Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation

Grigorios Georgolopoulos (), Nikoletta Psatha, Mineo Iwata, Andrew Nishida, Tannishtha Som, Minas Yiangou, John A. Stamatoyannopoulos and Jeff Vierstra ()
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Grigorios Georgolopoulos: Altius Institute for Biomedical Sciences
Nikoletta Psatha: Altius Institute for Biomedical Sciences
Mineo Iwata: Altius Institute for Biomedical Sciences
Andrew Nishida: Altius Institute for Biomedical Sciences
Tannishtha Som: Altius Institute for Biomedical Sciences
Minas Yiangou: School of Biology, Aristotle University of Thessaloniki
John A. Stamatoyannopoulos: Altius Institute for Biomedical Sciences
Jeff Vierstra: Altius Institute for Biomedical Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-27159-x

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