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 grow...

Full description

Bibliographic Details
Authors: Malla, Sandhya, Kumari, Kanchan, García-Prieto, Carlos A.|||0000-0001-5021-6916, Caroli, Jonatan, Nordin, Anna|||0000-0002-5868-4797, Phan, Trinh T.T.|||0000-0002-5850-0855, Bhattarai, Devi Prasad, Martinez-Gamero, Carlos, Dorafshan, Eshagh, Stransky, Stephanie|||0000-0003-0844-2754, Álvarez-Errico, Damiana|||0000-0002-7921-5164, Saiki, Paulina Avovome, Lai, Weiyi, Lyu, Cong, Lizana, Ludvig|||0000-0003-3174-8145, Gilthorpe, Jonathan D.|||0000-0002-6884-4774, Wang, Hailin|||0000-0002-1843-999X, Sidoli, Simone|||0000-0001-9073-6641, Mateus, Andre|||0000-0001-6870-0677, Lee, Dung-Fang Lee|||0000-0003-2387-597X, Cantù, Claudio|||0000-0003-1547-5415, Esteller, M.|||0000-0003-4490-6093, Mattevi, Andrea|||0000-0002-9523-7128, Roman, Angel-Carlos, Aguilo, Francesca|||0000-0002-2374-2045
Format: article
Publication Date:2024
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:309327
Online Access:https://ddd.uab.cat/record/309327
https://dx.doi.org/urn:doi:10.1038/s41467-024-51966-7
Access Level:Open access
Keyword:Animals
CCAAT-Enhancer-Binding Proteins
Cell Differentiation
Cell Proliferation
DNA (Cytosine-5-)-Methyltransferase 1
DNA Methylation
Histone Deacetylase 1
Histone Demethylases
Histones
Mice
Mice, Knockout
Mouse Embryonic Stem Cells
Ubiquitin-Protein Ligases
Ubiquitination
Description
Summary: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.

Similar Items