22.145 FEV MA0156.1 Winged Helix-Turn-Helix Ets vertebrates 12.121 0.442 620 182 15402 9350 4505 0.0196 81722 0.0182 14.227 43.317 IRF1 MA0050.1 Winged Helix-Turn-Helix IRF vertebrates 16.008 0.383 285 517 6075 18677 689 0.00449 11517 0.00384 14.225 25.888 REL MA0101.1 Ig-fold Rel vertebrates 10.515 0.559 473 329 10514 14238 1670 0.00907 29250 0.00813 14.19 45.432 Nkx3-2 MA0122.1 Helix-Turn-Helix Homeo vertebrates 8.542 0.463 603 199 15425 9327 4996 0.0244 91612 0.0229 13.614 31.797 SRF MA0083.1 Other Alpha-Helix MADS vertebrates 17.965 0.466 66 736 908 23844 79 0.000515 1019 0.00034 12.86 19.299 Myb MA0100.1 Helix-Turn-Helix Myb vertebrates 9.883 0.591 579 223 13518 11234 3237 0.0141 58600 0.013 12.359 53.58 Pax6 MA0069.1 Helix-Turn-Helix Homeo vertebrates 13.798 0.432 85 717 1218 23534 98 0.000745 1377 0.000536 12.255 22.706 Ddit3::Cebpa MA0019.1 Zipper-Type Leucine Zipper vertebrates 11.652 0.483 267 535 5576 19176 578 0.00377 9754 0.00325 12.228 26.049 Pax4 MA0068.1 Helix-Turn-Helix Homeo vertebrates 11.004 0.441 11 791 112 24640 11 0.000179 113 9.42E-05 11.844 6.36 Sox2 MA0143.1 Other Alpha-Helix High Mobility Group vertebrates 12.951 0.361 151 651 2809 21943 238 0.00194 3844 0.0016 11.393 20.884 NR2F1 MA0017.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 15.924 0.478 198 604 3735 21017 304 0.00231 5073 0.00197 10.302 26.755 Lhx3 MA0135.1 Helix-Turn-Helix Homeo vertebrates 16.354 0.131 263 539 5806 18946 722 0.0051 12758 0.00461 9.758 19.918 TEAD1 MA0090.1 Helix-Turn-Helix Homeo vertebrates 15.678 0.507 254 548 5222 19530 487 0.00317 8446 0.00282 9.124 26.132 HNF1B MA0153.1 Helix-Turn-Helix Homeo vertebrates 16.821 0.222 201 601 4107 20645 403 0.00263 6910 0.0023 9.091 20.411 Tal1::Gata1 MA0140.1 Zipper-Type Helix-Loop-Helix vertebrates 11.297 0.451 280 522 6212 18540 622 0.00608 11200 0.0056 8.662 21.006 NF-kappaB MA0061.1 Ig-fold Rel vertebrates 13.345 0.621 390 412 8381 16371 1047 0.00568 18865 0.00524 8.308 38.621 RELA MA0107.1 Ig-fold Rel vertebrates 14.757 0.567 335 467 7171 17581 768 0.00417 13690 0.0038 8.053 31.49 NFE2L2 MA0150.1 Zipper-Type Leucine Zipper vertebrates 14.394 0.486 278 524 5635 19117 511 0.00305 8970 0.00274 8.039 30.909 MAX MA0058.1 Zipper-Type Helix-Loop-Helix vertebrates 12.685 0.571 375 427 7993 16759 886 0.00481 15900 0.00442 8.018 37.751 TLX1::NFIC MA0119.1 Helix-Turn-Helix::Other Homeo::Nuclear Factor I-CCAAT-binding vertebrates 19.665 0.598 63 739 1066 23686 76 0.000578 1162 0.000452 8.003 11.765 FOXF2 MA0030.1 Winged Helix-Turn-Helix Forkhead vertebrates 14.824 0.334 195 607 4097 20655 369 0.0028 6459 0.00251 7.91 17.636 Stat3 MA0144.1 Ig-fold Stat vertebrates 13.601 0.505 437 365 9883 14869 1291 0.00701 23645 0.00657 7.367 36.189 Arnt::Ahr MA0006.1 Zipper-Type Helix-Loop-Helix vertebrates 9.532 0.715 564 238 13597 11155 3555 0.0116 66086 0.011 7.309 41.414 RORA_1 MA0071.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 13.19 0.424 383 419 8624 16128 1030 0.00559 18895 0.00525 6.412 29.963 HNF1A MA0046.1 Helix-Turn-Helix Homeo vertebrates 15.548 0.259 154 648 3044 21708 248 0.00188 4352 0.00169 6.329 17.375 NFYA MA0060.1 Other Alpha-Helix NFY CCAAT-binding vertebrates 12.925 0.523 302 500 5865 18887 519 0.00451 9476 0.00421 6.185 40.312 IRF2 MA0051.1 Winged Helix-Turn-Helix IRF vertebrates 21.134 0.412 50 752 844 23908 57 0.000557 923 0.000462 6.009 9.654 ELK1 MA0028.1 Winged Helix-Turn-Helix Ets vertebrates 8.812 0.568 588 214 13642 11110 2900 0.0157 54748 0.0152 5.893 57.662 Ar MA0007.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 15.703 0.498 31 771 534 24218 35 0.000418 554 0.000339 5.835 6.196 HNF4A MA0114.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 9.617 0.522 301 501 6389 18363 613 0.00433 11240 0.00406 5.677 28.301 USF1 MA0093.1 Zipper-Type Helix-Loop-Helix vertebrates 11.29 0.643 411 391 9330 15422 1197 0.00455 21993 0.00428 5.635 32.057 ELK4 MA0076.1 Winged Helix-Turn-Helix Ets vertebrates 14.123 0.583 307 495 6034 18718 519 0.00254 9342 0.00234 5.606 39.461 NR4A2 MA0160.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 10.165 0.491 569 233 13896 10856 3170 0.0138 60034 0.0133 5 38.825 CREB1 MA0018.2 Zipper-Type Leucine Zipper vertebrates 10.139 0.523 420 382 9204 15548 1064 0.00462 19712 0.00438 4.914 39.656 Hand1::Tcfe2a MA0092.1 Zipper-Type Helix-Loop-Helix vertebrates 10.144 0.507 550 252 13286 11466 2883 0.0157 54768 0.0152 4.807 38.545 T MA0009.1 Beta-Hairpin-Ribbon T vertebrates 17.863 0.452 99 703 1811 22941 123 0.000735 2114 0.000646 4.707 14.441 STAT1 MA0137.2 Ig-fold Stat vertebrates 13.119 0.452 292 510 6394 18358 591 0.00481 10990 0.00458 4.663 23.604 ESR2 MA0258.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 13.618 0.546 122 680 2219 22533 149 0.00146 2670 0.00134 4.474 18.01 RXR::RAR_DR5 MA0159.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 16.004 0.535 71 731 1313 23439 86 0.000794 1499 0.000708 4.356 10.296 EWSR1-FLI1 MA0149.1 Winged Helix-Turn-Helix Ets vertebrates 32.871 0.554 14 788 207 24545 14 0.000137 209 0.000105 4.249 4.571 E2F1 MA0024.1 Winged Helix-Turn-Helix E2F vertebrates 13.838 0.625 376 426 8113 16639 946 0.00411 17630 0.00392 4.115 35.871 PBX1 MA0070.1 Helix-Turn-Helix Homeo vertebrates 14.641 0.31 194 608 4107 20645 361 0.00235 6634 0.00221 4.032 16.986 MYC::MAX MA0059.1 Zipper-Type Helix-Loop-Helix vertebrates 14.237 0.602 174 628 3436 21316 249 0.00149 4535 0.00139 3.671 19.827 NR3C1 MA0113.