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

Author

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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)

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.

Suggested Citation

  • Pengfei Guo & Nam Hoang & Joseph Sanchez & Elaine H. Zhang & Keshari Rajawasam & Kristiana Trinidad & Hong Sun & Hui Zhang, 2022. "The assembly of mammalian SWI/SNF chromatin remodeling complexes is regulated by lysine-methylation dependent proteolysis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34348-9
    DOI: 10.1038/s41467-022-34348-9
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    References listed on IDEAS

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    1. Feng Leng & Jiekai Yu & Chunxiao Zhang & Salvador Alejo & Nam Hoang & Hong Sun & Fei Lu & Hui Zhang, 2018. "Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4DCAF5 ubiquitin ligase," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    2. Lena Ho & Gerald R. Crabtree, 2010. "Chromatin remodelling during development," Nature, Nature, vol. 463(7280), pages 474-484, January.
    3. Jianxun Wang & Kathleen Scully & Xiaoyan Zhu & Ling Cai & Jie Zhang & Gratien G. Prefontaine & Anna Krones & Kenneth A. Ohgi & Ping Zhu & Ivan Garcia-Bassets & Forrest Liu & Havilah Taylor & Jean Loza, 2007. "Opposing LSD1 complexes function in developmental gene activation and repression programmes," Nature, Nature, vol. 446(7138), pages 882-887, April.
    4. Michael A. Christopher & Dexter A. Myrick & Benjamin G. Barwick & Amanda K. Engstrom & Kirsten A. Porter-Stransky & Jeremy M. Boss & David Weinshenker & Allan I. Levey & David J. Katz, 2017. "LSD1 protects against hippocampal and cortical neurodegeneration," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
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