Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Mitchell A. Lazar

Abstract

Brown adipose tissue (BAT) is a thermogenic organ, which helps to protect body temperature against cold and can counteract metabolic disease. Numerous pathways modulate the activity of BAT in a highly regulated and coordinated manner to exert tight control over its immense calorie burning capacity. However, less is known regarding the transcriptional and epigenomic mechanisms controlling the thermogenic gene program of brown adipocytes. Here, we show that histone deacetylase 3 (HDAC3) is required for the activation of BAT enhancers to ensure thermogenic aptitude, thus enabling survival of dangerously cold environmental temperature. Loss of HDAC3 leads to deficient expression of uncoupling protein 1 (UCP1) and oxidative phosphorylation genes, resulting in an inability to survive severely cold temperatures. Mechanistic studies demonstrate BAT HDAC3 functions as a coactivator of the nuclear receptor estrogen-related receptor α (ERRα), through deacetylation of PGC-1α to promote enhancer activation and gene transcription. Remarkably, this coactivator function of HDAC3 is required for the basal expression of the thermogenic gene program and occurs independently of adrenergic signaling. Thus, HDAC3 primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for BAT to enable survival of dangerously cold temperature.

We further demonstrate that short environmental exposure to a moderate cold temperature circumvents the genetic requirement of HDAC3 for Ucp1 transcriptional activation. Environmental exposure facilitates a persistent epigenomic rescue mechanism permitting the prolonged expression of thermogenic genes and an acquired BAT aptitude to avert hypothermia. Notably, we discovered that moderate cold activates BAT ERRα enhancers in an HDAC3-independent manner. Together, these studies identify for the first time, that BAT HDAC3 coactivation of ERR enhancers promotes a basal thermogenic transcriptional program ensuring cold survival, while HDAC3-independent mechanisms, signaling from a moderate cold environment to genes, imparts epigenomic changes to influence the BAT thermogenic capacity against probable and impending dangerously cold temperatures.

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