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 14.749 0.432 123 679 2522 22230 172 0.00168 3161 0.00158 3.401 12.131 Arnt MA0004.1 Zipper-Type Helix-Loop-Helix vertebrates 10.992 0.642 335 467 7052 17700 742 0.00242 13904 0.00232 2.785 33.888 HIF1A::ARNT MA0259.1 Zipper-Type Helix-Loop-Helix vertebrates 9.74 0.657 485 317 10914 13838 1968 0.00855 37662 0.00837 2.611 44.747 Esrrb MA0141.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 12.806 0.524 424 378 10167 14585 1376 0.00896 26346 0.00878 2.61 24.477 NFKB1 MA0105.1 Ig-fold Rel vertebrates 15.627 0.758 201 601 3946 20806 340 0.00203 6372 0.00195 2.542 23.715 CTCF MA0139.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.205 0.645 171 631 3236 21516 212 0.00219 3982 0.0021 2.498 22.539 RREB1 MA0073.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 22.278 0.623 79 723 1520 23232 99 0.00107 1839 0.00102 2.238 10.037 Nr2e3 MA0164.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 12.028 0.373 291 511 6354 18398 650 0.00247 12287 0.00239 2.225 23.819 Evi1 MA0029.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.909 0.28 94 708 1931 22821 132 0.001 2457 0.000956 2.074 9.382 ESR1 MA0112.2 Zinc-coordinating Hormone-nuclear Receptor vertebrates 13.563 0.594 19 783 345 24407 20 0.000217 355 0.000197 1.895 3.819 MZF1_1-4 MA0056.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.586 0.725 660 142 16863 7889 10359 0.0337 201000 0.0335 1.757 42.724 MZF1_5-13 MA0057.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 9.4 0.588 560 242 13425 11327 4003 0.0217 77649 0.0216 1.46 42.21 Mycn MA0104.2 Zipper-Type Helix-Loop-Helix vertebrates 11.104 0.699 379 423 8332 16420 982 0.00533 18928 0.00526 1.344 33.248 Zfp423 MA0116.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.925 0.679 256 546 5691 19061 526 0.00428 10149 0.00423 1.112 18.634 ZEB1 MA0103.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.305 0.557 685 117 17454 7298 8797 0.0287 171132 0.0285 1.015 50.298 EBF1 MA0154.1 Zipper-Type Helix-Loop-Helix vertebrates 11.564 0.648 483 319 11288 13464 2013 0.0109 39149 0.0109 0.658 36.105 Pax5 MA0014.1 Helix-Turn-Helix Homeo vertebrates 12.432 0.575 65 737 1224 23528 71 0.000771 1364 0.000758 0.623 9.032 Spz1 MA0111.1 Other Other vertebrates 11.907 0.538 291 511 6658 18094 646 0.00386 12530 0.00383 0.611 18.812 PPARG::RXRA MA0065.2 Zinc-coordinating Hormone-nuclear Receptor vertebrates 11.663 0.547 262 540 6067 18685 558 0.00454 11080 0.00462 -1.486 15.473 ZNF354C MA0130.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.958 0.615 685 117 17566 7186 10559 0.0344 207738 0.0346 -1.773 47.78 REST MA0138.2 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 23.134 0.596 10 792 232 24520 11 0.000125 242 0.000141 -1.836 1.465 RORA_2 MA0072.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 17.425 0.369 171 631 3571 21181 252 0.00192 5079 0.00198 -1.855 15.711 Egr1 MA0162.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 14.456 0.739 306 496 6364 18388 609 0.00364 12188 0.00373 -1.974 31.55 NR1H2::RXRA MA0115.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 27.878 0.445 4 798 99 24653 4 3.69E-05 100 4.72E-05 -2.091 0.902 Myc MA0147.1 Zipper-Type Helix-Loop-Helix vertebrates 11.157 0.686 366 436 8288 16464 925 0.00502 18476 0.00513 -2.131 27.179 GABPA MA0062.2 Winged Helix-Turn-Helix Ets vertebrates 13.335 0.647 418 384 9355 15397 1049 0.00626 20927 0.0064 -2.248 35.475 MIZF MA0131.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 13.197 0.61 91 711 2080 22672 118 0.000641 2497 0.000694 -2.756 5.883 PLAG1 MA0163.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 19.352 0.798 91 711 1971 22781 117 0.000889 2462 0.000958 -3.016 7.429 TP53 MA0106.1 Zinc-coordinating Loop-Sheet-Helix vertebrates 26.239 0.603 0 802 8 24744 0 0 8 4.45E-06 -3.036 0 PPARG MA0066.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 20.365 0.523 2 800 62 24690 2 2.17E-05 64 3.56E-05 -3.214 0.509 RXRA::VDR MA0074.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 20.451 0.527 17 785 453 24299 20 0.000163 475 0.000198 -3.413 1.174 SP1 MA0079.2 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 11.129 0.82 559 243 12391 12361 4015 0.0218 79797 0.0222 -3.46 64.552 NHLH1 MA0048.1 Zipper-Type Helix-Loop-Helix vertebrates 14.132 0.674 261 541 5783 18969 479 0.00312 9874 0.00329 -4.075 19.385 Myf MA0055.1 Zipper-Type Helix-Loop-Helix vertebrates 15.914 0.609 428 374 10157 14595 1348 0.00878 27519 0.00918 -5.609 26.549 Klf4 MA0039.2 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 12.618 0.771 577 225 13645 11107 4418 0.024 88731 0.0247 -5.863 49.321 Tcfcp2l1 MA0145.1 Other CP2 vertebrates 11.65 0.609 445 357 10591 14161 1574 0.012 32190 0.0125 -6.823 27.865 INSM1 MA0155.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 14.862 0.667 331 471 7588 17164 835 0.00544 17685 0.0059 -8.104 22.059 znf143 MA0088.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.541 0.53 54 748 1301 23451 58 0.00063 1473 0.000819 -8.973 3.145 Zfx MA0146.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 13.077 0.749 429 373 9872 14880 1587 0.0121 33238 0.0129 -10.427 31.938
Also, look at that region on Chr1 near TARDBP, one of the most significant AGA risk locuses:
In the Chew paper, they show four contiguous genes in that region are upregulated in balding DPCs, including MTOR (they call it "FRAP1", which is another name for the MTOR gene). I was investigating mTOR before I was even aware of this, so it was kind of cool to see that. But anyway, I think this corroborates the idea that mTOR is a key player in AGA pathology.
