In collaboration with the Roberts laboratory, we have published three complementary papers in Nature Genetics (Wang X et al, Mathur R et al) and Nature Communications (Alver BH et al). We have been working with Charlie Roberts lab for some time now; Charlie was previously at the Dana-Farber Cancer Center; he is now the director of the Cancer Center at St. Jude Children's Hospital in Memphis.
SWI/SNF is a chromatin remodeling protein complex that is mutated in >20% of all cancers. In these three manuscripts, we studied six different cell types, including both normal and cancer cells, with or without the presence of different SWI/SNF subunits. A consistent picture that emerged in all these studies is that the predominant function of the SWI/SNF complex is maintaining developmental enhancers. The papers demonstrate that loss of SWI/SNF subunits in normal cells leads specifically to inactivation of enhancers (Alver BH et al) and that the SWI/SNF independent super-enhancers pose targetable vulnerabilities of SWI/SNF mutant cancers (Wang X et al). We also show that loss of the ARID1A subunit in mice leads invasive adenocarcinomas resembling human colorectal cancer, via a mechanism that is distinct from the highly studied APC/β-catenin models (Mathur R et al).
Congratulations to Burak who led the bioinformatic analysis in all three papers!
Alver BH*, Kim KH*, Lu P, Wang X, Manchester HE, Wang W, Haswell JR, Park PJ**, Roberts CWM**. The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers. Nat Commun 2017;8:14648.
Wang X*, Lee RS*, Alver BH*, Haswell JR, Wang S, Mieczkowski J, Drier Y, Gillespie SM, Archer TC, Wu JN, Tzvetkov EP, Troisi EC, Pomeroy SL, Biegel JA, Tolstorukov MY, Bernstein BE**, Park PJ**, Roberts CWM**. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat Genet 2017;49(2):289-295.
Mathur R, Alver BH, San Roman AK, Wilson BG, Wang X, Agoston AT, Park PJ, Shivdasani RA, Roberts CWM. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet 2017;49(2):296-302.