1: Cell Cycle. 2004 Dec;3(12):1645-50. Epub 2004 Dec 4. 

A dynamic switch in the replication timing of key regulator genes in embryonic
stem cells upon neural induction.

Perry P, Sauer S, Billon N, Richardson WD, Spivakov M, Warnes G, Livesey FJ,
Merkenschlager M, Fisher AG, Azuara V.

Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College
School of Medicine, Hammersmith Hospital, London, UK.

Mammalian embryonic stem (ES) cells can either self-renew or generate progenitor
cells that have a more restricted developmental potential. This provides an
important model system to ask how pluripotency, cell commitment and
differentiation are regulated at the level of chromatin-based changes that
distinguish stem cells from their differentiated progeny. Here we show that the
differentiation of ES cells to neural progenitors results in dynamic changes in
the epigenetic status of multiple genes that encode transcription factors
critical for early embryonic development or lineage specification. In
particular, we demonstrate that DNA replication at a subset of neural-associated
genes including Pax3, Pax6, Irx3, Nkx2.9 and Mash1 is advanced upon neural
induction, consistent with increased locus accessibility. Conversely, many
ES-associated genes including Oct4, Nanog, Utf1, Foxd3, Cripto and Rex1 that
replicate early in ES cells switch their replication timing to later in S-phase
in response to differentiation. Detailed analysis of the Rex1 locus reveals that
delayed replication extends to a 2.8 Mb region surrounding the gene and is
associated with substantial reductions in the level of histone H3K9 and H4
acetylation at the promoter. These results show that loss of pluripotency (and
lineage choice) is associated with extensive and predictable changes in the
replication timing of key regulator genes.

PMID: 15611653 [PubMed - in process]


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