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

Pengfei Guo, Nam Hoang, Joseph Sanchez, Elaine H. Zhang, Keshari Rajawasam, Kristiana Trinidad, Hong Sun and Hui Zhang ()
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Pengfei Guo: University of Nevada
Nam Hoang: University of Nevada
Joseph Sanchez: University of Nevada
Elaine H. Zhang: University of California
Keshari Rajawasam: University of Nevada
Kristiana Trinidad: University of Nevada
Hong Sun: University of Nevada
Hui Zhang: University of Nevada

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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 CRL4DCAF5 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.

Date: 2022
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DOI: 10.1038/s41467-022-34348-9

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