Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 38, Pages 23626-23635Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2003228117
Keywords
hematopoiesis; RUNX1; CHD7
Categories
Funding
- NIH [R01 HL089969, R01 HL091724, U01HL100405, R01 HL04880, PPG-P015PO1HL32262-32, 5P30 DK49216, 5R01 DK53298, 5U01 HL10001-05, R24 DK092760, R01 HG002668, 4R00CA148963, 5-T32-HL-007439-34, K12CA076931]
- Intramural Research Program of the National Human Genome Research Institute
- Bloodwise Grant [12029]
- Leukemia and Lymphoma Society [7001-12]
- Cancer Research UK [C1163/A12765]
- MRC Cambridge Stem Cell Institute [097922/Z/11/Z]
- NYSTEM Training Grant [C026880]
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Hematopoietic stem and progenitor cell (HSPC) formation and lineage differentiation involve gene expression programs orchestrated by transcription factors and epigenetic regulators. Genetic disruption of the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7) expanded phenotypic HSPC5, erythroid, and myeloid lineages in zebrafish and mouse embryos. CHD7 acts to suppress hematopoietic differentiation. Binding motifs for RUNX and other hematopoietic transcription factors are enriched at sites occupied by CHD7, and decreased RUNX1 occupancy correlated with loss of CHD7 localization. CHD7 physically interacts with RUNX1 and suppresses RUNX1-induced expansion of HSPC5 during development through modulation of RUNX1 activity. Consequently, the RUNX1:CHD7 axis provides proper timing and function of HSPCs as they emerge during hematopoietic development or mature in adults, representing a distinct and evolutionarily conserved control mechanism to ensure accurate hematopoietic lineage differentiation.
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