title: Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes.
abstract: The mammalian heart loses its regenerative potential soon after birth. Adult cardiac myocytes (ACMs) permanently exit the cell cycle, and E2F-dependent genes are stably silenced, although the underlying mechanism is unclear. Heterochromatin, which silences genes in many biological contexts, accumulates with cardiac differentiation. H3K9me3, a histone methylation characteristic of heterochromatin, also increases in ACMs and at E2F-dependent promoters. We hypothesize that genes relevant for cardiac proliferation are targeted to heterochromatin by retinoblastoma (Rb) family members interacting with E2F transcription factors and recruiting heterochromatin protein 1 (HP1) proteins. To test this hypothesis, we created cardiac-specific Rb and p130 inducible double knockout (IDKO) mice. IDKO ACMs showed a decrease in total heterochromatin, and cell cycle genes were derepressed, leading to proliferation of ACMs. Although Rb/p130 deficiency had no effect on total H3K9me3 levels, recruitment of HP1-γ to promoters was lost. Depleting HP1-γ up-regulated proliferation-promoting genes in ACMs. Thus, Rb and p130 have overlapping roles in maintaining the postmitotic state of ACMs through their interaction with HP1-γ to direct heterochromatin formation and silencing of proliferation-promoting genes.
authors.affiliation: Cardiovascular Research Laboratory, Department of Medicine and Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Patima
authors.initials: P
authors.lastname: Sdek
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Yaping
authors.initials: Y
authors.lastname: Wang
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Huang
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Ko
authors.forename: Peter C
authors.initials: PC
authors.lastname: Butler
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.forename: W Robb
authors.initials: WR
authors.lastname: Maclellan
mesh_terms: D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D050684:E2F Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D016161:Genes, Retinoblastoma / Q000235:genetics; D006570:Heterochromatin; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D050684:E2F Transcription Factors; D006570:Heterochromatin; D034741:RNA, Small Interfering; C493838:Rbl2 protein, mouse; D016160:Retinoblastoma Protein; D050717:Retinoblastoma-Like Protein p130; D000090266:Chromobox Protein Homolog 5; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse