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An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation

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  • Min Gyu Lee

    (The Wistar Institute)

  • Christopher Wynder

    (The Wistar Institute)

  • Neil Cooch

    (The Wistar Institute)

  • Ramin Shiekhattar

    (The Wistar Institute)

Abstract

We have previously described a multiprotein complex termed the BHC or BRAF–HDAC complex, which is required for the repression of neuronal-specific genes1. We have shown that the BHC complex is recruited by a neuronal silencer, REST (RE1-silencing transcription factor), and mediates the repression of REST-responsive genes1. BHC is a multiprotein complex consisting of two enzymatic activities: a histone deacetylase (HDAC1 or 2) and a recently described histone demethylase (BHC110, also known as LSD1 or AOF2)1,2,3. Here we show that BHC110-containing complexes show a nearly fivefold increase in demethylation of histone H3 lysine 4 (H3K4) compared to recombinant BHC110. Furthermore, recombinant BHC110 is unable to demethylate H3K4 on nucleosomes, but BHC110-containing complexes readily demethylate nucleosomes. In vitro reconstitution of the BHC complex using recombinant subunits reveals an essential role for the REST corepressor CoREST, not only in stimulating demethylation on core histones but also promoting demethylation of nucleosomal substrates. We find that nucleosomal demethylation is the result of CoREST enhancing the association between BHC110 and nucleosomes. Depletion of CoREST in in vivo cell culture results in de-repression of REST-responsive gene expression and increased methylation of H3K4. Together, these results highlight an essential role for CoREST in demethylation of H3K4 both in vitro and in vivo.

Suggested Citation

  • Min Gyu Lee & Christopher Wynder & Neil Cooch & Ramin Shiekhattar, 2005. "An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation," Nature, Nature, vol. 437(7057), pages 432-435, September.
    • Handle: RePEc:nat:nature:v:437:y:2005:i:7057:d:10.1038_nature04021
    DOI: 10.1038/nature04021
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    Cited by:

    1. Lei Tao & Yue Zhou & Xiangyu Pan & Yuan Luo & Jiahao Qiu & Xia Zhou & Zhiqian Chen & Yan Li & Lian Xu & Yang Zhou & Zeping Zuo & Chunqi Liu & Liang Wang & Xiaocong Liu & Xinyu Tian & Na Su & Zhengnan , 2023. "Repression of LSD1 potentiates homologous recombination-proficient ovarian cancer to PARP inhibitors through down-regulation of BRCA1/2 and RAD51," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Yi Liu & Brian Debo & Mingfeng Li & Zhennan Shi & Wanqiang Sheng & Yang Shi, 2021. "LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Cheng Zeng & Jiwei Chen & Emmalee W. Cooke & Arijita Subuddhi & Eliana T. Roodman & Fei Xavier Chen & Kaixiang Cao, 2023. "Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Sandhya Malla & Kanchan Kumari & Carlos A. García-Prieto & Jonatan Caroli & Anna Nordin & Trinh T. T. Phan & Devi Prasad Bhattarai & Carlos Martinez-Gamero & Eshagh Dorafshan & Stephanie Stransky & Da, 2024. "The scaffolding function of LSD1 controls DNA methylation in mouse ESCs," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    5. Tiantian Jing & Dianhui Wei & Xiaoli Xu & Chengsi Wu & Lili Yuan & Yiwen Huang & Yizhen Liu & Yanyi Jiang & Boshi Wang, 2024. "Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    6. Xue Zhong & Nagesh Peddada & Jianhui Wang & James J. Moresco & Xiaowei Zhan & John M. Shelton & Jeffrey A. SoRelle & Katie Keller & Danielle Renee Lazaro & Eva Marie Y. Moresco & Jin Huk Choi & Bruce , 2023. "OVOL2 sustains postnatal thymic epithelial cell identity," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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