Abstract
Dynamic exchange of a subset of nucleosomes in vivo plays important roles in epigenetic inheritance of chromatin states, chromatin insulator function, chromosome folding, and the maintenance of the pluripotent state of embryonic stem cells. Here, we extend a pulse-chase strategy for carrying out genome-wide measurements of histone dynamics to several histone variants in murine embryonic stem cells and somatic tissues, recapitulating expected characteristics of the well characterized H3.3 histone variant. We extended this system to the less-studied MacroH2A2 variant, commonly described as a “repressive” histone variant whose accumulation in chromatin is thought to fix the epigenetic state of differentiated cells. Unexpectedly, we found that while large intergenic blocks of MacroH2A2 were stably associated with the genome, promoter-associated peaks of MacroH2A2 exhibited relatively rapid exchange dynamics in ES cells, particularly at highly-transcribed genes. Upon differentiation to embryonic fibroblasts, MacroH2A2 was gained primarily in additional long, stably associated blocks across gene-poor regions, while overall turnover at promoters was greatly dampened. Our results reveal unanticipated dynamic behavior of the MacroH2A2 variant in pluripotent cells, and provide a resource for future studies of tissue-specific histone dynamics in vivo.
Highlights
All genomic transactions in eukaryotes occur in the context of chromatin
These correlations, in which histone exchange is slow over epigenetically-heritable heterochromatin domains but is rapid at boundary elements, raise the question of how histone dynamics contribute to epigenetic inheritance
MacroH2A2 is highly dynamic in Embryonic stem (ES) cells, with rapid exchange occurring over gene promoters, alongside much more stably-bound domains that cover large blocks of the genome
Summary
All genomic transactions in eukaryotes occur in the context of chromatin. While histones are generally among the most stablyassociated DNA-binding proteins known [1], a subset of histones exhibit dynamic replication-independent exchange with the soluble pool of nucleoplasmic histones [2,3,4]. H3 exchange is rapid at boundary elements that block the spread of heterochromatin [5,7], raising the possibility that rapid histone exchange could function mechanistically to erase laterally spreading chromatin states. These correlations, in which histone exchange is slow over epigenetically-heritable heterochromatin domains but is rapid at boundary elements, raise the question of how histone dynamics contribute to epigenetic inheritance. The rapid histone turnover observed at promoter regions of actively transcribed genes suggests that histone turnover may have an important role in gene regulation, as higher histone turnover rates could provide greater access of regulatory proteins to specific DNA elements. Much remains to be learned about the mechanistic basis for, and the biological consequences of, dynamic chromatin states
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