Yeah, I think oxidative stress plays a critical role not only in inducing senescence, but also in progressively increasing androgen sensitivity. For example, p38 MAPK is a major oxidative stress-induced senescence pathway, and its downstream target HSP27 can stabilize AR and therefore increase AR protein levels and androgen sensitivity (Zoubeidi et. al, 2007). p38 MAPK also produces a lot of inflammatory cytokines (it plays a role in SASP), so maybe some of the inflammatory part of AGA is because of that pathway. Also, you mentioned Twist1 (another AGA risk gene) upregulating AR. Look at this:
So these factors might cooperate in a vicious positive feedback loop, where once the genetic network hits a certain tipping point, it gains momentum and progresses toward the inevitable.Leave a comment:
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God damn it. I screwed up the page and I can't edit it now.Leave a comment:
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Unfortunately, it looks like I can't access my inbox...? I get the following message:@InBeforeTheCure,
I agree.
I'm very curious to your findings/thoughts! I need to educate myself better on literature and methods so I can stay relevant in this discussion though. I have PM'ed you and it would be cool if you can teach me some things and give me more insight into your thought process etc.
InBeforeTheCure, you do not have permission to access this page. This could be due to one of several reasons:
Your user account may not have sufficient privileges to access this page. Are you trying to edit someone else's post, access administrative features or some other privileged system?
If you are trying to post, the administrator may have disabled your account, or it may be awaiting activation.That sucks. Facial hair develops in a pattern too, of course, so it would be interesting to know.Originally posted by Swooping
Originally posted by SwoopingActually, the interesting thing is that the expression of anti-oxidation genes are not necessarily "upregulated". In fact, they fluctuate over time. For example...Furthermore, the up-regulation of anti-oxidation genes (GPX4 and PRX3) suggests that patient vertex scalps may be exposed to greater oxidative stress than control scalps, possibly resultant from increased respiratory chain activity 9, 10.
GPX4 expression vs. hours of DHT exposure, for Balding DPCs of Subject A:
Subject B:
Subject C:
Now, you probably know about FoxO genes and mTOR, right?
Link to pathway diagram: mTOR signaling at a glance
Here are the most upregulated genes in balding DPCs with 100 nM DHT added from that study by Kwack et. al that focused on DKK1:
DHT induces expression of SLC3A2 and SLC7A5, which you can see in the mTOR pathway diagram. These are amino acid transporters that act upstream of mTORC1-mediated anabolic processes. Also, SGK is 4.53x upregulated, which you can also see in the diagram is a substrate of mTORC2. SGK is similar in structure and function to Akt. FoxO1/FoxO3 enforce quiescence of cells and play a critical role in homeostasis and stress resistance -- they transcribe a lot of ROS scavenger genes, for example.
So Akt/SGK, to promote cell proliferation, phosphorylate FoxO. This allows a protein called 14-3-3 to bind it and move it from the nucleus into the cytoplasm where it undergoes proteasomal degradation. It's also important to note that in response to ROS, MST1 and JNK phosphorylate FoxO to keep it in the nucleus, and this signal overrides the Akt/SGK-induced nuclear exclusion signal.
Now imagine what would happen if you were to take this system in its "ground state" (low ROS, low Akt/SGK). Add DHT and you induce FoxO nuclear exclusion and proteasomal degradation through mTORC2 -> Akt + highly upregulated SGK. ROS start to accumulate, but since FoxO protein levels are low, the cells are unable to respond despite the MST1/JNK override signal. Then there's a lag time while new FoxO mRNA are being transcribed and then translated while ROS accumulate, and the newly produced nuclear FoxOs transcribe ROS scavenger genes and the ROS levels drop. Now it's in the ground state once more, and the process repeats itself. If it's an oscillating system like this, static measurements might be misleading and give contradictory results between different experiments.
BTW, here's a nice review paper on FoxOs from Nature: https://www.dropbox.com/s/fpwoka8h9n...m2013.pdf?dl=0
PAX1 has been shown to interact directly with FOXO1, especially under hypoxic stress, while an interaction between PAX9 (a PAX1 paralog) was not detected (see Section 3.6). But maybe PAX1 could play in a role in coordinating homeobox genes as well. Speaking of that, I ran another quick analysis with oPossum on the top 1000 upregulated genes in balding DPCs. What this does is search for enriched transcription factor binding motifs in a list of genes, which gives clues as to which TFs may be differentially regulated. These were the results:
Interesting that lots of homeobox genes show up. Also, SRY (a Y-chromosomal gene responsible for male sex determination). AR is there, lots of FOX genes, AP1, STATs, NF-kB, and more.Code:TF JASPAR ID Class Family Tax Group IC GC Content Target gene hits Target gene non-hits Background gene hits Background gene non-hits Target TFBS hits Target TFBS nucleotide rate Background TFBS hits Background TFBS nucleotide rate Z-score Fisher score HOXA5 MA0158.1 Helix-Turn-Helix Homeo vertebrates 8.759 0.315 673 129 17629 7123 12090 0.0525 205993 0.0458 43.625 36.952 Nkx2-5 MA0063.1 Helix-Turn-Helix Homeo vertebrates 8.27 0.218 663 139 16973 7779 11546 0.0439 197210 0.0384 39.008 42.733 SRY MA0084.1 Other Alpha-Helix High Mobility Group vertebrates 9.193 0.238 603 199 14714 10038 6056 0.0296 101929 0.0255 35.306 45.351 Pdx1 MA0132.1 Helix-Turn-Helix Homeo vertebrates 9.04 0.194 618 184 15507 9245 8348 0.0272 140973 0.0235 33.057 39.832 ARID3A MA0151.1 Helix-Turn-Helix Arid vertebrates 9.896 0.062 619 183 16086 8666 9711 0.0316 166235 0.0277 32.395 29.867 FOXA1 MA0148.1 Winged Helix-Turn-Helix Forkhead vertebrates 12.533 0.332 550 252 13355 11397 3731 0.0223 63112 0.0193 29.512 37.245 Foxd3 MA0041.1 Winged Helix-Turn-Helix Forkhead vertebrates 12.945 0.223 491 311 11354 13398 2950 0.0192 49535 0.0165 28.77 39.588 FOXI1 MA0042.1 Winged Helix-Turn-Helix Forkhead vertebrates 13.183 0.263 505 297 11680 13072 2917 0.019 49366 0.0165 27.126 41.788 FOXO3 MA0157.1 Winged Helix-Turn-Helix Forkhead vertebrates 11.734 0.298 561 241 13611 11141 4116 0.0179 69410 0.0154 26.948 39.221 Foxa2 MA0047.2 Winged Helix-Turn-Helix Forkhead vertebrates 13.268 0.315 493 309 11656 13096 2581 0.0168 43535 0.0145 26.08 35.049 CEBPA MA0102.2 Zipper-Type Leucine Zipper vertebrates 8.712 0.358 543 259 12828 11924 3306 0.0162 55606 0.0139 26.048 43.054 Sox5 MA0087.1 Other Alpha-Helix High Mobility Group vertebrates 10.831 0.199 541 261 13087 11665 4272 0.0162 72042 0.014 25.659 36.79 Nobox MA0125.1 Helix-Turn-Helix Homeo vertebrates 9.573 0.26 556 246 13558 11194 4512 0.0196 77190 0.0172 25.477 37.118 AP1 MA0099.2 Zipper-Type Leucine Zipper vertebrates 9.193 0.405 640 162 16390 8362 6497 0.0247 113253 0.022 24.617 37.724 Prrx2 MA0075.1 Helix-Turn-Helix Homeo vertebrates 9.063 0.027 595 207 15063 9689 7172 0.0195 123270 0.0171 24.5 33.384 ELF5 MA0136.1 Winged Helix-Turn-Helix Ets vertebrates 8.693 0.429 644 158 16547 8205 6604 0.0323 117435 0.0294 23.311 37.45 FOXD1 MA0031.1 Winged Helix-Turn-Helix Forkhead vertebrates 11.926 0.275 551 251 13087 11665 3680 0.016 62921 0.014 23.068 43.075 NKX3-1 MA0124.1 Helix-Turn-Helix Homeo vertebrates 11.127 0.179 524 278 12654 12098 4026 0.0153 68823 0.0134 22.597 34.707 NFATC2 MA0152.1 Ig-fold Rel vertebrates 9.859 0.346 618 184 15176 9576 5597 0.0213 97757 0.019 22.418 46.546 TBP MA0108.2 Beta-sheet TATA-binding vertebrates 10.086 0.377 447 355 10389 14363 1966 0.016 33775 0.0141 22.265 32.386 Gfi MA0038.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 9.47 0.391 576 226 13731 11021 3747 0.0203 65844 0.0183 20.727 46.787 SPIB MA0081.1 Winged Helix-Turn-Helix Ets vertebrates 9.06 0.466 677 125 17547 7205 9699 0.0369 175639 0.0342 20.147 41.641 SOX9 MA0077.1 Other Alpha-Helix High Mobility Group vertebrates 9.079 0.358 491 311 11417 13335 2415 0.0118 41403 0.0104 19.385 38.365 Foxq1 MA0040.1 Winged Helix-Turn-Helix Forkhead vertebrates 14.07 0.202 372 430 8007 16745 1308 0.00781 22088 0.00675 17.565 35.701 Gata1 MA0035.2 Zinc-coordinating GATA vertebrates 10.878 0.373 583 219 14350 10402 4194 0.025 75905 0.0232 16.64 39.077 SPI1 MA0080.2 Winged Helix-Turn-Helix Ets vertebrates 9.64 0.435 622 180 15792 8960 5329 0.0203 95792 0.0186 16.257 37.032 Sox17 MA0078.1 Other Alpha-Helix High Mobility Group vertebrates 10.502 0.384 584 218 13879 10873 3668 0.0179 65883 0.0165 15.419 49.338 TAL1::TCF3 MA0091.1 Zipper-Type Helix-Loop-Helix vertebrates 14.07 0.453 367 435 7491 17261 873 0.00569 14681 0.0049 15.401 43.825 RUNX1 MA0002.2 Ig-fold Runt vertebrates 10.401 0.502 557 245 13641 11111 3248 0.0194 58648 0.0179 15.045 36.189 YY1 MA0095.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.101 0.51 679 123 17190 7562 9001 0.0293 165054 0.0275 14.953 51.067 Pou5f1 MA0142.1 Helix-Turn-Helix Homeo vertebrates 14.808 0.308 187 615 3402 21350 329 0.00268 5205 0.00217 14.863 28.176 MEF2A MA0052.1 Other Alpha-Helix MADS vertebrates 15.709 0.179 328 474 7006 17746 930 0.00505 15631 0.00434 14.559 30.883 HLF MA0043.1 Zipper-Type Leucine Zipper vertebrates 11.147 0.394 263 539 5508 19244 604 0.00394 9969 0.00332 14.399 25.267 NFIL3 MA0025.1 Zipper-Type Leucine Zipper vertebrates 14.139 0.265 301 501 6731 18021 933 0.00557 15828 0.00484 14.352 22.145 FEV MA0156.1 Winged Helix-Turn-Helix Ets vertebrates 12.121 0.442 620 182 15402 9350 4505 0.0196 81722 0.0182 14.227 43.317 IRF1 MA0050.1 Winged Helix-Turn-Helix IRF vertebrates 16.008 0.383 285 517 6075 18677 689 0.00449 11517 0.00384 14.225 25.888 REL MA0101.1 Ig-fold Rel vertebrates 10.515 0.559 473 329 10514 14238 1670 0.00907 29250 0.00813 14.19 45.432 Nkx3-2 MA0122.1 Helix-Turn-Helix Homeo vertebrates 8.542 0.463 603 199 15425 9327 4996 0.0244 91612 0.0229 13.614 31.797 SRF MA0083.1 Other Alpha-Helix MADS vertebrates 17.965 0.466 66 736 908 23844 79 0.000515 1019 0.00034 12.86 19.299 Myb MA0100.1 Helix-Turn-Helix Myb vertebrates 9.883 0.591 579 223 13518 11234 3237 0.0141 58600 0.013 12.359 53.58 Pax6 MA0069.1 Helix-Turn-Helix Homeo vertebrates 13.798 0.432 85 717 1218 23534 98 0.000745 1377 0.000536 12.255 22.706 Ddit3::Cebpa MA0019.1 Zipper-Type Leucine Zipper vertebrates 11.652 0.483 267 535 5576 19176 578 0.00377 9754 0.00325 12.228 26.049 Pax4 MA0068.1 Helix-Turn-Helix Homeo vertebrates 11.004 0.441 11 791 112 24640 11 0.000179 113 9.42E-05 11.844 6.36 Sox2 MA0143.1 Other Alpha-Helix High Mobility Group vertebrates 12.951 0.361 151 651 2809 21943 238 0.00194 3844 0.0016 11.393 20.884 NR2F1 MA0017.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 15.924 0.478 198 604 3735 21017 304 0.00231 5073 0.00197 10.302 26.755 Lhx3 MA0135.1 Helix-Turn-Helix Homeo vertebrates 16.354 0.131 263 539 5806 18946 722 0.0051 12758 0.00461 9.758 19.918 TEAD1 MA0090.1 Helix-Turn-Helix Homeo vertebrates 15.678 0.507 254 548 5222 19530 487 0.00317 8446 0.00282 9.124 26.132 HNF1B MA0153.1 Helix-Turn-Helix Homeo vertebrates 16.821 0.222 201 601 4107 20645 403 0.00263 6910 0.0023 9.091 20.411 Tal1::Gata1 MA0140.1 Zipper-Type Helix-Loop-Helix vertebrates 11.297 0.451 280 522 6212 18540 622 0.00608 11200 0.0056 8.662 21.006 NF-kappaB MA0061.1 Ig-fold Rel vertebrates 13.345 0.621 390 412 8381 16371 1047 0.00568 18865 0.00524 8.308 38.621 RELA MA0107.1 Ig-fold Rel vertebrates 14.757 0.567 335 467 7171 17581 768 0.00417 13690 0.0038 8.053 31.49 NFE2L2 MA0150.1 Zipper-Type Leucine Zipper vertebrates 14.394 0.486 278 524 5635 19117 511 0.00305 8970 0.00274 8.039 30.909 MAX MA0058.1 Zipper-Type Helix-Loop-Helix vertebrates 12.685 0.571 375 427 7993 16759 886 0.00481 15900 0.00442 8.018 37.751 TLX1::NFIC MA0119.1 Helix-Turn-Helix::Other Homeo::Nuclear Factor I-CCAAT-binding vertebrates 19.665 0.598 63 739 1066 23686 76 0.000578 1162 0.000452 8.003 11.765 FOXF2 MA0030.1 Winged Helix-Turn-Helix Forkhead vertebrates 14.824 0.334 195 607 4097 20655 369 0.0028 6459 0.00251 7.91 17.636 Stat3 MA0144.1 Ig-fold Stat vertebrates 13.601 0.505 437 365 9883 14869 1291 0.00701 23645 0.00657 7.367 36.189 Arnt::Ahr MA0006.1 Zipper-Type Helix-Loop-Helix vertebrates 9.532 0.715 564 238 13597 11155 3555 0.0116 66086 0.011 7.309 41.414 RORA_1 MA0071.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 13.19 0.424 383 419 8624 16128 1030 0.00559 18895 0.00525 6.412 29.963 HNF1A MA0046.1 Helix-Turn-Helix Homeo vertebrates 15.548 0.259 154 648 3044 21708 248 0.00188 4352 0.00169 6.329 17.375 NFYA MA0060.1 Other Alpha-Helix NFY CCAAT-binding vertebrates 12.925 0.523 302 500 5865 18887 519 0.00451 9476 0.00421 6.185 40.312 IRF2 MA0051.1 Winged Helix-Turn-Helix IRF vertebrates 21.134 0.412 50 752 844 23908 57 0.000557 923 0.000462 6.009 9.654 ELK1 MA0028.1 Winged Helix-Turn-Helix Ets vertebrates 8.812 0.568 588 214 13642 11110 2900 0.0157 54748 0.0152 5.893 57.662 Ar MA0007.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 15.703 0.498 31 771 534 24218 35 0.000418 554 0.000339 5.835 6.196 HNF4A MA0114.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 9.617 0.522 301 501 6389 18363 613 0.00433 11240 0.00406 5.677 28.301 USF1 MA0093.1 Zipper-Type Helix-Loop-Helix vertebrates 11.29 0.643 411 391 9330 15422 1197 0.00455 21993 0.00428 5.635 32.057 ELK4 MA0076.1 Winged Helix-Turn-Helix Ets vertebrates 14.123 0.583 307 495 6034 18718 519 0.00254 9342 0.00234 5.606 39.461 NR4A2 MA0160.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 10.165 0.491 569 233 13896 10856 3170 0.0138 60034 0.0133 5 38.825 CREB1 MA0018.2 Zipper-Type Leucine Zipper vertebrates 10.139 0.523 420 382 9204 15548 1064 0.00462 19712 0.00438 4.914 39.656 Hand1::Tcfe2a MA0092.1 Zipper-Type Helix-Loop-Helix vertebrates 10.144 0.507 550 252 13286 11466 2883 0.0157 54768 0.0152 4.807 38.545 T MA0009.1 Beta-Hairpin-Ribbon T vertebrates 17.863 0.452 99 703 1811 22941 123 0.000735 2114 0.000646 4.707 14.441 STAT1 MA0137.2 Ig-fold Stat vertebrates 13.119 0.452 292 510 6394 18358 591 0.00481 10990 0.00458 4.663 23.604 ESR2 MA0258.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 13.618 0.546 122 680 2219 22533 149 0.00146 2670 0.00134 4.474 18.01 RXR::RAR_DR5 MA0159.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 16.004 0.535 71 731 1313 23439 86 0.000794 1499 0.000708 4.356 10.296 EWSR1-FLI1 MA0149.1 Winged Helix-Turn-Helix Ets vertebrates 32.871 0.554 14 788 207 24545 14 0.000137 209 0.000105 4.249 4.571 E2F1 MA0024.1 Winged Helix-Turn-Helix E2F vertebrates 13.838 0.625 376 426 8113 16639 946 0.00411 17630 0.00392 4.115 35.871 PBX1 MA0070.1 Helix-Turn-Helix Homeo vertebrates 14.641 0.31 194 608 4107 20645 361 0.00235 6634 0.00221 4.032 16.986 MYC::MAX MA0059.1 Zipper-Type Helix-Loop-Helix vertebrates 14.237 0.602 174 628 3436 21316 249 0.00149 4535 0.00139 3.671 19.827 NR3C1 MA0113.