Updated Research and Knowledge - Cutting Edge

[Swooping]

@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"

http://onlinelibrary.wiley.com/doi/10.1111/bjd.14767/abstract;jsessionid=6D87B15F1DB95025982274A6C41B62BA.f03t02

"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"

Underlines the possibility of oxidative stress being implicated in AGA again.

[TheKingofFighters]

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.

[InBeforeTheCure]

@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.

Unfortunately, it looks like I can't access my inbox...? I get the following message:

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?
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I can't recall if Hamilton describes anything about facial hair growth in these two groups, don't think so to be honest.

That sucks. Facial hair develops in a pattern too, of course, so it would be interesting to know.

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"

http://onlinelibrary.wiley.com/doi/1...41B62BA.f03t02

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.

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:

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

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.

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.

Underlines the possibility of oxidative stress being implicated in AGA again.

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:

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.

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.

[InBeforeTheCure]

God damn it. I screwed up the page and I can't edit it now.

[TheKingofFighters]

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:

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

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.

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.

From where was the 'top 1000 genes in balding DPCs' from?

[TheKingofFighters]

Inbeforethecure:

This is the holy bible.

http://ctdbase.org/detail.go?type=ge...=2475&view=ixn for mTOR(and all other genes)

[TheKingofFighters]

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.

[TheKingofFighters]

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 mRNA

[InBeforeTheCure]

From where was the 'top 1000 genes in balding DPCs' from?

It's from the Chew/Philpott study (accession GSE66663 for untreated cells, GSE66664 for DHT-treated cells).

Inbeforethecure:

This is the holy bible.

http://ctdbase.org/detail.go?type=ge...=2475&view=ixn for mTOR(and all other genes)

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.

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

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.

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.

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).

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 mRNA

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.

[InBeforeTheCure]

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.

[TheKingofFighters]

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

[TheKingofFighters]

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.

Estradiol results in increased activity of SOD2 protein
Estradiol results in increased expression of and results in increased activity of SOD2 protein
Estradiol results in increased expression of SOD2 mRNA
Estradiol results in increased expression of SOD2 protein

[TheKingofFighters]

the angle im looking at is there must be some causative ROS-related gene(s) deficient in AGA that work(s) hand-in-hand with Estradiol(which we are already lacking in) to grow hair.

So it's Estradiol + ? =hair. Estradiol by itself is not enough. I have 1 gram of it in my fridge(and the dosage is in the mcgs/ml of vehicle).

I have not seen appreciable results 1 despite trying it out for weeks. It brings on numerous sides like gyno- though IMO, i assume this has something to do with the vehicle itself that results in more systemic penetration instead of remaining in the scalp.

[TheKingofFighters]

Estradiol:





The powder is not in a conventional 'powdery' form- it's in a crystaline state that resembles table sugar

[TheKingofFighters]

inbeforethecure:

Im not too sure about minoxidil 'growing hair everywhere' it doesnt seems to have any noticeable results on my scalp at all- while it did help grow my eyebrows

raw powder is a conventional, slightly bitter-tasting form

BTW, I should mention that SARMS like Ostarine still causes hairloss despite 'not affecting non-muscle tissues'. Perhaps muscle layers in the scalp are a factor to AGA? It gves me scalp itch everytime i use it:

helps alleviate oxidative stress- but it stop b-catenin. So again, ROS is defnitely a factor in AGA.
B2 adrenaagic agonists like Bambuterol are VERY anabolic(via cAMP upregulation). But I found that the more buffed up i became- the more hair i loss. and as mentioned before. Im not too sure about this 1 on whether it's helping or causing hairloss.

WORSENED my hairloss- it also gave me body odour and severe scalp itch. Something about the GABA receptors as well. It could be the N type voltage-gated calcium channels involved too.