Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals

Abstract

In female mammals one of the X chromosomes is rendered almost completely transcriptionally inactive to equalize expression of X-linked genes in males and females. The inactive X chromosome is distinguished from its active counterpart by its condensed appearance in interphase nuclei, late replication, altered DNA methylation, hypoacetylation of histone H4, and by transcription of a large cis-acting nuclear RNA called Xist. Although it is believed that the inactivation process involves the association of specific protein(s) with the chromatin of the inactive X, no such proteins have been identified. We discovered a new gene family encoding a core histone which we called macroH2A (mH2A). The amino-terminal third of mH2A proteins is similar to a full-length histone H2A, but the remaining two-thirds is unrelated to any known histones. Here we show that an mH2A1 subtype is preferentially concentrated in the inactive X chromosome of female mammals. Our results link X inactivation with a major alteration of the nucleosome, the primary structural unit of chromatin.

Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging

“…MacroH2As contain an N-terminal histone H2A-like domain and a Cterminal "macro domain" of more than 200 residues that is unrelated to other histones. MacroH2A clearly contributes to gene silencing, since it is inserted into the inactive X chromosome (23,27,28) and macroH2A-containing chromatin is resistant to ATP-dependent remodeling proteins and binding of transcription factors in vitro (4).…”

Heterochromatin and its Relationship to Cell Senescence and Cancer Therapy

“…MacroH2As contain an N-terminal histone H2A-like domain and a C-terminal "macro domain" of more than 200 residues that is unrelated to other histones. MacroH2A clearly contributes to gene silencing, since it is depleted from active genes, 39 inserted into the inactive X chromosome [39][40][41][42][43] and macroH2A-containing chromatin is resistant to ATP-dependent remodeling proteins and binding of transcription factors in vitro and in vivo. [44][45][46] Moreover, genetic inactivation of macroH2A1.1 and 1.2 in mice caused increased expression of some genes that are normally enriched in macroH2A1.1 and 1.2 and silenced.…”

The Mitotic Protein Kinase Haspin and Its Inhibitors

“…Histone macroH2A is an histone variant found enriched on inactive X chromosome of female mammals [20]. Several studies demonstrated that histone macroH2A functions both as a positive and a negative regulator of gene transcription.…”