The assembly of mammalian SWI/SNF chromatin remodeling complexes is regulated by lysine-methylation dependent proteolysis

Here the authors show the assembly/disassembly of mammalian SWI/SNF complexes is dynamically regulated by a lysine methylation mechanism involving the demethylase LSD1 and the methyl-lysine reader L3MBTL3, which recognizes SET7-methylated lysines in SMARCC1 and SMARCC2 to target them for CRL4 ubiquitin ligase-mediated proteolysis. The assembly of mammalian SWI/SNF chromatin remodeling complexes is developmentally programed, and loss/mutations of SWI/SNF subunits alter the levels of other components through proteolysis, causing cancers. Here, we show that mouse Lsd1/Kdm1a deletion causes dramatic dissolution of SWI/SNF complexes and that LSD1 demethylates the methylated lysine residues in SMARCC1 and SMARCC2 to preserve the structural integrity of SWI/SNF complexes. The methylated SMARCC1/SMARCC2 are targeted for proteolysis by L3MBTL3 and the CRL4(DCAF5) ubiquitin ligase complex. We identify SMARCC1 as the critical target of LSD1 and L3MBTL3 to maintain the pluripotency and self-renewal of embryonic stem cells. L3MBTL3 also regulates SMARCC1/SMARCC2 proteolysis induced by the loss of SWI/SNF subunits. Consistently, mouse L3mbtl3 deletion causes striking accumulation of SWI/SNF components, associated with embryonic lethality. Our studies reveal that the assembly/disassembly of SWI/SNF complexes is dynamically controlled by a lysine-methylation dependent proteolytic mechanism to maintain the integrity of the SWI/SNF complexes.

Automated summary

The authors demonstrate that the assembly/disassembly of mammalian SWI/SNF complexes is dynamically regulated by a lysine methylation mechanism involving LSD1 demethylase and L3MBTL3 methyl-lysine reader protein. This mechanism targets SET7-methylated lysines in SMARCC1 and SMARCC2 for proteolysis by CRL4 ubiquitin ligase. The study also reveals the critical role of LSD1 and L3MBTL3 in maintaining the pluripotency and self-renewal of embryonic stem cells, as well as regulating proteolysis induced by loss of SWI/SNF subunits.