Electronic Theses and Dissertations

Date

2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Biology

Committee Chair

Amy Abell

Committee Member

Judith Cole

Committee Member

Bernie Daigle

Committee Member

Carlos Estrano

Abstract

Phenotypic switching occurs during normal development, and these processes are reactivated in several disease states. We have previously demonstrated the critical role of the MAP3K4 regulated chromatin modifiers CBP and HDAC6 in controlling this switching in trophoblast stem (TS) cells. We hypothesized that genes co-regulated by CBP and HDAC6 represent critical regulators of phenotypic switching. Bioinformatic analyses identify 183 co-regulated genes of which 12% are DNA binding proteins. The highest-ranking gene is the NF-B family member Rel. Both CBP and HDAC6 bind the regulatory regions of Rel, controlling histone H2BK5 and H3K27 acetylation on both promoter and predicted enhancer regions. Re-expression of Rel in mesenchymal-like TS cells induces a mesenchymal to epithelial transition, in part by promoting expression of CBP/HDAC6 co-regulated genes. Further, REL binds the Hdac6 promoter, decreasing both expression and nuclear localization of HDAC6. Together, our work defines an epigenetic program controlling switching between epithelial and mesenchymal phenotypes.

Comments

Data is provided by the student.

Library Comment

Dissertation or thesis originally submitted to ProQuest

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