Interdisciplinary Graduate Program
Molecular, Cell and Cancer Biology Department
First Thesis Advisor
Thomas Fazzio, PhD
Chromatin, Embryonic Stem Cells, Developmental Gene Expression Regulation, Histone Acetyltransferases
Dissertations, UMMS; Chromatin; Embryonic Stem Cells; Gene Expression Regulation, Developmental; Histone Acetyltransferases
The following work examines the mechanisms by which Tip60-p400 chromatin remodeling complex regulates gene expression in embryonic stem cells (ESCs). Tip60-p400 complex has distinct functions in undifferentiated and differentiated cells. While Tip60-p400 is often associated with gene activation in differentiated cells, its most prominent function in ESCs is to repress differentiation-related genes. I show that Tip60-p400 interacts with Hdac6 and other proteins to form a unique form of the complex in ESCs. Tip60-Hdac6 interaction is stem cell specific and is necessary for Tip60-p400 mediated gene regulation, indicating that Tip60- p400 function is controlled in part through the regulation of Hdac6 during development. Furthermore, I find that Hdac6 is required for the binding of Tip60- p400 to many of its target genes, indicating Hdac6 is necessary for the unique function of Tip60-p400 in ESCs. In addition to accessory proteins like Hdac6, Tip60-p400 also interacts with thousands of coding and noncoding RNAs in ESCs. I show that R-loops, DNA-RNA hybrids formed during transcription of many genes, are important for regulation of chromatin binding by at least two chromatin regulators (Tip60-p400 and PRC2). This finding suggests that transcripts produced by many genes in ESC may serve as a signal to modulate binding of chromatin regulators. However, R-loops might also function to regulate chromatin architecture in differentiated cells as well. Future studies based on this work will be necessary to understand the full repertoire of cell types and chromatin regulators regulated by these structures.
Chen, PB. Function and Regulation of the Tip60-p400 Complex in Embryonic Stem Cells: A Dissertation. (2015). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 785. DOI: 10.13028/M2SW20. http://escholarship.umassmed.edu/gsbs_diss/785
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