Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes

J Cell Biol. 2011 Aug 8;194(3):407-23. doi: 10.1083/jcb.201012049.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Chromatin
  • Chromobox Protein Homolog 5
  • Chromosomal Proteins, Non-Histone / metabolism
  • E2F Transcription Factors / genetics*
  • E2F Transcription Factors / metabolism*
  • Genes, Retinoblastoma / genetics
  • Heterochromatin
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / physiology*
  • Patch-Clamp Techniques
  • Polymerase Chain Reaction
  • RNA Interference
  • RNA, Small Interfering
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism*
  • Retinoblastoma-Like Protein p130 / genetics
  • Retinoblastoma-Like Protein p130 / metabolism*

Substances

  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • E2F Transcription Factors
  • Heterochromatin
  • RNA, Small Interfering
  • Rbl2 protein, mouse
  • Retinoblastoma Protein
  • Retinoblastoma-Like Protein p130
  • Chromobox Protein Homolog 5
  • Jumonji Domain-Containing Histone Demethylases
  • Kdm6b protein, mouse