Regulation of chromatin accessibility by the histone chaperone CAF-1 sustains lineage fidelity

Cell fate commitment is driven by dynamic changes in chromatin architecture and activity of lineage-specific transcription factors (TFs). The chromatin assembly factor-1 (CAF-1) is a histone chaperone that regulates chromatin architecture by facilitating nucleosome assembly during DNA replication. A...

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Published in:	Nature communications Vol. 13; no. 1; pp. 2350 - 17
Main Authors:	Franklin, Reuben, Guo, Yiming, He, Shiyang, Chen, Meijuan, Ji, Fei, Zhou, Xinyue, Frankhouser, David, Do, Brian T., Chiem, Carmen, Jang, Mihyun, Blanco, M. Andres, Vander Heiden, Matthew G., Rockne, Russell C., Ninova, Maria, Sykes, David B., Hochedlinger, Konrad, Lu, Rui, Sadreyev, Ruslan I., Murn, Jernej, Volk, Andrew, Cheloufi, Sihem
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 29-04-2022 Nature Publishing Group Nature Portfolio
Subjects:	13/100 13/106 13/31 38 38/15 38/39 38/89 38/91 45 631/208/176/2016 631/337/100/102 631/532/1360 631/532/1542 64 64/60 Accessibility Accuracy Assembly Biology Blood Bone marrow Cancer Cell fate Cells (biology) Chromatin Chromatin Assembly Factor-1 - genetics Chromatin Assembly Factor-1 - metabolism Chromatin remodeling Chromosomes - metabolism Cloning Differentiation DNA biosynthesis Fidelity Granulocytes Hematology Histone Chaperones - metabolism Histones Histones - metabolism Humanities and Social Sciences multidisciplinary Progenitor cells Regulatory sequences Science Science (multidisciplinary) Stem cells Stems Transcription factors
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Summary:	Cell fate commitment is driven by dynamic changes in chromatin architecture and activity of lineage-specific transcription factors (TFs). The chromatin assembly factor-1 (CAF-1) is a histone chaperone that regulates chromatin architecture by facilitating nucleosome assembly during DNA replication. Accumulating evidence supports a substantial role of CAF-1 in cell fate maintenance, but the mechanisms by which CAF-1 restricts lineage choice remain poorly understood. Here, we investigate how CAF-1 influences chromatin dynamics and TF activity during lineage differentiation. We show that CAF-1 suppression triggers rapid differentiation of myeloid stem and progenitor cells into a mixed lineage state. We find that CAF-1 sustains lineage fidelity by controlling chromatin accessibility at specific loci, and limiting the binding of ELF1 TF at newly-accessible diverging regulatory elements. Together, our findings decipher key traits of chromatin accessibility that sustain lineage integrity and point to a powerful strategy for dissecting transcriptional circuits central to cell fate commitment. Cell fate commitment involves transcription factor activity and changes in chromatin architecture. Here the authors show that CAF-1 maintains lineage fidelity by controlling chromatin accessibility at specific sites; suppressing CAF-1 triggers differentiation of myeloid stem and progenitor cells into a mixed lineage state.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-022-29730-6