Epigenetic mechanisms in cardiac development and disease  

作　　者：Marcus Vallaster Caroline Dacwag Vallaster Sean M.Wu 

机构地区：[1]Cardiovascular Research Center,Massachusetts General Hospital,Boston,MA 02114,USA [2]Harvard Medical School,Boston,MA 02115,USA [3]Harvard Stem Cell Institute,Cambridge,MA 02138,USA

出　　处：《Acta Biochimica et Biophysica Sinica》2012年第1期92-102,共11页生物化学与生物物理学报（英文版）

摘　　要：During mammalian development, cardiac specification and ultimately lineage commitment to a specific cardiac cell type is accomplished by the action of specific tran- scription factors （TFs） and their meticulous control on an epigenetic level. In this review, we detail how cardiacspecific TFs function in concert with nucleosome remodel- ing and histone-modifying enzymes to regulate a diverse network of genes required for processes such as cell growth and proliferation, or epithelial to mesenchymal transition （EMT）, for instance. We provide examples of how several cardiac TFs, such as Nkx2.5, WHSC1, Tbx5, and Tbxl, which are associated with developmental and congenital heart defects, are required for the recruitment of histone modifiers, such as Jarid2, p300, and Ash21, and components of ATP-dependent remodeling enzymes like Brgl, Baf60c, and Bafl80. Binding of these TFs to their respective sites at cardiac genes coincides with a distinct pattern of histone marks, indicating that the precise regu- lation of cardiac gene networks is orchestrated by interactions between TFs and epigenetic modifiers. Furthermore, we speculate that an epigenetic signature, comprised of TF occupancy, histone modifications, and overall chromatin organization, is an underlying mechanism that governs cardiac morphogenesis and disease.During mammalian development, cardiac specification and ultimately lineage commitment to a specific cardiac cell type is accomplished by the action of specific tran- scription factors （TFs） and their meticulous control on an epigenetic level. In this review, we detail how cardiacspecific TFs function in concert with nucleosome remodel- ing and histone-modifying enzymes to regulate a diverse network of genes required for processes such as cell growth and proliferation, or epithelial to mesenchymal transition （EMT）, for instance. We provide examples of how several cardiac TFs, such as Nkx2.5, WHSC1, Tbx5, and Tbxl, which are associated with developmental and congenital heart defects, are required for the recruitment of histone modifiers, such as Jarid2, p300, and Ash21, and components of ATP-dependent remodeling enzymes like Brgl, Baf60c, and Bafl80. Binding of these TFs to their respective sites at cardiac genes coincides with a distinct pattern of histone marks, indicating that the precise regu- lation of cardiac gene networks is orchestrated by interactions between TFs and epigenetic modifiers. Furthermore, we speculate that an epigenetic signature, comprised of TF occupancy, histone modifications, and overall chromatin organization, is an underlying mechanism that governs cardiac morphogenesis and disease.

关 键 词：EPIGENETICS histone modifications DNAMETHYLATION congenital heart disease 

分 类 号：Q344.5[生物学—遗传学] Q943