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Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis

Mammalian erythroid development can be divided into three stages: hematopoietic stem and progenitor cell (HSPC), erythroid progenitor (Ery-Pro), and erythroid precursor (Ery-Pre). However, the mechanisms by which the 3D genome changes to establish the stage-specific transcription programs that are c...

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Autores principales: Li, Dong, Zhao, Xin-Ying, Zhou, Shuo, Hu, Qi, Wu, Fan, Lee, Hsiang-Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10359633/
https://www.ncbi.nlm.nih.gov/pubmed/37254808
http://dx.doi.org/10.1093/nar/gkad468
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author Li, Dong
Zhao, Xin-Ying
Zhou, Shuo
Hu, Qi
Wu, Fan
Lee, Hsiang-Ying
author_facet Li, Dong
Zhao, Xin-Ying
Zhou, Shuo
Hu, Qi
Wu, Fan
Lee, Hsiang-Ying
author_sort Li, Dong
collection PubMed
description Mammalian erythroid development can be divided into three stages: hematopoietic stem and progenitor cell (HSPC), erythroid progenitor (Ery-Pro), and erythroid precursor (Ery-Pre). However, the mechanisms by which the 3D genome changes to establish the stage-specific transcription programs that are critical for erythropoiesis remain unclear. Here, we analyze the chromatin landscape at multiple levels in defined populations from primary human erythroid culture. While compartments and topologically associating domains remain largely unchanged, ∼50% of H3K27Ac-marked enhancers are dynamic in HSPC versus Ery-Pre. The enhancer anchors of enhancer–promoter loops are enriched for occupancy of respective stage-specific transcription factors (TFs), indicating these TFs orchestrate the enhancer connectome rewiring. The master TF of erythropoiesis, GATA1, is found to occupy most erythroid gene promoters at the Ery-Pro stage, and mediate conspicuous local rewiring through acquiring binding at the distal regions in Ery-Pre, promoting productive erythroid transcription output. Knocking out GATA1 binding sites precisely abrogates local rewiring and corresponding gene expression. Interestingly, knocking down GATA1 can transiently revert the cell state to an earlier stage and prolong the window of progenitor state. This study reveals mechanistic insights underlying chromatin rearrangements during development by integrating multidimensional chromatin landscape analyses to associate with transcription output and cellular states.
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spelling pubmed-103596332023-07-22 Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis Li, Dong Zhao, Xin-Ying Zhou, Shuo Hu, Qi Wu, Fan Lee, Hsiang-Ying Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Mammalian erythroid development can be divided into three stages: hematopoietic stem and progenitor cell (HSPC), erythroid progenitor (Ery-Pro), and erythroid precursor (Ery-Pre). However, the mechanisms by which the 3D genome changes to establish the stage-specific transcription programs that are critical for erythropoiesis remain unclear. Here, we analyze the chromatin landscape at multiple levels in defined populations from primary human erythroid culture. While compartments and topologically associating domains remain largely unchanged, ∼50% of H3K27Ac-marked enhancers are dynamic in HSPC versus Ery-Pre. The enhancer anchors of enhancer–promoter loops are enriched for occupancy of respective stage-specific transcription factors (TFs), indicating these TFs orchestrate the enhancer connectome rewiring. The master TF of erythropoiesis, GATA1, is found to occupy most erythroid gene promoters at the Ery-Pro stage, and mediate conspicuous local rewiring through acquiring binding at the distal regions in Ery-Pre, promoting productive erythroid transcription output. Knocking out GATA1 binding sites precisely abrogates local rewiring and corresponding gene expression. Interestingly, knocking down GATA1 can transiently revert the cell state to an earlier stage and prolong the window of progenitor state. This study reveals mechanistic insights underlying chromatin rearrangements during development by integrating multidimensional chromatin landscape analyses to associate with transcription output and cellular states. Oxford University Press 2023-05-31 /pmc/articles/PMC10359633/ /pubmed/37254808 http://dx.doi.org/10.1093/nar/gkad468 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Gene regulation, Chromatin and Epigenetics
Li, Dong
Zhao, Xin-Ying
Zhou, Shuo
Hu, Qi
Wu, Fan
Lee, Hsiang-Ying
Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis
title Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis
title_full Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis
title_fullStr Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis
title_full_unstemmed Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis
title_short Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis
title_sort multidimensional profiling reveals gata1-modulated stage-specific chromatin states and functional associations during human erythropoiesis
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10359633/
https://www.ncbi.nlm.nih.gov/pubmed/37254808
http://dx.doi.org/10.1093/nar/gkad468
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