HDAC-mediated suppression of histone turnover promotes epigenetic stability of heterochromatin

Abstract

Heterochromatin causes epigenetic repression that can be transmitted through multiple cell divisions. However, the mechanisms underlying silencing and stability of heterochromatin are not fully understood. We show that heterochromatin differs from euchromatin in histone turnover, and identify histone deacetylase (HDAC) Clr3 as a factor required for inhibiting histone turnover across heterochromatin domains in Schizosaccharomyces pombe. Loss of RNAi factors, Clr4 methyltransferase, or HP1 proteins involved in HDAC localization causes increased histone turnover across pericentromeric domains. Clr3 also affects histone turnover at the silent mating–type region where it can be recruited by alternative mechanisms acting in parallel to H3K9me–HP1. Importantly, the JmjC–domain protein Epe1 promotes histone exchange, and loss of Epe1 suppresses both histone turnover and defects in heterochromatic silencing. Our results suggest that heterochromatic silencing factors preclude histone turnover to promote silencing and inheritance of repressive chromatin.

A nucleosome turnover map reveals that the stability of histone H4 Lys20 methylation depends on histone recycling in transcribed chromatin

“…Also with this ChIP- microarray, although with lower resolution than ChIP-exo, we detected the histones from the RITE system surrounding the NDR with H3-T7 close to promoters and H3-HA inside CDSs. Comparisons with a published data set generated using the pInv-H3 technique (Aygün et al 2013) confirmed the overall similar results between the two histone exchange techniques (pInv-H3 and RITE) and also the incorporation of H3 from the pInv-H3 system at the NDRs (Supplemental Fig. S1F).…”

“…Turnover was particularly low in regions of the genome that translates into proteins (CDS) and was high in nucleosomes immediately flanking NDRs. The stability of nucleosomes in the heterochromatin was previously described (Aygün et al 2013), as was the high turnover of nucleosomes at promoter regions (Guillemette et al 2005;Zhang et al 2005;Jin and Felsenfeld 2007;Rufiange et al 2007). However, this study revealed several new features of nucleosome turnover in transcribed regions.…”

“…Stable nucleosomes that have low histone turnover rates have been found in heterochromatin, marked by H3K9me2 in S. pombe (Aygün et al 2013). Compared to promoter regions, gene bodies show relatively low levels of nucleosome turnover (Dion et al 2007;Jamai et al 2007;Rufiange et al 2007;Skene et al 2014).…”

“…Locus-specific nucleosome turnover is commonly measured by the incorporation of epitope-tagged H3 that is expressed using an inducible promoter (Iacovoni et al 1999;Choi et al 2005;Aygün et al 2013;Kraushaar et al 2013). However, histone expression at nonphysiological levels may be problematic in that histone transcription is normally highly regulated in a cell cycle-dependent manner, and histone expression is extremely low, except during S phase (Rustici et al 2004).…”

Inflammatory factor receptor Toll‐like receptor 4 controls telomeres through heterochromatin protein 1 isoforms in liver cancer stem cell

“…Strikingly, heterochromatic‐silencing factors preclude histone turnover to promote silencing and inheritance of repressive chromatin 40. Particularly, HP1α nucleates with high affinity independently of H3K9me in promoters of active genes and then spreads via H3K9 methylation and transient looping contacts with those H3K9me target sites 41.…”