Journal
JOURNAL OF CELL BIOLOGY
Volume 194, Issue 3, Pages 407-423Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201012049
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Funding
- National Institutes of Health (NIH) [HL70748, HL080111, DK077967]
- Laubisch and Cardiovascular Development funds
- Larry Hillblom Foundation [2007-D-003-NET]
- NIH-National Center for Research Resources [CJX1-443835-WS-29646]
- National Science Foundation [CHE-0722519]
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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-gamma to promoters was lost. Depleting HP1-gamma 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-gamma to direct heterochromatin formation and silencing of proliferation-promoting genes.
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