Cargando…

Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function

Tight control of cell fate choices is crucial for normal development. Here we show that lamin A/C plays a key role in chromatin organization in embryonic stem cells (ESCs), which safeguards naïve pluripotency and ensures proper cell fate choices during cardiogenesis. We report changes in chromatin c...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Yinuo, Elsherbiny, Adel, Kessler, Linda, Cordero, Julio, Shi, Haojie, Serke, Heike, Lityagina, Olga, Trogisch, Felix A., Mohammadi, Mona Malek, El-Battrawy, Ibrahim, Backs, Johannes, Wieland, Thomas, Heineke, Joerg, Dobreva, Gergana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636150/
https://www.ncbi.nlm.nih.gov/pubmed/36333314
http://dx.doi.org/10.1038/s41467-022-34366-7
_version_ 1784824873673031680
author Wang, Yinuo
Elsherbiny, Adel
Kessler, Linda
Cordero, Julio
Shi, Haojie
Serke, Heike
Lityagina, Olga
Trogisch, Felix A.
Mohammadi, Mona Malek
El-Battrawy, Ibrahim
Backs, Johannes
Wieland, Thomas
Heineke, Joerg
Dobreva, Gergana
author_facet Wang, Yinuo
Elsherbiny, Adel
Kessler, Linda
Cordero, Julio
Shi, Haojie
Serke, Heike
Lityagina, Olga
Trogisch, Felix A.
Mohammadi, Mona Malek
El-Battrawy, Ibrahim
Backs, Johannes
Wieland, Thomas
Heineke, Joerg
Dobreva, Gergana
author_sort Wang, Yinuo
collection PubMed
description Tight control of cell fate choices is crucial for normal development. Here we show that lamin A/C plays a key role in chromatin organization in embryonic stem cells (ESCs), which safeguards naïve pluripotency and ensures proper cell fate choices during cardiogenesis. We report changes in chromatin compaction and localization of cardiac genes in Lmna−/− ESCs resulting in precocious activation of a transcriptional program promoting cardiomyocyte versus endothelial cell fate. This is accompanied by premature cardiomyocyte differentiation, cell cycle withdrawal and abnormal contractility. Gata4 is activated by lamin A/C loss and Gata4 silencing or haploinsufficiency rescues the aberrant cardiovascular cell fate choices induced by lamin A/C deficiency. We uncover divergent functions of lamin A/C in naïve pluripotent stem cells and cardiomyocytes, which have distinct contributions to the transcriptional alterations of patients with LMNA-associated cardiomyopathy. We conclude that disruption of lamin A/C-dependent chromatin architecture in ESCs is a primary event in LMNA loss-of-function cardiomyopathy.
format Online
Article
Text
id pubmed-9636150
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-96361502022-11-06 Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function Wang, Yinuo Elsherbiny, Adel Kessler, Linda Cordero, Julio Shi, Haojie Serke, Heike Lityagina, Olga Trogisch, Felix A. Mohammadi, Mona Malek El-Battrawy, Ibrahim Backs, Johannes Wieland, Thomas Heineke, Joerg Dobreva, Gergana Nat Commun Article Tight control of cell fate choices is crucial for normal development. Here we show that lamin A/C plays a key role in chromatin organization in embryonic stem cells (ESCs), which safeguards naïve pluripotency and ensures proper cell fate choices during cardiogenesis. We report changes in chromatin compaction and localization of cardiac genes in Lmna−/− ESCs resulting in precocious activation of a transcriptional program promoting cardiomyocyte versus endothelial cell fate. This is accompanied by premature cardiomyocyte differentiation, cell cycle withdrawal and abnormal contractility. Gata4 is activated by lamin A/C loss and Gata4 silencing or haploinsufficiency rescues the aberrant cardiovascular cell fate choices induced by lamin A/C deficiency. We uncover divergent functions of lamin A/C in naïve pluripotent stem cells and cardiomyocytes, which have distinct contributions to the transcriptional alterations of patients with LMNA-associated cardiomyopathy. We conclude that disruption of lamin A/C-dependent chromatin architecture in ESCs is a primary event in LMNA loss-of-function cardiomyopathy. Nature Publishing Group UK 2022-11-04 /pmc/articles/PMC9636150/ /pubmed/36333314 http://dx.doi.org/10.1038/s41467-022-34366-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wang, Yinuo
Elsherbiny, Adel
Kessler, Linda
Cordero, Julio
Shi, Haojie
Serke, Heike
Lityagina, Olga
Trogisch, Felix A.
Mohammadi, Mona Malek
El-Battrawy, Ibrahim
Backs, Johannes
Wieland, Thomas
Heineke, Joerg
Dobreva, Gergana
Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function
title Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function
title_full Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function
title_fullStr Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function
title_full_unstemmed Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function
title_short Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function
title_sort lamin a/c-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636150/
https://www.ncbi.nlm.nih.gov/pubmed/36333314
http://dx.doi.org/10.1038/s41467-022-34366-7
work_keys_str_mv AT wangyinuo laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT elsherbinyadel laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT kesslerlinda laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT corderojulio laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT shihaojie laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT serkeheike laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT lityaginaolga laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT trogischfelixa laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT mohammadimonamalek laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT elbattrawyibrahim laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT backsjohannes laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT wielandthomas laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT heinekejoerg laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction
AT dobrevagergana laminacdependentchromatinarchitecturesafeguardsnaivepluripotencytopreventaberrantcardiovascularcellfateandfunction