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The scaffolding function of LSD1 controls DNA methylation in mouse ESCs

Author

Listed:
  • Sandhya Malla

    (Umeå University
    Umeå University)

  • Kanchan Kumari

    (Umeå University
    Umeå University)

  • Carlos A. García-Prieto

    (Josep Carreras Leukaemia Research Institute
    Barcelona Supercomputing Center (BSC))

  • Jonatan Caroli

    (University of Pavia)

  • Anna Nordin

    (Linköping University
    Linköping University)

  • Trinh T. T. Phan

    (The University of Texas Health Science Center at Houston)

  • Devi Prasad Bhattarai

    (Umeå University
    Umeå University)

  • Carlos Martinez-Gamero

    (Umeå University
    Umeå University)

  • Eshagh Dorafshan

    (Umeå University
    Umeå University)

  • Stephanie Stransky

    (Albert Einstein College of Medicine)

  • Damiana Álvarez-Errico

    (Josep Carreras Leukaemia Research Institute)

  • Paulina Avovome Saiki

    (Umeå University
    Umeå University)

  • Weiyi Lai

    (Chinese Academy of Sciences)

  • Cong Lyu

    (Chinese Academy of Sciences)

  • Ludvig Lizana

    (Umeå University)

  • Jonathan D. Gilthorpe

    (Umeå University)

  • Hailin Wang

    (Chinese Academy of Sciences)

  • Simone Sidoli

    (Albert Einstein College of Medicine)

  • Andre Mateus

    (Umeå University
    The Laboratory for Molecular Infection Medicine Sweden (MIMS))

  • Dung-Fang Lee

    (The University of Texas Health Science Center at Houston
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
    The University of Texas Health Science Center at Houston
    The University of Texas Health Science Center at Houston)

  • Claudio Cantù

    (Linköping University
    Linköping University)

  • Manel Esteller

    (Josep Carreras Leukaemia Research Institute
    Centro de Investigacion Biomedica en Red Cancer (CIBERONC)
    Institucio Catalana de Recerca i Estudis Avançats (ICREA)
    University of Barcelona (UB))

  • Andrea Mattevi

    (University of Pavia)

  • Angel-Carlos Roman

    (University of Extremadura)

  • Francesca Aguilo

    (Umeå University
    Umeå University)

Abstract

Lysine-specific histone demethylase 1 (LSD1), which demethylates mono- or di- methylated histone H3 on lysine 4 (H3K4me1/2), is essential for early embryogenesis and development. Here we show that LSD1 is dispensable for mouse embryonic stem cell (ESC) self-renewal but is required for mouse ESC growth and differentiation. Reintroduction of a catalytically-impaired LSD1 (LSD1MUT) recovers the proliferation capability of mouse ESCs, yet the enzymatic activity of LSD1 is essential to ensure proper differentiation. Indeed, increased H3K4me1 in Lsd1 knockout (KO) mouse ESCs does not lead to major changes in global gene expression programs related to stemness. However, ablation of LSD1 but not LSD1MUT results in decreased DNMT1 and UHRF1 proteins coupled to global hypomethylation. We show that both LSD1 and LSD1MUT control protein stability of UHRF1 and DNMT1 through interaction with HDAC1 and the ubiquitin-specific peptidase 7 (USP7), consequently, facilitating the deacetylation and deubiquitination of DNMT1 and UHRF1. Our studies elucidate a mechanism by which LSD1 controls DNA methylation in mouse ESCs, independently of its lysine demethylase activity.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51966-7
    DOI: 10.1038/s41467-024-51966-7
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    References listed on IDEAS

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