The Scaffolding Function of LSD1 Controls DNA Methylation in Mouse ESCs

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Sep 5

PMID 39237615

Authors

Sandhya Malla

Kanchan Kumari

Carlos A Garcia-Prieto

Jonatan Caroli

Anna Nordin

Trinh T T Phan

Devi Prasad Bhattarai

Carlos Martinez-Gamero

Eshagh Dorafshan

Stephanie Stransky

Damiana Alvarez-Errico

Paulina Avovome Saiki

Weiyi Lai

Cong Lyu

Ludvig Lizana

Jonathan D Gilthorpe

Hailin Wang

Simone Sidoli

Andre Mateus

Dung-Fang Lee

Claudio Cantu

Manel Esteller

Andrea Mattevi

Angel-Carlos Roman

Francesca Aguilo

Affiliations

Soon will be listed here.

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 (LSD1) 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 results in decreased DNMT1 and UHRF1 proteins coupled to global hypomethylation. We show that both LSD1 and LSD1 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.

Citing Articles

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Cooperative role of LSD1 and CHD7 in regulating differentiation of mouse embryonic stem cells.

Malla S, Martinez-Gamero C, Kumari K, Achour C, Mermelekas G, Martinez-Delgado D Sci Rep. 2024; 14(1):28495.

PMID: 39557885 PMC: 11574112. DOI: 10.1038/s41598-024-78920-3.

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