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DNA methylation safeguards the generation of hematopoietic stem and progenitor cells by repression of Notch signaling

The earliest hematopoietic stem and progenitor cells (HSPCs) are generated from the ventral wall of the dorsal aorta, through endothelial-to-hematopoietic transition during vertebrate embryogenesis. Notch signaling is crucial for HSPC generation across vertebrates; however, the precise control of No...

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Autores principales: Li, Yan, Tang, Chao, Liu, Fan, Zhu, Caiying, Liu, Feng, Zhu, Ping, Wang, Lu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9188753/
https://www.ncbi.nlm.nih.gov/pubmed/35502759
http://dx.doi.org/10.1242/dev.200390
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author Li, Yan
Tang, Chao
Liu, Fan
Zhu, Caiying
Liu, Feng
Zhu, Ping
Wang, Lu
author_facet Li, Yan
Tang, Chao
Liu, Fan
Zhu, Caiying
Liu, Feng
Zhu, Ping
Wang, Lu
author_sort Li, Yan
collection PubMed
description The earliest hematopoietic stem and progenitor cells (HSPCs) are generated from the ventral wall of the dorsal aorta, through endothelial-to-hematopoietic transition during vertebrate embryogenesis. Notch signaling is crucial for HSPC generation across vertebrates; however, the precise control of Notch during this process remains unclear. In the present study, we used multi-omics approaches together with functional assays to assess global DNA methylome dynamics during the endothelial cells to HSPCs transition in zebrafish, and determined that DNA methyltransferase 1 (Dnmt1) is essential for HSPC generation via repression of Notch signaling. Depletion of dnmt1 resulted in decreased DNA methylation levels and impaired HSPC production. Mechanistically, we found that loss of dnmt1 induced hypomethylation of Notch genes and consequently elevated Notch activity in hemogenic endothelial cells, thereby repressing the generation of HSPCs. This finding deepens our understanding of HSPC specification in vivo, which will provide helpful insights for designing new strategies for HSPC generation in vitro.
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spelling pubmed-91887532022-07-01 DNA methylation safeguards the generation of hematopoietic stem and progenitor cells by repression of Notch signaling Li, Yan Tang, Chao Liu, Fan Zhu, Caiying Liu, Feng Zhu, Ping Wang, Lu Development Stem Cells and Regeneration The earliest hematopoietic stem and progenitor cells (HSPCs) are generated from the ventral wall of the dorsal aorta, through endothelial-to-hematopoietic transition during vertebrate embryogenesis. Notch signaling is crucial for HSPC generation across vertebrates; however, the precise control of Notch during this process remains unclear. In the present study, we used multi-omics approaches together with functional assays to assess global DNA methylome dynamics during the endothelial cells to HSPCs transition in zebrafish, and determined that DNA methyltransferase 1 (Dnmt1) is essential for HSPC generation via repression of Notch signaling. Depletion of dnmt1 resulted in decreased DNA methylation levels and impaired HSPC production. Mechanistically, we found that loss of dnmt1 induced hypomethylation of Notch genes and consequently elevated Notch activity in hemogenic endothelial cells, thereby repressing the generation of HSPCs. This finding deepens our understanding of HSPC specification in vivo, which will provide helpful insights for designing new strategies for HSPC generation in vitro. The Company of Biologists Ltd 2022-05-25 /pmc/articles/PMC9188753/ /pubmed/35502759 http://dx.doi.org/10.1242/dev.200390 Text en © 2022. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Stem Cells and Regeneration
Li, Yan
Tang, Chao
Liu, Fan
Zhu, Caiying
Liu, Feng
Zhu, Ping
Wang, Lu
DNA methylation safeguards the generation of hematopoietic stem and progenitor cells by repression of Notch signaling
title DNA methylation safeguards the generation of hematopoietic stem and progenitor cells by repression of Notch signaling
title_full DNA methylation safeguards the generation of hematopoietic stem and progenitor cells by repression of Notch signaling
title_fullStr DNA methylation safeguards the generation of hematopoietic stem and progenitor cells by repression of Notch signaling
title_full_unstemmed DNA methylation safeguards the generation of hematopoietic stem and progenitor cells by repression of Notch signaling
title_short DNA methylation safeguards the generation of hematopoietic stem and progenitor cells by repression of Notch signaling
title_sort dna methylation safeguards the generation of hematopoietic stem and progenitor cells by repression of notch signaling
topic Stem Cells and Regeneration
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9188753/
https://www.ncbi.nlm.nih.gov/pubmed/35502759
http://dx.doi.org/10.1242/dev.200390
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