Diffusion controls local versus dispersed inheritance of histones during replication and shapes epigenomic architecture

Author:

Singh Archit,Chakrabarti Shaon

Abstract

AbstractThe dynamics of inheritance of histones and their associated modifications across cell divisions can have major consequences on maintenance of the cellular epigenomic state. Recent experiments contradict the long-held notion that histone inheritance during replication is always local, suggesting that active and repressed regions of the genome exhibit fundamentally different histone dynamics independent of transcription-coupled turnover. Here we develop a stochastic model of histone dynamics at the replication fork and demonstrate that differential diffusivity of histones in active versus repressed chromatin is sufficient to quantitatively explain these recent experiments. Further, we use the model to predict patterns in histone mark similarity between pairs of genomic loci that should be developed as a result of diffusion, but not from PRC2 mediated mark spreading or transcriptional processes. Interestingly, using a combination of CHIP-seq, replication timing and Hi-C datasets we demonstrate that all the computationally predicted patterns are consistently observed for both active and repressive histone marks in two different cell lines. Our results suggest that in contrast to current models that posit histone transfer exclusively between parental and daughter DNA strands, dislodged histones in euchromatin and facultative heterochromatin diffuse within larger “Diffusion-Accessible-Domains” (DADs), leading to redistribution of epigenetic marks both within and across chromosomes. Preservation of the epigenomic state across cell divisions therefore might be achieved not by passing on strict positional information of histone marks, but by maintaining the marks in somewhat larger DADs of the genome.

Publisher

Cold Spring Harbor Laboratory

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