2. Academic Validation
  3. The scaffolding function of LSD1 controls DNA methylation in mouse ESCs

The scaffolding function of LSD1 controls DNA methylation in mouse ESCs

  • Nat Commun. 2024 Sep 5;15(1):7758. doi: 10.1038/s41467-024-51966-7.
Sandhya Malla 1 2,  Kanchan Kumari 1 2,  Carlos A García-Prieto 3 4,  Jonatan Caroli 5,  Anna Nordin 6 7,  Trinh T T Phan 8,  Devi Prasad Bhattarai 1 2,  Carlos Martinez-Gamero 1 2,  Eshagh Dorafshan 1 2,  Stephanie Stransky 9,  Damiana Álvarez-Errico 3,  Paulina Avovome Saiki 1 2,  Weiyi Lai 10,  Cong Lyu 10,  Ludvig Lizana 11,  Jonathan D Gilthorpe 12,  Hailin Wang 10,  Simone Sidoli 9,  Andre Mateus 13 14,  Dung-Fang Lee 8 15 16 17,  Claudio Cantù 6 7,  Manel Esteller 3 18 19 20,  Andrea Mattevi 5,  Angel-Carlos Roman 21,  Francesca Aguilo 22 23
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Umeå University, Umeå, Sweden.
  • 2 Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
  • 3 Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
  • 4 Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona, Spain.
  • 5 Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
  • 6 Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden.
  • 7 Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
  • 8 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 9 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 10 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
  • 11 Department of Physics, Integrated Science Lab, Umeå University, Umeå, Sweden.
  • 12 Department of Medical and Translational Biology, Umeå University, Umeå, Sweden.
  • 13 Department of Chemistry, Umeå University, Umeå, Sweden.
  • 14 The Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå, Sweden.
  • 15 The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 16 Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 17 Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 18 Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain.
  • 19 Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
  • 20 Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain.
  • 21 Department of Biochemistry, Molecular Biology and Genetics, University of Extremadura, Badajoz, Spain.
  • 22 Department of Molecular Biology, Umeå University, Umeå, Sweden. francesca.aguilo@umu.se.
  • 23 Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden. francesca.aguilo@umu.se.
PMID: 39237615 DOI: 10.1038/s41467-024-51966-7
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z