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EBF2 Puts the “Brown” in Brown Fat

August 27, 2017

Fat has a bad reputation for its negative contribution to a host of diseases such as cardiovascular disease, diabetes, and obesity. However, not all fat is created equally. The study of brown adipose tissue (BAT) is becoming a hot topic in the world of gene regulation, metabolic diseases, and in the exercise industry. Rising interest in brown adipose tissue research parallels the growing efforts to combat rising obesity rates in America. The exercise industry is interested in understanding BAT for weight loss and healthy lifestyle maintenance. BAT is a highly metabolically active tissue that converts food energy into heat, which subsequently regulates thermogenesis. In contrast, white adipose tissue (WAT) stores food energy as triglyceride deposits and is a dreaded enemy of anyone trying to achieve a “beach body”. While a healthy amount of WAT is critical to cushion vital organs and provide insulation to maintain body temperature, too much WAT adversely affects metabolic functions and leads to disease, such as obesity and heart disease. Luckily, cold exposure or β-adrenergic stimulation can increase brown fat mass to counteract the negative effects of WAT. Part of appreciating how BAT functions is understanding its genetic regulation at the core of its biologic function. Insights into genetic regulation of BAT could uncover potential therapeutic targets for weight loss and disease management.

 

 

 

Figure 1: EBP2 physically interacts with the chromatin remodeler BRG1 and the BAF chromatin remodeling complex in brown adipocytes. The histone reader protein DPF3 is the brown fat-selective component of the BAF complex required for brown fat gene programming. EBF2 recruits DPF3/BAF to Ucp1, PPARα, etc. These results reveal a novel mechanism by which EBF2 cooperates with a tissue-specific chromatin remodeling complex to activate brown fat identity genes.

Dr. Patrick Seale’s laboratory focuses on elucidating the regulatory pathways that control the development, differentiation, and function of adipose cells. Dr. Seale identified Prdm16 (protein domain 16) as a vital cell-autonomous regulator of brown adipose cell fate. Recently, the lab identified Ebf2 (Early B-Cell Factor 2) as an upstream regulator of Prdm16. Ebf2 is required for the differentiation and function of BAT, with Ebf2 knockout mice developing WAT-like tissue where BAT usually is. Ebf2 is necessary for binding of a key adipogenic transcription factor, Pparα, to Ucp1. Uncoupling protein 1 (Ucp1) regulates energy transfer in BAT by uncoupling of the respiratory chain mitochondria and allowing for fast glucose oxidation with a low rate of ATP production. However, it remained unclear how EBF2 facilitated this PPARα/UCP1 interaction on a molecular level. Suzi Shapira, a GGR student in the Seale lab, took on the enormous task of unpacking the details of BAT fate commitment using ChIP (chromatin immunoprecipitation) followed by deep sequencing (ChIP-seq). She discovered that Ebf2 binds directly to lineage-specific enhancer regions to regulate brown fat differentiation and homeostasis (Figure 1A). Her work uncovered a novel molecular mechanism of adipocyte fate regulation, and BAT function at the chromatin level.

 

 

Suzi first assessed whether EBF2 directly binds chromatin or indirectly regulates PPARα/UCP1 interactions. Among the 28,000 binding-site hits were genes controlling fatty acid/glucose metabolism and BAT-specific differentiation. Using an Ebf2 knockout mouse, she found that EBF2 binding at brown-fat genes enhancer sites was reduced, but binding was not altered at enhancers shared by both WAT and BAT. This confirms Ebf2’s specificity as a transcriptional activator for BAT fate.

 

Co-immunoprecipitation experiments showed a physical interaction between EBF2 and the BAF (BRG1-associated factor) chromatin remodeling complex in mature brown adipocytes (Figure 1B). The BAF complex is an epigenetic regulator of several cell types, including adipocytes. Suzi identified Dpf3 (double PHD fingers 3), a regulatory subunit of the BAF DNA remodeling complex, as specifically required for brown fat induction in WAT, both in basal conditions and in response to β-adrenergic stimulation (Figure 1A). Similar to Ebf2 knockouts, her Dpf3 knockout mice showed decreased accessibility at Pparα and Ucp1 enhancer regions in both basal conditions and with β-adrenergic stimulation. This finding established that Dpf3 is required to promote permissive chromatin state at brown-fat specific enhancers to allow for differentiation (Figure 1C). The Dpf3 knockout also showed it is required for recruitment of other BAF complex subunits, but not Ebf2, to enhancer sites of brown fat specific genes. Therefore, Dpf3 functions downstream from Ebf2 to regulate the BAT genetic program.

 

In conclusion, Ebf2 is an indispensable lineage-specific enhancer activator for the genes that control the BAT cell lineage program. Dpf3 expression downstream of Ebf2 is necessary for Ebf2 to facilitate Pparα and Ucp1 interactions in BAT. Taken together, Suzi’s paper identifies a molecular mechanism that orchestrates the BAT genetic program, shedding light on Dpf3 as a key downstream target of Ebf2-mediated Pparα and Ucp1 activity. By identifying both Ebf2 and Dpf3 as particular regulators of the BAT lineage, she has presented two points of possible therapeutic modulation to treat metabolic disease.

 

Suzi is currently writing her thesis manuscript and is defending this fall. She aims to do a post-doctoral fellowship that continues to focus on genetics and epigenetics. She says, “I really enjoy bench science and my long-term goal is to pursue drug discovery/therapeutics development based on the skills I gained during my PhD work and future training”.

 

We are excited to see what she does next.

 

 

Suzanne N. Shapira, Hee-Woong Lim, Sona Rajakumari, Alexander P. Sakers, Jeff Ishibashi, Matthew J. Harms, Kyoung-Jae Won, and Patrick Seale. EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex. Genes Dev. 2017 Apr 1;31(7):660-673. doi: 10.1101/gad.294405.116.

 

 

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