macroH2A and gene silencing
The most extensive histone modification is the complete exchange of canonical histones for variant ones. Among all known histone variants, the so-called macroH2A is the one that is the most divergent from its canonical histone and is the least understood in its function. In addition to a homologous histone domain, macroH2A possesses a large C-terminal domain of unknown function - the macro domain.
The H2A domain of macroH2A histones is ~65% identical to that of the conventional H2A.
The early observation that macroH2A is enriched on the inactive X chromosome and centrosomes suggested an involvement in gene repression and heterochromatinization. Biochemical studies using synthetic templates have indicated that macroH2A-containing nucleosomes are structurally different in the vicinity of the dyad axis, and this correlates with the inability of transcription factors to bind to DNA sites inserted nearby. These observations suggest that incorporation of macroH2A into nucleosomes could confer an epigenetic mark for gene repression. However, there are no known gene targets for macroH2A-dependent transcriptional repression, and no evidence for the mechanisms by which macroH2A could be recruited to specific genes and repress transcription in vivo.
Our ChIP-on-chip analysis, using Agilent microarray, shows that macroH2A is deposited in the regulatory regions of tumor suppressor genes and genes regulated by Polycomb group in an isoform-specific fashion. We are studying the role of macroH2A in transcriptional regulation of these genes during cell fate decisions and cancer development.