Differentially methylated forms of histone H3 show unique association patterns with inactive human X chromosomes

Abstract

Studies of histone methylation have shown that H3 can be methylated at lysine 4 (Lys4) or lysine 9 (Lys9). Whereas H3-Lys4 methylation has been correlated with active gene expression, H3-Lys9 methylation has been linked to gene silencing and assembly of heterochromatin in mouse and Schizosaccharomyces pombe. The chromodomain of mouse HP1 (and Swi6 in S. pombe) binds H3 methylated at Lys9, and methylation at this site is thought to mark and promote heterochromatin assembly. We have used a well-studied model of mammalian epigenetic silencing, the human inactive X chromosome, to show that enrichment for H3 methylated at Lys9 is also a distinguishing mark of facultative heterochromatin. In contrast, H3 methylated at Lys4 is depleted in the inactive X chromosome, except in three 'hot spots' of enrichment along its length. Chromatin immunoprecipitation analyses further show that Lys9 methylation is associated with promoters of inactive genes, whereas Lys4 methylation is associated with active genes on the X chromosome. These data demonstrate that differential methylation at two distinct sites of the H3 amino terminus correlates with contrasting gene activities and may be part of a 'histone code' involved in establishing and maintaining facultative heterochromatin.

Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

“…In contrast, methylation of lysine 9 of H3 is a marker of condensed, inactive chromatin of the sort associated with the inactive X-chromosome and pericentromeric heterochromatin. [48][49][50][51] There is a report that cancer cells have increased overall levels of deacetylation of the known histone target of SIRT1, H4-K16. 52 Moreover, a recent study also suggested that global histone modification in prostate cancer, including acetylation of H3K18 and H4K12, dimethylation of H3K4 and H4R3 and acetylation of H3K9, a target of SIRT1, 53 predict a risk of prostate cancer recurrence.…”

Specific patterns of histone marks accompany X chromosome inactivation in a marsupial

“…In humans and mice, histone H3 dimethylated at lysine 4 (H3K4me2) has been shown to be distributed throughout most of the interphase nucleus as well as on metaphase chromosomes, but to be absent from the inactive X chromosome (Heard et al 2001;Boggs et al 2002;Chaumeil et al 2002). However, three H3K4me2 hotspots can still be observed on the inactive human X (Boggs et al 2002).…”

“…Profile of active histone marks on the marsupial inactive X chromosome In humans and mice, the inactive X is depleted in histone H3 dimethylated at lysine 4 (H3K4me2), as well as in acetylated H3 and H4, three histone modifications that are associated with active chromatin (Jeppesen and Turner 1993;Heard et al 2001;Boggs et al 2002;Chaumeil et al 2002;Okamoto et al 2004). We performed immunofluorescences on metaphase spreads in order to investigate their status on the marsupial inactive X chromosome (n=20 for each of the 3 independent experiments done).…”

“…However, three H3K4me2 hotspots can still be observed on the inactive human X (Boggs et al 2002). These correspond to the pseudo-autosomal region (PAR) Fig.…”

Genome imprinting regulated by the mouse Polycomb group protein Eed

“…Additionally, recent studies have shown correlations between covalent histone modifications and the transcriptional status of imprinted alleles 5 . In particular, methylation of histone H3 has been associated with the inactive X chromosome 6 .…”