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
Departments of Medicine and Cell and Developmental Biology, Institute for Regenerative Medicine, and the Penn Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Cell, Developmental, and Regenerative Biology, Mindich Child Health and Development Institute, and Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Cell. 2017 Oct 19;171(3):573-587.e14. doi: 10.1016/j.cell.2017.09.018. Epub 2017 Oct 12.
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.
祖细胞通过谱系特异性基因的协调表达和复杂染色质构型的修饰分化为特定的细胞类型。我们证明，一种组蛋白脱乙酰酶（Hdac3）在心脏祖细胞谱系限制过程中在核纤层组织异染色质。心肌细胞的特化与外周异染色质的重组相关，并且独立于脱乙酰酶活性，Hdac3将含有谱系相关基因的外周异染色质拴系到核纤层。心脏祖细胞中Hdac3的缺失使基因组区域从核周边释放，导致心脏基因的早熟表达并分化为心肌细胞；相反，将Hdac3限制在核周边可挽救原本缺乏Hdac3的祖细胞中的肌生成。我们的结果表明，谱系特异性因子激活基因组区域的可用性部分通过动态染色质-核纤层相互作用来调节，并且祖细胞对分化信号作出反应的能力可能取决于响应基因位点远离核周边的协调运动。
