Chromatin dynamics, diabetes, and beyond: balancing the homeostatic equation

Speaker Name: 
Zong Wei
Speaker Title: 
Postdoctoral Fellow
Speaker Organization: 
Salk Institute for Biological Studies
Start Time: 
Monday, March 11, 2019 - 10:45am
End Time: 
Monday, March 11, 2019 - 11:45am
Location: 
Biomed 300
Organizer: 
Nader Pourmand

Abstract                                                                                                                                                                                                    Rapid and chronic molecular responses are induced when living cells are exposed to adverse environmental conditions. Whereas these responses at protein and transcriptional levels are well studied, the molecular underpinnings of chromatin dynamics in response to environmental cues are largely unclear. Through CRISPR screening in human stem cell derived beta cells, we recently identified a novel mechanism connecting signal-dependent transcription by vitamin D receptor (VDR) and fine-tuning of chromatin accessibility by a balance between SWI/SNF complexes, BAF and PBAF. Our studies revealed that VDR recruits BAF and PBAF complexes through two bromodomain proteins, BRD9 and BRD7, respectively. The balance between BAF-BRD9 and PBAF-BRD7 determines the VDR-driven anti-inflammatory and pro-survival response in b cells. In a dual regulatory mechanism, inhibition of the VDR-BRD9 interaction in combination with ligand activation of VDR cooperate to dismiss the BAF-BRD9 complex and shift the balance to the activating PBAF-BRD7 complex to induce a coordinated transcriptional response. Notably, pharmacologically potentiated VDR signaling by a synthetic ligand in combination with a BRD9 inhibitor can partially restore b cell function and glucose homeostasis in various T2D mouse models. Together, our results revealed that an unexpected epigenetic balance between the bromodomain readers has a major impact on b cell survival and glucose homeostasis, and demonstrated the therapeutic potential of targeting inflammatory/metabolic stress through an epigenetic approach.

 

Biography

Dr. Zong Wei graduated from the University of Southern California with a Ph.D. in Genetics, Molecular and Cellular Biology in 2012. He is currently a staff scientist in the Gene Expression Laboratory at the Salk Institute for Biological Studies. Working with Ron Evans, Dr. Wei combines techniques at forefront of genomics, stem cell biology, and protein chemistry to develop a comprehensive understanding of the epigenomic dynamics in cellular dysfunction in metabolic diseases, and to explore the therapeutic potential of stem cell derived organoids and epigenetic modulation in diabetes.