Journal
CELL
Volume 171, Issue 3, Pages 573-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.09.018
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Funding
- NIH [RO1 HL131611, R01 HL071546, K08 HL119553, 5 T32 GM-007170, T32 HL007954-13, K99/R00 DK099443, R01 DK111436, R37 DK43806]
- Cotswold Foundation
- WW Smith endowed chair
- Spain Fund for Cardiovascular Research
- WW Smith Foundation
- Burroughs Welcome Career Award for Medical Scientists
- NSF [CMMI-1548571]
- Div Of Civil, Mechanical, & Manufact Inn
- Directorate For Engineering [1548571] Funding Source: National Science Foundation
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Progenitor cells differentiate into specialized cell types through coordinated expression of lineagespecific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin, and independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina. Deletion of Hdac3 in cardiac progenitor cells releases genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes; in contrast, restricting Hdac3 to the nuclear periphery rescues myogenesis in progenitors otherwise lacking Hdac3. Our results suggest that availability of genomic regions for activation by lineage-specific factors is regulated in part through dynamic chromatin-nuclear lamina interactions and that competence of a progenitor cell to respond to differentiation signals may depend upon coordinated movement of responding gene loci away from the nuclear periphery.
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