The scaffolding function of LSD1 controls DNA methylation in mouse ESCs

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, Damiana Álvarez-Errico, Paulina Avovome Saiki, Weiyi Lai, Cong Lyu, Ludvig Lizana, Jonathan D. Gilthorpe, Hailin Wang, Simone Sidoli, Andre Mateus, Dung-Fang Lee, Claudio Cantù, Manel Esteller, Andrea Mattevi, Angel-Carlos Roman and Francesca Aguilo ()
Additional contact information
Sandhya Malla: Umeå University
Kanchan Kumari: Umeå University
Carlos A. García-Prieto: Josep Carreras Leukaemia Research Institute
Jonatan Caroli: University of Pavia
Anna Nordin: Linköping University
Trinh T. T. Phan: The University of Texas Health Science Center at Houston
Devi Prasad Bhattarai: Umeå University
Carlos Martinez-Gamero: Umeå University
Eshagh Dorafshan: Umeå University
Stephanie Stransky: Albert Einstein College of Medicine
Damiana Álvarez-Errico: Josep Carreras Leukaemia Research Institute
Paulina Avovome Saiki: 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
Dung-Fang Lee: The University of Texas Health Science Center at Houston
Claudio Cantù: Linköping University
Manel Esteller: Josep Carreras Leukaemia Research Institute
Andrea Mattevi: University of Pavia
Angel-Carlos Roman: University of Extremadura
Francesca Aguilo: Umeå University

Nature Communications, 2024, vol. 15, issue 1, 1-24

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51966-7

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