Three papers published on the SWI/SNF chromatin remodeler and enhancers

See the news release from Harvard Medical School and the news article on ScienceDaily.

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!

References:

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.