美国洛克菲勒大学Elaine Fuchs小组在研究中取得进展。他们发现先锋因子SOX9通过与表观遗传因子竞争以改变干细胞命运。2023年7月24日出版的《自然—细胞生物学》杂志发表了这项成果。

研究人员利用SOX9揭示了先锋因子决定细胞命运的机制，SOX9是一种主调节因子，调控胚胎表皮干细胞（EpdSCs）向毛囊干细胞的转换。研究人员通过改造小鼠重新激活成年EpdSC的SOX9触发了命运转换。通过表观遗传学、蛋白质组学和功能分析，研究人员探究了随后的染色质和转录动力学，这些动力学在成熟的EpdSC生态位微环境中暂时减慢。

研究表明，当SOX9结合并开启EpdSCs中的关键毛囊增强子时，它同时从表皮增强子中招募辅助因子，这些因子先前处在沉默状态。与其正常调节脱节，持续的SOX9随后激活致癌转录调节因子，这些调节因子绘制了以组成型SOX9表达为代表的癌症调控路径。

研究人员表示，在发育过程中，祖细胞在激活一个谱系的同时沉默另一个谱系，这一特征在成体干细胞中受到高度调控，但在癌症细胞中失调。先锋因子能够在闭合染色质中结合同源基序，并在命运决定的十字路口起作用，但不清楚它们决定命运转换的机制。

附：英文原文

Title: The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates

Author: Yang, Yihao, Gomez, Nicholas, Infarinato, Nicole, Adam, Rene C., Sribour, Megan, Baek, Inwha, Laurin, Mlanie, Fuchs, Elaine

Issue&Volume: 2023-07-24

Abstract: During development, progenitors simultaneously activate one lineage while silencing another, a feature highly regulated in adult stem cells but derailed in cancers. Equipped to bind cognate motifs in closed chromatin, pioneer factors operate at these crossroads, but how they perform fate switching remains elusive. Here we tackle this question with SOX9, a master regulator that diverts embryonic epidermal stem cells (EpdSCs) into becoming hair follicle stem cells. By engineering mice to re-activate SOX9 in adult EpdSCs, we trigger fate switching. Combining epigenetic, proteomic and functional analyses, we interrogate the ensuing chromatin and transcriptional dynamics, slowed temporally by the mature EpdSC niche microenvironment. We show that as SOX9 binds and opens key hair follicle enhancers de novo in EpdSCs, it simultaneously recruits co-factors away from epidermal enhancers, which are silenced. Unhinged from its normal regulation, sustained SOX9 subsequently activates oncogenic transcriptional regulators that chart the path to cancers typified by constitutive SOX9 expression.

DOI: 10.1038/s41556-023-01184-y

Source: https://www.nature.com/articles/s41556-023-01184-y