Replication-Independent Histone Turnover Underlines the Epigenetic Homeostasis in Adult Heart

Circ Res. 2019 Jul 5;125(2):198-208. doi: 10.1161/CIRCRESAHA.118.314366. Epub 2019 May 20.


Rationale: Replication-independent histone turnover has been linked to cis-regulatory chromatin domains in cultured cell lines, but its molecular underpinnings and functional relevance in adult mammalian tissues remain yet to be defined.

Objective: We investigated regulatory functions of replication-independent histone turnover in chromatin states of postmitotic cardiomyocytes from adult mouse heart.

Methods and results: We used H2B-GFP (histone 2B-green fluorescent protein) fusion protein pulse-and-chase approaches to measure histone turnover rate in mouse cardiomyocytes. Surprisingly, we found that the short histone half-life (≈2 weeks) contrasted dramatically with the long lifetime of cardiomyocytes, and rapid histone turnover regions corresponded to cis-regulatory domains of heart genes. Interestingly, recruitment of chromatin modifiers, including Polycomb EED (embryonic ectoderm development), was positively correlated with histone turnover rate at enhancers. Mechanistically, through directly interacting with and engaging the BAF (BRG1 [Brahma-related gene-1]-associated factor) complex for nucleosome exchange for stereotyped histone modifications from the free histone pool, EED augmented histone turnover to restrain enhancer overactivation.

Conclusions: We propose a model in which replication-independent histone turnover reinforces robustness of local chromatin states for adult tissue homeostasis.

Keywords: chromatin; epigenetics; histone; homeostasis; nucleosomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chromatin Assembly and Disassembly*
  • DNA Helicases / metabolism
  • DNA Replication
  • Epigenesis, Genetic*
  • Female
  • Histone Code*
  • Histones / metabolism*
  • Homeostasis*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / metabolism*
  • Nuclear Proteins / metabolism
  • Polycomb Repressive Complex 2 / metabolism
  • Transcription Factors / metabolism


  • Histones
  • Nuclear Proteins
  • Transcription Factors
  • Polycomb Repressive Complex 2
  • Smarca4 protein, mouse
  • DNA Helicases