Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction

• Published in: Cell 2017-10, Vol.171 (3), p.573-587.e14
• Main Authors: Poleshko, Andrey, Shah, Parisha P., Gupta, Mudit, Babu, Apoorva, Morley, Michael P., Manderfield, Lauren J., Ifkovits, Jamie L., Calderon, Damelys, Aghajanian, Haig, Sierra-Pagán, Javier E., Sun, Zheng, Wang, Qiaohong, Li, Li, Dubois, Nicole C., Morrisey, Edward E., Lazar, Mitchell A., Smith, Cheryl L., Epstein, Jonathan A., Jain, Rajan
• Format: Article
• Language: English
• Subjects: Animals; cardiac specification; cellular competence; Chromatin - metabolism; Gene Expression Regulation, Developmental; Genome; genome organization; Histone Deacetylases - metabolism; lineage restriction; Mice; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; nuclear lamina; Nuclear Lamina - metabolism; Stem Cells - cytology; Stem Cells - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.09.018

Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific 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. [Display omitted] •Hdac3 retards cardiac progenitor differentiation independent of deacetylase activity•Chromatin-nuclear lamina interactions regulate gene accessibility during development•Gene accessibility may equate to competence of a stem cell to respond to lineage cues•Nuclear architecture provides a distinct layer of gene regulation to impact cell fate Nuclear architecture provides a distinct layer of gene regulation during development, coordinating cell fate determination through changes in chromatin accessibility that are mediated by chromatin-nuclear lamina interactions.