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Abstract
Epigenetic regulation of the replication program during mammalian cell differentiation remains poorly understood. We performed an integrative analysis of eleven genome-wide epigenetic profiles at 100 kb resolution of Mean Replication Timing (MRT) data in six human cell lines. Compared to the organization in four chromatin states shared by the five somatic cell lines, embryonic stem cell (ESC) line H1 displays (i) a gene-poor but highly dynamic chromatin state (EC4) associated to histone variant H2AZ rather than a HP1-associated heterochromatin state (C4) and (ii) a mid-S accessible chromatin state with bivalent gene marks instead of a polycomb-repressed heterochromatin state. Plastic MRT regions (≲ 20% of the genome) are predominantly localized at the borders of U-shaped timing domains. Whereas somatic-specific U-domain borders are gene-dense GC-rich regions, 31.6% of H1-specific U-domain borders are early EC4 regions enriched in pluripotency transcription factors NANOG and OCT4 despite being GC poor and gene deserts. Silencing of these ESC-specific “master” replication initiation zones during differentiation corresponds to a loss of H2AZ and an enrichment in H3K9me3 mark characteristic of late replicating C4 heterochromatin. These results shed a new light on the epigenetically regulated global chromatin reorganization that underlies the loss of pluripotency and lineage commitment.
Highlights
One of the most remarkable phenomenon in biology is the generation of a whole organism containing a large and phenotypically diverse collection of cells and tissues from a single totipotent cell
Embryonic stem cell (ESC) enter a program of cell differentiation eventually leading to all the necessary differentiated cell types
We show that besides some epigenetic regulation, ubiquitous master replication origins at replication timing U-domain borders shared by 6 human cell types are transcriptionally active open chromatin regions specified by a local enrichment in nucleosome free regions encoded in the DNA sequence suggesting that they have been selected
Summary
One of the most remarkable phenomenon in biology is the generation of a whole organism containing a large and phenotypically diverse collection of cells and tissues from a single totipotent cell This tremendous level of diversity in cellular functions originates from a unique genomic DNA sequence. Epigenetic mechanisms including DNA methylation [4], histone modifications [5,6,7,8,9,10,11,12,13] and chromatin structure and dynamics [14,15,16,17,18,19,20,21,22,23,24,25] have been proposed to play a key role in regulation of embryonic development, the maintenance of pluripotency and self-renewal of ESCs, lineage specification and the maintenance of cellular identity during differentiation [26,27,28,29,30]. As differentiation progresses, chromatin structure switches from a highly dynamic, accessible and permissive euchromatin in ESCs to a less open chromatin riddled with accumulating highly condensed transcriptionally inactive heterochromatin regions [26,27,28, 38, 39]
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