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 14.749 0.432 123 679 2522 22230 172 0.00168 3161 0.00158 3.401 12.131 Arnt MA0004.1 Zipper-Type Helix-Loop-Helix vertebrates 10.992 0.642 335 467 7052 17700 742 0.00242 13904 0.00232 2.785 33.888 HIF1A::ARNT MA0259.1 Zipper-Type Helix-Loop-Helix vertebrates 9.74 0.657 485 317 10914 13838 1968 0.00855 37662 0.00837 2.611 44.747 Esrrb MA0141.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 12.806 0.524 424 378 10167 14585 1376 0.00896 26346 0.00878 2.61 24.477 NFKB1 MA0105.1 Ig-fold Rel vertebrates 15.627 0.758 201 601 3946 20806 340 0.00203 6372 0.00195 2.542 23.715 CTCF MA0139.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.205 0.645 171 631 3236 21516 212 0.00219 3982 0.0021 2.498 22.539 RREB1 MA0073.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 22.278 0.623 79 723 1520 23232 99 0.00107 1839 0.00102 2.238 10.037 Nr2e3 MA0164.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 12.028 0.373 291 511 6354 18398 650 0.00247 12287 0.00239 2.225 23.819 Evi1 MA0029.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.909 0.28 94 708 1931 22821 132 0.001 2457 0.000956 2.074 9.382 ESR1 MA0112.2 Zinc-coordinating Hormone-nuclear Receptor vertebrates 13.563 0.594 19 783 345 24407 20 0.000217 355 0.000197 1.895 3.819 MZF1_1-4 MA0056.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.586 0.725 660 142 16863 7889 10359 0.0337 201000 0.0335 1.757 42.724 MZF1_5-13 MA0057.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 9.4 0.588 560 242 13425 11327 4003 0.0217 77649 0.0216 1.46 42.21 Mycn MA0104.2 Zipper-Type Helix-Loop-Helix vertebrates 11.104 0.699 379 423 8332 16420 982 0.00533 18928 0.00526 1.344 33.248 Zfp423 MA0116.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.925 0.679 256 546 5691 19061 526 0.00428 10149 0.00423 1.112 18.634 ZEB1 MA0103.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.305 0.557 685 117 17454 7298 8797 0.0287 171132 0.0285 1.015 50.298 EBF1 MA0154.1 Zipper-Type Helix-Loop-Helix vertebrates 11.564 0.648 483 319 11288 13464 2013 0.0109 39149 0.0109 0.658 36.105 Pax5 MA0014.1 Helix-Turn-Helix Homeo vertebrates 12.432 0.575 65 737 1224 23528 71 0.000771 1364 0.000758 0.623 9.032 Spz1 MA0111.1 Other Other vertebrates 11.907 0.538 291 511 6658 18094 646 0.00386 12530 0.00383 0.611 18.812 PPARG::RXRA MA0065.2 Zinc-coordinating Hormone-nuclear Receptor vertebrates 11.663 0.547 262 540 6067 18685 558 0.00454 11080 0.00462 -1.486 15.473 ZNF354C MA0130.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.958 0.615 685 117 17566 7186 10559 0.0344 207738 0.0346 -1.773 47.78 REST MA0138.2 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 23.134 0.596 10 792 232 24520 11 0.000125 242 0.000141 -1.836 1.465 RORA_2 MA0072.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 17.425 0.369 171 631 3571 21181 252 0.00192 5079 0.00198 -1.855 15.711 Egr1 MA0162.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 14.456 0.739 306 496 6364 18388 609 0.00364 12188 0.00373 -1.974 31.55 NR1H2::RXRA MA0115.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 27.878 0.445 4 798 99 24653 4 3.69E-05 100 4.72E-05 -2.091 0.902 Myc MA0147.1 Zipper-Type Helix-Loop-Helix vertebrates 11.157 0.686 366 436 8288 16464 925 0.00502 18476 0.00513 -2.131 27.179 GABPA MA0062.2 Winged Helix-Turn-Helix Ets vertebrates 13.335 0.647 418 384 9355 15397 1049 0.00626 20927 0.0064 -2.248 35.475 MIZF MA0131.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 13.197 0.61 91 711 2080 22672 118 0.000641 2497 0.000694 -2.756 5.883 PLAG1 MA0163.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 19.352 0.798 91 711 1971 22781 117 0.000889 2462 0.000958 -3.016 7.429 TP53 MA0106.1 Zinc-coordinating Loop-Sheet-Helix vertebrates 26.239 0.603 0 802 8 24744 0 0 8 4.45E-06 -3.036 0 PPARG MA0066.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 20.365 0.523 2 800 62 24690 2 2.17E-05 64 3.56E-05 -3.214 0.509 RXRA::VDR MA0074.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 20.451 0.527 17 785 453 24299 20 0.000163 475 0.000198 -3.413 1.174 SP1 MA0079.2 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 11.129 0.82 559 243 12391 12361 4015 0.0218 79797 0.0222 -3.46 64.552 NHLH1 MA0048.1 Zipper-Type Helix-Loop-Helix vertebrates 14.132 0.674 261 541 5783 18969 479 0.00312 9874 0.00329 -4.075 19.385 Myf MA0055.1 Zipper-Type Helix-Loop-Helix vertebrates 15.914 0.609 428 374 10157 14595 1348 0.00878 27519 0.00918 -5.609 26.549 Klf4 MA0039.2 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 12.618 0.771 577 225 13645 11107 4418 0.024 88731 0.0247 -5.863 49.321 Tcfcp2l1 MA0145.1 Other CP2 vertebrates 11.65 0.609 445 357 10591 14161 1574 0.012 32190 0.0125 -6.823 27.865 INSM1 MA0155.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 14.862 0.667 331 471 7588 17164 835 0.00544 17685 0.0059 -8.104 22.059 znf143 MA0088.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.541 0.53 54 748 1301 23451 58 0.00063 1473 0.000819 -8.973 3.145 Zfx MA0146.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 13.077 0.749 429 373 9872 14880 1587 0.0121 33238 0.0129 -10.427 31.938
Also, look at that region on Chr1 near TARDBP, one of the most significant AGA risk locuses:
In the Chew paper, they show four contiguous genes in that region are upregulated in balding DPCs, including MTOR (they call it "FRAP1", which is another name for the MTOR gene). I was investigating mTOR before I was even aware of this, so it was kind of cool to see that. But anyway, I think this corroborates the idea that mTOR is a key player in AGA pathology.
