利用比较转录组谱分析研究男性雄激素性脱发：缺氧诱导因子-1 和 Wnt/β-连环蛋白信号通路。
Insights into male androgenetic alopecia using comparative transcriptome profiling: hypoxia-inducible factor-1 and Wnt/β-catenin signalling pathways.
机构信息
Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China.
出版信息
Br J Dermatol. 2022 Dec;187(6):936-947. doi: 10.1111/bjd.21783. Epub 2022 Sep 1.
BACKGROUND
The key pathophysiological changes in androgenetic alopecia (AGA) are limited to hair follicles (HFs) in frontal and vertex regions, sparing the occipital region.
OBJECTIVES
To identify biological differences among HF subpopulations.
METHODS
Paired vertex and occipital HFs from 10 male donors with AGA were collected for RNA sequencing assay. Furthermore, HF and cell experiments were conducted on the identified key genes to reveal their roles in AGA.
RESULTS
Transcriptome profiles revealed that 506 mRNAs, 55 microRNAs and 127 long noncoding RNAs were differentially expressed in the AGA vertex HFs. Pathway analysis of mRNAs and microRNAs revealed involvement of the hypoxia-inducible factor (HIF)-1, Wnt/β-catenin, and focal adhesion pathways. Differential expression of HIF-1 prolyl hydroxylase enzymes (EGLN1, EGLN3) and Wnt/β-catenin pathway inhibitors (SERPINF1, SFRP2) was experimentally validated. In vitro studies revealed that reduction of EGLN1, EGLN3, SERPINF1 and SFRP2 stimulated proliferation of dermal papilla cells. Ex vivo HF studies showed that downregulation of EGLN1, EGLN3 and SERPINF1 promoted HF growth, postponed HF catagen transition, and prolonged the anagen stage, suggesting that these genes may be potentially utilized as therapeutic targets for AGA.
CONCLUSIONS
We characterized key transcriptome changes in male AGA HFs, and found that HIF-1 pathway-related genes (EGLN1, EGLN3) and Wnt pathway inhibitors (SERPINF1, SFRP2) may play important roles in AGA. What is already known about this topic? Multiple differentially expressed genes and signalling pathways have been found between hair follicles (HFs) in the balding area (frontal and vertex regions) and nonbalding area (occipital region) of individuals with androgenetic alopecia (AGA). A whole-transcriptome atlas of the vertex and occipital region is lacking. What does this study add? We identified a number of differentially expressed genes and pathways between balding vertex and nonbalding occipital AGA HFs by using whole-transcriptome analyses. We identified pathways not previously reported in AGA, such as the hypoxia-inducible factor (HIF)-1 signalling pathway. We verified that HIF-1 pathway-related genes (EGLN1, EGLN3) and Wnt pathway inhibitors (PEDF, SFRP2) played important roles in dermal papilla cell activity, hair growth and the hair cycle. What is the translational message? The EGLN1, EGLN3, SERPINF1 and SFRP2 genes may be potentially utilized as therapeutic targets for AGA.
背景
雄激素性脱发（AGA）的关键病理生理变化仅限于额部和顶部区域的毛囊（HFs），而枕部区域不受影响。
目的
鉴定 HF 亚群之间的生物学差异。
方法
从 10 名男性 AGA 患者的配对额部和枕部 HF 中采集 RNA 测序样本。此外，对鉴定出的关键基因进行 HF 和细胞实验，以揭示它们在 AGA 中的作用。
结果
转录组谱分析显示，506 个 mRNA、55 个 microRNA 和 127 个长链非编码 RNA 在 AGA 顶部 HF 中差异表达。mRNA 和 microRNA 的通路分析显示缺氧诱导因子（HIF）-1、Wnt/β-catenin 和黏附斑通路的参与。HIF-1 脯氨酰羟化酶（EGLN1、EGLN3）和 Wnt/β-catenin 通路抑制剂（SERPINF1、SFRP2）的差异表达通过实验得到验证。体外研究表明，EGLN1、EGLN3、SERPINF1 和 SFRP2 的减少刺激了真皮乳头细胞的增殖。HF 体外研究表明，EGLN1、EGLN3 和 SERPINF1 的下调促进了 HF 的生长，推迟了 HF 的退行期转换，并延长了生长期，表明这些基因可能作为 AGA 的潜在治疗靶点。
结论
我们描述了 AGA 男性 HF 中的关键转录组变化，并发现 HIF-1 通路相关基因（EGLN1、EGLN3）和 Wnt 通路抑制剂（SERPINF1、SFRP2）可能在 AGA 中发挥重要作用。
已知关于这一主题的信息
已经在雄激素性脱发（AGA）患者的脱发区域（额部和顶部区域）和非脱发区域（枕部区域）的毛囊（HFs）之间发现了多个差异表达的基因和信号通路。缺乏关于额部和枕部 AGA HF 的全转录组图谱。
本研究有何新发现
通过全转录组分析，我们在 AGA 脱发的顶部和非脱发的枕部 HF 之间鉴定出了一些差异表达的基因和通路。我们发现了一些之前未在 AGA 中报道的通路，例如缺氧诱导因子（HIF）-1 信号通路。我们验证了 HIF-1 通路相关基因（EGLN1、EGLN3）和 Wnt 通路抑制剂（PEDF、SFRP2）在真皮乳头细胞活性、毛发生长和毛发周期中发挥重要作用。
研究的转化意义
EGLN1、EGLN3、SERPINF1 和 SFRP2 基因可能作为 AGA 的潜在治疗靶点。
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