Pioneer Factors Compete for Epigenetic Factors in Switching Stem Cell Fates

<p>During development, progenitor cells can activate one cell fate while simultaneously silencing another, a process that is tightly regulated in adult tissues. However, this process is often derailed in diseases such as cancers, leading to uncontrolled growth and malignancy. At the crossroads of fate-switching, pioneer factors are a class of transcription factors equipped to bind cognate motifs in closed chromatin. Once they access the closed chromatin, pioneer factors can either act as transcriptional activators or repressors of cell fates by recruiting co-activators or co-repressors. Nevertheless, whether and how a single factor can simultaneously silence the old fate while activating the new cell fate remains largely unknown. Here, I tackled this question with SOX9, a master regulator that diverts embryonic epidermal stem cells (EpdSCs) into becoming hair follicle stem cells (HFSCs). I triggered a temporal fate-switching by engineering mice to re-activate SOX9 in adult EpdSCs. Combining epigenetic, proteomic, and functional analyses, I interrogated the ensuing transcriptional and epigenetic dynamics, slowed temporally by the mature EpdSC niche microenvironment. My findings demonstrate that SOX9 plays a dual role in the fate-switching process. As it binds and opens key HFSC enhancers, it also redistributes co-factors away from EpdSC enhancers, leading to their silencing. Furthermore, in the absence of its normal regulation, prolonged expression of SOX9 in EpdSCs leads to the activation of downstream transcriptional regulators associated with basal cell carcinoma.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year

2024

Author dc:creator

• Yang, Yihao

Contributors dc:contributor

• Elaine Fuchs

• fate switching
• SOX9
• epidermal stem cells
• hair follicle stem cells
• pioneer factors
• epigenetics
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/781

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1785