Student Theses and Dissertations

Yihao Yang

Date of Award

2023

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Fuchs Laboratory

Abstract

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.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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