The scaffolding function of LSD1 controls DNA methylation in mouse ESCs
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 (LSD1<sup>MUT</sup>) 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 LSD1<sup>MUT</sup> results in decreased DNMT1 and UHRF1 proteins coupled to global hypomethylation. We show that both LSD1 and LSD1<sup>MUT</sup> 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.
Authors
- Kanchan Kumari (ORCID: https://orcid.org/0000-0001-7546-4174)
- Manel Esteller (ORCID: https://orcid.org/0000-0003-4490-6093)
- Carlos Martinez‐Gamero (ORCID: https://orcid.org/0000-0001-7652-1695)
- Jonatan Caroli
- Andrea Mattevi (ORCID: https://orcid.org/0000-0002-9523-7128)
- Jonathan D. Gilthorpe (ORCID: https://orcid.org/0000-0002-6884-4774)
- Weiyi Lai (ORCID: https://orcid.org/0000-0002-8010-2490)
- Ángel Román (ORCID: https://orcid.org/0000-0002-5868-6768)
- Trinh T. T. Phan
- Sandhya Malla (ORCID: https://orcid.org/0000-0001-9103-844X)
- Devi Prasad Bhattarai (ORCID: https://orcid.org/0000-0001-9659-4613)
- André Mateus (ORCID: https://orcid.org/0000-0001-6870-0677)
- Cong Lyu (ORCID: https://orcid.org/0000-0002-2474-830X)
- Simone Sidoli (ORCID: https://orcid.org/0000-0001-9073-6641)
- Ludvig Lizana (ORCID: https://orcid.org/0000-0003-3174-8145)
- Stephanie Stransky (ORCID: https://orcid.org/0000-0003-0844-2754)
- Claudio Cantù (ORCID: https://orcid.org/0000-0003-1547-5415)
- Dung‐Fang Lee (ORCID: https://orcid.org/0000-0003-2387-597X)
- Eshagh Dorafshan
- Carlos A. García‐Prieto (ORCID: https://orcid.org/0000-0001-5021-6916)
- Anna Nordin (ORCID: https://orcid.org/0000-0002-5868-4797)
- Francesca Aguiló (ORCID: https://orcid.org/0000-0002-2374-2045)
- Paulina Avovome Saiki
- Hailin Wang (ORCID: https://orcid.org/0000-0002-1843-999X)
- Damiana Álvarez‐Errico
Institutions
- Linköping University (SE)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Albert Einstein College of Medicine (US)
- The University of Texas MD Anderson Cancer Center (US)
- Chinese Academy of Sciences (CN)
- University of Pavia (IT)
- Barcelona Supercomputing Center (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- Brown Foundation (US)
- Research Center for Eco-Environmental Sciences (CN)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Universitat de Barcelona (ES)
- Universidad de Extremadura (ES)
- Umeå University (SE)
- The University of Texas Health Science Center at Houston (US)
- Universitat Politècnica de Catalunya (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-05
- DOI
- https://doi.org/10.1038/s41467-024-51966-7
- Citations
- 17
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 3.97
Funders
- Cancer Prevention and Research Institute of Texas
- Kempe Foundation
- Cancerfonden
- Västerbotten Läns Landsting
- Lunds Universitet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Umeå Universitet
- National Institutes of Health