The Histone Variant MacroH2A Interferes with Transcription Factor Binding and SWI/SNF Nucleosome Remodeling

Abstract

The unusual histone variant macroH2A (mH2A) has been associated with repression of transcription, but the molecular mechanisms by which it exerts this function are unknown. Here we have identified a mechanism by which the different domains of mH2A may be involved in the repression of transcription. Evidence is presented that the presence of mH2A in a positioned nucleosome interferes with the binding of the transcription factor NF-kappaB. The nonhistone region of mH2A was identified to be associated with this interference. Importantly, the presence of macroH2A was found to severely impede SWI/SNF nucleosome remodeling and movement to neighboring DNA segments. This property of mH2A was demonstrated to reside only in its H2A-like domain. A hypothesis explaining the role of histone variants in transcriptional regulation is proposed.

Histone chaperones in nucleosome eviction and histone exchange

“…For example, H2A.Z stabilizes the nucleosome [11] [12] and higher order structures [13] in vitro. Histone octamers reconstituted with macroH2A (a histone variant associated with repressive chromatin) appear to be stabilized [14]; and chaperone-mediated removal of macro-H2A-H2B dimers as well as remodeling of nucleosomes is disfavored [15]. H2A.Bbd (a H2A variant generally associated with transcriptionally active chromatin) lacks the carboxy-terminal tail as well as a signature acidic surface.…”

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).…”

The macroPARP genes parp‐9 and parp‐14 are developmentally and differentially regulated in mouse tissues

“…A macro domain is present within the histone variant macroH2A that is associated to transcriptional repression and X chromosome inactivation (Angelov et al, 2003). Interestingly, this domain is able to negatively regulate PARP-1 activity on particular promoters that must remain inactive in the absence of appropriated stimulation or on the inactive X chromosome (Ouararhni et al, 2006;Nusinow et al, 2007).…”