Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Mitchell A. Lazar

Abstract

The daily rotation of the Earth around its axis generates a light-day cycle that occurs every 24 hours. To cope with this environmental stress, every photosensitive organism has evolved with circadian rhythms to anticipate and adapt to recurring changes in the environment. Circadian rhythms are pervasive features in biology and nearly all cells have their own clocks, which coordinate various aspects of mammalian physiology, including sleep, behavior, and metabolism throughout the day. My thesis work aimed to dissect the molecular mechanism by which circadian rhythms are transcriptionally controlled. More specifically, we investigated how the core clock transcriptional factor Rev-erbα regulates enhancer-promoters loops to repress circadian gene transcription. We demonstrate that as a transcriptional repressor, Rev-erbα opposes enhancer-promoter loops in a circadian manner by evicting chromatin-associated factors involved in looping, thus revealing genome-wide plasticity of 3D chromatin organization. Broadly, this mechanism of action may be generalizable to other transcriptional repressors, including nuclear receptors. In addition, we also sought to characterize circadian transcriptional regulation by an unknown ETS transcription factor. From an unbiased approach, we identified the ETS transcription factor GABPα, which exhibited a circadian rhythm of nascent transcription at its cistrome despite no circadian change in its genomic occupancy. Genetic knock out of GABPα led to phenotypes and patterns of differential gene expression resembling cellular senescence likely due to mitochondrial dysfunction. Interestingly, we observed that GABPα knock out gave rise to a pathologic circadian rhythm of the senescence-associated secretory phenotype gene program. Taken together, my thesis work has provided a novel insight into how circadian rhythms are transcriptionally coordinated by complex interplays among the genome, transcription factors, and other chromatin-associated factors.

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