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

Reuben Franklin, Yiming Guo, Shiyang He, Meijuan Chen, Fei Ji, Xinyue Zhou, David Frankhouser, Brian T. Do, Carmen Chiem, Mihyun Jang, M. Andres Blanco, Matthew G. Vander Heiden, Russell C. Rockne, Maria Ninova, David B. Sykes, Konrad Hochedlinger, Rui Lu, Ruslan I. Sadreyev, Jernej Murn (), Andrew Volk () and Sihem Cheloufi ()
Additional contact information
Reuben Franklin: University of California, Riverside
Yiming Guo: University of California, Riverside
Shiyang He: University of California, Riverside
Meijuan Chen: University of California, Riverside
Fei Ji: Massachusetts General Hospital
Xinyue Zhou: O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham
David Frankhouser: Department of Population Sciences City of Hope National Medical Center
Brian T. Do: Massachusetts Institute of Technology
Carmen Chiem: University of California, Riverside
Mihyun Jang: Division of Mathematical Oncology, City of Hope National Medical Center
M. Andres Blanco: University of Pennsylvania
Matthew G. Vander Heiden: Massachusetts Institute of Technology
Russell C. Rockne: Division of Mathematical Oncology, City of Hope National Medical Center
Maria Ninova: University of California, Riverside
David B. Sykes: Massachusetts General Hospital
Konrad Hochedlinger: Massachusetts General Hospital
Rui Lu: O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham
Ruslan I. Sadreyev: Massachusetts General Hospital
Jernej Murn: University of California, Riverside
Andrew Volk: Cincinnati Children’s Hospital Medical Center
Sihem Cheloufi: University of California, Riverside

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29730-6

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