Yeah, I think oxidative stress plays a critical role not only in inducing senescence, but also in progressively increasing androgen sensitivity. For example, p38 MAPK is a major oxidative stress-induced senescence pathway, and its downstream target HSP27 can stabilize AR and therefore increase AR protein levels and androgen sensitivity (Zoubeidi et. al, 2007). p38 MAPK also produces a lot of inflammatory cytokines (it plays a role in SASP), so maybe some of the inflammatory part of AGA is because of that pathway. Also, you mentioned Twist1 (another AGA risk gene) upregulating AR. Look at this:Underlines the possibility of oxidative stress being implicated in AGA again.
So these factors might cooperate in a vicious positive feedback loop, where once the genetic network hits a certain tipping point, it gains momentum and progresses toward the inevitable.There are few successful therapies for castration-resistant prostate cancer (CRPC). Recently, CRPC has been thought to result from augmented androgen/androgen receptor (AR) signaling pathway, for most of which AR overexpression has been observed. In this study, Twist1, a member of basic helix-loop-helix transcription factors as well as AR was upregulated in response to hydrogen peroxide, and the response to which was abolished by an addition of N-acetyl-L-cysteine and Twist1 knockdown. In addition, castration-resistant LNCaP derivatives and hydrogen peroxide-resistant LNCaP derivatives exhibited a similar phenotype to each other. Then, both castration and AR knockdown increased intracellular reactive oxygen species level. Moreover, Twist1 was shown to regulate AR expression through binding to E-boxes in AR promoter region. Silencing of Twist1 suppressed cell growth of AR-expressing LNCaP cells as well as castration-resistant LNCaP derivatives by inducing cell-cycle arrest at G1 phase and cellular apoptosis. These findings indicated that castration-induced oxidative stress may promote AR overexpression through Twist1 overexpression, which could result in a gain of castration resistance. Modulation of castration-induced oxidative stress or Twist1/AR signaling might be a useful strategy for developing a novel therapeutics in prostate cancer, even in CRPC, which remains dependent on AR signaling by overexpressing AR.Leave a comment:
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The vast majority of the genes below are not the causative AGA locus genes mentioned in the study- but they are the 1s that are expressed selectively in balding/non-balding scalp follicles just after being freshly dissected. So, it is likely the AGA causative locus genes influences the appropriate expression of hair growth genes in the DPC.
Derma papilla signature genes expressed only in non-balding scalp follicles:
APOD = Estradiol, VPA,
ARHGEF3 = VPA
BMP4 = Estradiol via ESR2, but downs it via ESR1, VPA
DIO2 = Estradiol
FOXO1 = Estradiol via ESR1, VPA
GAS7 = VPA, Ascorbic acid,
GMFG = Butyraldehyde , VPA
GUCY1A3 = Estradiol, VPA
IFI27 = Ascorbic acid, Estradiol, Butyraldehyde,
LXN = Ascorbic acid,
LZTS1 = Butyraldehyde, VPA
NOG = Estradiol via ESR1 but downs it via ESR2, Butyraldehyde, VPA
PLCG2 = Estradiol, VPA, Ethanol
RBP1 = Estradiol via ESR1, Butyraldehyde, VPA, Ethanol,
Derma pailla signature genes expressed only in balding scalp follicles
BMP2 = VPA half/half
CCND2 =VPA half/half, Ethanol
GPM6B = VPA half/half,
MEF2C = ?
SOSTDC1 = Estradiol
STON1 = Butyraldhye is safe, VPA is half/half
It should be noted that the discoveries made by this study are almost completely at odds with those in made in Dr Cotsarelis's study.
Example:
IFI27 is a gene upregulated in balding scalp- but is expressed in non-balding scalps instead in http://www.ncbi.nlm.nih.gov/pubmed/27060448 <=== The researcher that participated in this study, AM Hilmer- is also the 1 that discovered the PAX1/FOXA2 AGA locus along with several other AGA causative gene locus.
And becos we know that Vitamin C and its derivatives inhibits DKK1(L-threonate, L ascorbyl 2 phosphate, etc)- it is IMO that this study seems to have more credibility n makes more sense.
However, it is also plausible that the subjects Dr Cotsarelis used in his study were carrying different AGA causative genes than those listed in this study.Leave a comment:
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@InBeforeTheCure,
I agree.
I'm very curious to your findings/thoughts! I need to educate myself better on literature and methods so I can stay relevant in this discussion though. I have PM'ed you and it would be cool if you can teach me some things and give me more insight into your thought process etc.
I can't recall if Hamilton describes anything about facial hair growth in these two groups, don't think so to be honest. Speaking of "stress", check out this recent study guys;
"Comparative Transcriptome profiling provides new insights into mechanisms of androgenetic alopecia progression: Whole transcriptome discovery study identifies altered oxidation-reduction state in hair follicles of androgenetic alopecia patients"
Underlines the possibility of oxidative stress being implicated in AGA again."The up-regulation of genes in the respiratory chain (CYB5R3, SDHA) may impact on the redox state in AGA-affected hairs 7, 8. Furthermore, the up-regulation of anti-oxidation genes (GPX4 and PRX3) suggests that patient vertex scalps may be exposed to greater oxidative stress than control scalps, possibly resultant from increased respiratory chain activity 9, 10. Increased levels of GPX4 would also protect the increased amount of lipid synthesized in the patient vertex scalp from phospholipid hydroperoxides-mediated oxidation 11. The occurrence of oxidative stress in DP cells may account for impaired hair growth in AGA as elevated reactive oxidative species in balding DP cells are known to cause elevated secretion of hair growth inhibitors TGFβ1/TGFβ2 and cell senescence"Leave a comment:
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4 of them were not differentially-regulated when exposed to DHT:
14)WNT10A
15)Between SUCNR1 and MBNL1
16)SETBP1
17)Between PAX1 and FOXA2. FOXA2's expression were not detected in balding scalp and PAX1's expression was not found to be differentially expressed when DPCs were exposed to DHT.
