No.1068:   REPLICATION TIMING AS AN EPIGENETIC FINGERPRINT OF STEM CELL IDENTITY

We have constructed high-resolution genome-wide replication timing profiles of mouse and human embryonic stem cells (ESCs), their differentiated counterparts, fetal and adult cell types. Replication profiles are highly cell type specific; widespread developmentally programmed changes in replication timing occur at the level of 4-800 kb chromosome segments. Cell lines modeling stages of the post-implantation epiblast indicate that early development involves extensive lineage-independent early-to-late (EtoL) replication timing switches that are completed prior to germ layer specification and down-regulation of key pluripotency transcription factors. These changes remain stable in all subsequent cell lineages and involve a class of irreversibly silenced genes. Lineage-specific, mostly late-to-early (LtoE) replication switches follow, creating cell-type specific replication profiles. Importantly, partially reprogrammed murine iPSCs reproducibly fail to restore mESC-specific replication timing and transcription programs within regions of lineage-independent replication timing changes. Interestingly, human ESC replication profiles were considerably more aligned with those from mouse epiblast-derived stem cells (mEpiSCs) than with mouse ESCs. Together, our results demonstrate the power of replication profiling to identify important epigenetic distinctions between closely related stem cell populations and identify replication-timing switches occurring in the epiblast that embody an epigenetic commitment to differentiation prior to germ layer specification.

Invitator:
Experimental Research Center for Infectious Diseases
Lab. of Gene-modified Mouse
Yoichi Shinkai
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