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Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation

Lineage commitment and differentiation is driven by the concerted action of master transcriptional regulators at their target chromatin sites. Multiple efforts have characterized the key transcription factors (TFs) that determine the various hematopoietic lineages. However, the temporal interactions...

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Autores principales: Georgolopoulos, Grigorios, Psatha, Nikoletta, Iwata, Mineo, Nishida, Andrew, Som, Tannishtha, Yiangou, Minas, Stamatoyannopoulos, John A., Vierstra, Jeff
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8611072/
https://www.ncbi.nlm.nih.gov/pubmed/34815405
http://dx.doi.org/10.1038/s41467-021-27159-x
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author Georgolopoulos, Grigorios
Psatha, Nikoletta
Iwata, Mineo
Nishida, Andrew
Som, Tannishtha
Yiangou, Minas
Stamatoyannopoulos, John A.
Vierstra, Jeff
author_facet Georgolopoulos, Grigorios
Psatha, Nikoletta
Iwata, Mineo
Nishida, Andrew
Som, Tannishtha
Yiangou, Minas
Stamatoyannopoulos, John A.
Vierstra, Jeff
author_sort Georgolopoulos, Grigorios
collection PubMed
description Lineage commitment and differentiation is driven by the concerted action of master transcriptional regulators at their target chromatin sites. Multiple efforts have characterized the key transcription factors (TFs) that determine the various hematopoietic lineages. However, the temporal interactions between individual TFs and their chromatin targets during differentiation and how these interactions dictate lineage commitment remains poorly understood. Here we perform dense, daily, temporal profiling of chromatin accessibility (DNase I-seq) and gene expression changes (total RNA-seq) along ex vivo human erythropoiesis to comprehensively define developmentally regulated DNase I hypersensitive sites (DHSs) and transcripts. We link both distal DHSs to their target gene promoters and individual TFs to their target DHSs, revealing that the regulatory landscape is organized in distinct sequential regulatory modules that regulate lineage restriction and maturation. Finally, direct comparison of transcriptional dynamics (bulk and single-cell) and lineage potential between erythropoiesis and megakaryopoiesis uncovers differential fate commitment dynamics between the two lineages as they exit the stem and progenitor stage. Collectively, these data provide insights into the temporally regulated synergy of the cis- and the trans-regulatory components underlying hematopoietic lineage commitment and differentiation.
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spelling pubmed-86110722021-12-01 Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation Georgolopoulos, Grigorios Psatha, Nikoletta Iwata, Mineo Nishida, Andrew Som, Tannishtha Yiangou, Minas Stamatoyannopoulos, John A. Vierstra, Jeff Nat Commun Article Lineage commitment and differentiation is driven by the concerted action of master transcriptional regulators at their target chromatin sites. Multiple efforts have characterized the key transcription factors (TFs) that determine the various hematopoietic lineages. However, the temporal interactions between individual TFs and their chromatin targets during differentiation and how these interactions dictate lineage commitment remains poorly understood. Here we perform dense, daily, temporal profiling of chromatin accessibility (DNase I-seq) and gene expression changes (total RNA-seq) along ex vivo human erythropoiesis to comprehensively define developmentally regulated DNase I hypersensitive sites (DHSs) and transcripts. We link both distal DHSs to their target gene promoters and individual TFs to their target DHSs, revealing that the regulatory landscape is organized in distinct sequential regulatory modules that regulate lineage restriction and maturation. Finally, direct comparison of transcriptional dynamics (bulk and single-cell) and lineage potential between erythropoiesis and megakaryopoiesis uncovers differential fate commitment dynamics between the two lineages as they exit the stem and progenitor stage. Collectively, these data provide insights into the temporally regulated synergy of the cis- and the trans-regulatory components underlying hematopoietic lineage commitment and differentiation. Nature Publishing Group UK 2021-11-23 /pmc/articles/PMC8611072/ /pubmed/34815405 http://dx.doi.org/10.1038/s41467-021-27159-x Text en © The Author(s) 2021 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
Georgolopoulos, Grigorios
Psatha, Nikoletta
Iwata, Mineo
Nishida, Andrew
Som, Tannishtha
Yiangou, Minas
Stamatoyannopoulos, John A.
Vierstra, Jeff
Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation
title Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation
title_full Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation
title_fullStr Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation
title_full_unstemmed Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation
title_short Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation
title_sort discrete regulatory modules instruct hematopoietic lineage commitment and differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8611072/
https://www.ncbi.nlm.nih.gov/pubmed/34815405
http://dx.doi.org/10.1038/s41467-021-27159-x
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