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Genome-wide profile of 5-hydroxymethylcytosine (5-hmC) in H9 human embryonic stem cells (hESCs)

ABSTRACT: The link between single cell variation and population level fate choices lacks an explanation despite extensive observations of gene expression and epigenetic variation among individual cells. Here, we found that single human embryonic stem cells (hESCs) have different and biased differentiation potentials toward either neuroectoderm or mesendoderm depending on their G1 lengths before the onset of differentiation. Single cell variation in G1 length establishes a probability distribution in which increased variation biases stem cells toward neuroectoderm. Although sister stem cells generally share G1 lengths, a variable proportion of cells have asymmetric G1 lengths, which maintains the population dispersion. WNT levels control the G1 length distribution apparently as a means of priming the fate of hESC populations once they undergo differentiation. Global 5-hydroxymethylcytosine levels are regulated by G1 length and thereby link G1 length to differentiation outcomes of hESCs. Our findings suggest G1 length distribution links intra-population heterogeneity to population outcome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113236 | GEO | 2019/01/01

REPOSITORIES: GEO

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Project description:The transcription factors Nanog, Oct4 and Sox2 are the master regulators of pluripotency in mouse embryonic stem cells (mESCs), however, their functions in human ESCs (hESCs) have not been rigorously defined. Here we show that the requirements for NANOG, OCT4 and SOX2 in hESCs differ from those in mESCs. Both NANOG and OCT4 are required for self-renewal and repress differentiation. OCT4 controls both extraembryonic and epiblast-derived cell fates in a BMP4-dependent manner. OCT4-depleted hESCs commit to trophectoderm and primitive endoderm in the presence of BMP4, but undergo neuroectoderm differentiation in the absence of BMP4. NANOG represses neuroectoderm and neural crest commitment, but has little or no effect on the other lineages. We find that SOX2 is not required for self-renewal because it is redundant with SOX3, which is induced in SOX2-depleted hESCs. Simultaneous depletion of both SOX2 and SOX3 induces differentiation into the primitive streak. Unexpectedly, we identify significant variability in the usage of pluripotency factors by individual hESC lines, suggesting that the pluripotency network is remodelled to support a continuum of developmental states. Our study revises the general view of how NANOG, OCT4 and SOX2 orchestrate self-renewal in hESCs. Total RNA obtained from H1P (control)-, shNANOG (Nanog shRNA knockdown)-, shOCT4 (Oct4 shRNA knockdown)- or shSOX2 (Sox2 shRNA knockdown)-transduced hESCs for 8 days time course.

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