Molecular networks and epigenomic mechanisms underpinning white fat browning capacity

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Obesity develops when energy intake chronically exceeds energy expenditure. The capacity for thermogenic adipocytes (brown and brite/beige) to dissipate chemical energy therefore increasing energy expenditure offers great potential to combat obesity. With limited amount of human brown fat, increasing the relative abundance of brite cells in white fat (WAT browning) offers an opportunity to increase the mass of thermogenic brite adipose tissues and meanwhile decrease the amount of WAT, thereby turning an energy-storing organ into an energy-dissipating one. However, a comprehensive understanding of the regulatory mechanisms mediating WAT browning is still lacking. Variation in white fat browning propensity among inbred mouse strains provides a unique opportunity to zoom in on the core regulators of the browning program across different genotypes. In previous studies, combining comparative transcriptomics, perturbation-based assays and gene network analyses, I revealed novel regulators as well as a core regulatory network that contributes to brite adipogenesis. Although these results constitute the most comprehensive attempt to define the regulatory network underlying white fat browning, further efforts are needed to perform in-depth characterization of key factors, refine the organization of the network and draw a more complete canvas of the sources of gene expression variability in this system. Moreover, there is a more complex source of strain variation in browning propensity, exemplified by cis-driven between C57BL/6J and 129S6/SvEvTac, while trans-driven between C57BL/6J and FVB/NJ. My future work now aims at the systematic analyses of transcription factor binding, epigenetic state and gene expression to identify natural genetic variants that affect the browning capacity. Specifically, I hypothesize that distinct genetic variants affect DNA-binding of transcription factors, which lead to variable histone modifications and collectively influence gene expression and browning propensity (Objective A) and operating through highly connected cellular networks of genes targeting browning capacity (Objective B). Testing these hypotheses will lead to the discovery of novel functional regulatory elements, candidate genes, epigenetic basis and molecular networks underlying white fat browning. Combined with further extensive validation both in vitro and in vivo (Objective C) through gain- and loss-of-function experiments as well as simultaneous activation of multiple genes with the CRISPR–dCas9-activator system, an in-depth understanding of novel key transcription factor(s) as well as molecular networks in the control of browning capability will be obtained. Together, we aim to devise a comprehensive molecular network that regulates white fat browning. In the long run, a full understanding of the molecular architecture underlying brite cell recruitment could facilitate the development of therapeutic approaches for combating metabolic imbalance.