This could mean that these AGA-causing locus are androgen pathway-independent in the DPCs of the balding scalp.
In any case:
1)WNT10A = Estradiol(UP), Butyraldehyde =(UP)- assuming that WNT10A is downregulated in balding scalp
2a)SUCNR1, from genecards:
This gene encodes a G-protein-coupled receptor for succinate, an intermediate molecule of the citric acid cycle. It is involved in the promotion of hematopoietic progenitor cell development, and it has a potential role in renovascular hypertension which has known correlations to renal failure, diabetes and atherosclerosis. [provided by RefSeq, Oct 2009]
2b)MBNL1, from genecards:
This gene encodes a member of the muscleblind protein family which was initially described in Drosophila melanogaster. The encoded protein is a C3H-type zinc finger protein that modulates alternative splicing of pre-mRNAs. Muscleblind proteins bind specifically to expanded dsCUG RNA but not to normal size CUG repeats and may thereby play a role in the pathophysiology of myotonic dystrophy. Mice lacking this gene exhibited muscle abnormalities and cataracts. Several alternatively spliced transcript variants have been described but the full-length natures of only some have been determined. The different isoforms are thought to have different binding specificities and/or splicing activities. [provided by RefSeq, Sep 2015]
3)SETBP1, from genecards:
This gene encodes a protein which contains a several motifs including a ski homology region and a SET-binding region in addition to three nuclear localization signals. The encoded protein has been shown to bind the SET nuclear oncogene which is involved in DNA replication. Mutations in this gene are associated with Schinzel-Giedion midface retraction syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]
4)Pax1(Estradiol=UP, Butyraldehyde=UP), from genecards:
This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. This gene plays a role in pattern formation during embryogenesis and may be essential for development of the vertebral column. This gene is silenced by methylation in ovarian and cervical cancers and may be a tumor suppressor gene. Mutations in this gene are also associated with vertebral malformations. [provided by RefSeq, Mar 2012]Leave a comment:
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Furthermore, the identification of MAPT as the relevant AGA candidate gene at 17q21.31
instead of SPPL2C suggests that changes in MAPT function connect the risk for AGA with the risk for
Parkinson’s disease (Li et al., 2012).
Those who have a family history of Parkinson's could be a carrier of the AGA variant of MAPT.Leave a comment:
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1)MAPT is 1 of the root causative AGA gene downregulated in balding scalp=> need to UP(Estradiol)
2)SSPN is 1 of the root causative AGA gene downregulated in balding scalp => need to UP(PPAR Alpha)
3)AUTS2 is 1 of the root causative AGA gene downregulated in balding scalp => need to UP(PPAR Alpha)
4)TWIST1 is 1 of the root causative AGA gene upregulated in balding scalp => need to DOWN(Estradiol)
5)RNF145 is 1 of the root causative AGA gene downregulated in balding scalp => need to UP(Phenobarbital)
6)TWIST2 is 1 of the causative AGA gene downregulated in balding scalp => need to UP(Estradiol)
7)PER2 is 1 of the causative AGA gene downregulated in balding scalp => need to UP(Estradiol)
8)UBIAD1 is 1 of the causative AGA gene upregulated in balding scalp => need to DOWN(Dibutyl Phthalate, Caffeine)
9)SRM is 1 of the causative AGA gene upregulated in balding scalp => Need to DOWN(Estradiol) <=== this gene stands for 'Spermidine synthase'. seems like those that carry the AGA variant of this gene has too much of Spermidine production in the balding scalp:
At the 1p36 locus, non-differentially-expressed candidate gene TARDBP (TAR DNA binding protein) is
unlikely to be causative. Instead, SRM, previously mentioned as a potential candidate gene due to its
proximity to rs12565727 (Li et al., 2012), was up-regulated in BAB(balding scalp) compared to BAN. SRM is involved
in the synthesis of spermidine which acts on matrix keratinocytes to promote hair elongation and prolong
anagen (Ramot et al., 2011). However, the effect of SRM activity and the resultant spermidine
synthesized in DPC is unknown. Further, we found CASZ1, EXOSC10, FRAP1, and UBIAD1 to be
differentially-expressed at this locus. They provide new potential candidate genes for hair loss/growth
modulation.
10)FRAP1 is 1 of the causative AGA gene upregulated in balding scalp => Need to DOWN(?)
11)EXOSC10 => is 1 of the causative AGA gene upregulated in balding scalp => need to DOWN(Dibutyl Phthalate)
12)CASZ1 is 1 of the causative AGA gene downregulated in balding scalp => need to UP(PPAR ALpha, Butyraldehyde)
13)AR is 1 of the causative gene upregulated in balding scalp => need to DOWN(AR blockers) <== the AGA-variants of this gene are not present in East Asians.
Total = 17 AGA locus genes known so far. 4 of them were not differentially-regulated when exposed to DHT:
14)WNT10A
15)Between SUCNR1 and MBNL1
16)SETBP1
17)Between PAX1 and FOXA2. FOXA2's expression were not detected in balding scalp and PAX1's expression was not found to be differentially expressed when DPCs were exposed to DHT.
Seems like a PPAR Alpha agonist and Estradiol are what we need to regrow hairLeave a comment:
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"So, both groups of eunuchs are perfect NW 1's. You inject them with androgens for the first time in their life. The older group tends to bald extremely fast, way faster than the younger group. Why?
Doesnt this though perfectly explain why in most men as they get older fin seems to stop working? There rate of sensitivity increases as they get older, and the androgens left over are enough to continue the balding process. It also explains why men as they age even when androgen levels naturally decline actually keep balding sometimes it even speeds up. Of course why is hair sensitive to begin with is the million dollar question, and the answer is probably pretty complicated.Leave a comment:
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