Functional compensation in chromatin remodeling and transcription regulation

Benjamin Martin, PhD 
Postdoctoral Research Fellow
Department of Biological Chemistry and Molecular Pharmacology
Harvard Medical School
Boston, MA, USA 
 

This conference is part of the the IRCM Early-Career Scientist Seminar Series (ECS3), a groundbreaking initiative whose mission is to showcase early career scientists. This is a great opportunity to discover the exciting projects of these researchers in training in front of a multidisciplinary audience.

In person : 
IRCM Auditorium
110, avenue des Pins O, H2W 1R7 Montreal

About this conference : 
Mammalian SWI/SNF chromatin remodeling complexes move and evict nucleosomes at gene promoters and enhancers to modulate DNA access. Although SWI/SNF subunits are commonly mutated in disease, therapeutic options are limited by our inability to predict SWI/SNF gene targets and conflicting studies on functional significance. Here, I will describe our recent results where we have leveraged a fast-acting inhibitor of SWI/SNF remodeling to elucidate the direct targets and effects of SWI/SNF. We find that blocking SWI/SNF activity causes a rapid and global loss of chromatin accessibility and transcription. Whereas repression persists at most enhancers, we uncover a compensatory role for the EP400/TIP60 remodeler, which reestablishes accessibility at most promoters during prolonged loss of SWI/SNF. Indeed, we observe synthetic lethality between EP400 and SWI/SNF in cancer cell lines and human cancer patient data. Our data define a set of molecular genomic features that accurately predict gene sensitivity to SWI/SNF inhibition in diverse cancer cell lines, thereby improving the therapeutic potential of SWI/SNF inhibitors.

About  Benjamin Martin: 
Dr. Benjamin Martin undertook his PhD at the University of British Columbia with Dr. LeAnn Howe in the department of biochemistry and molecular biology, studying the interplay between chromatin and transcription. Following his PhD, he joined the lab of Dr. Karen Adelman at Harvard Medical School for his postdoc, supported by a CIHR Banting Postdoctoral Fellowship. His research uses pluripotent stem cell and cancer models to investigate mechanisms of functional compensation in mammalian chromatin remodeling and transcriptional regulation, with recent publication detailing his work on SWI/SNF and the cohesin complex.