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Genetic control of pluripotency epigenome determines differentiation bias in embryonic stem cells

ABSTRACT: Genetically diverse pluripotent stem cells display varied, heritable responses to differentiation cues. Here we harnessed these disparities through derivation of mouse embryonic stem cells from the BXD genetic reference panel, along with C57BL/6J (B6) and DBA/2J (D2) parental strains, to identify loci regulating cell state transitions. Upon transition to formative pluripotency, B6 stem cells quickly dissolved naïve networks adopting gene expression modules indicative of neuroectoderm lineages; whereas D2 retained aspects of naïve pluripotency. Spontaneous formation of embryoid bodies identified divergent differentiation where B6 showed a propensity towards neuroectoderm and D2 towards definitive endoderm. Genetic mapping identified major trans-acting loci co-regulating chromatin accessibility and gene expression in both naïve and formative pluripotency. These loci distally modulated occupancy of pluripotency factors at hundreds of regulatory elements. One trans-acting locus on Chr 12 primarily impacted chromatin accessibility in embryonic stem cells; while in epiblast-like cells the same locus subsequently influenced expression of genes enriched for neurogenesis, suggesting early chromatin priming. These results demonstrate genetically determined biases in lineage commitment and identify major regulators of the pluripotency epigenome.

SUBMITTER: Candice Byers

PROVIDER: S-SCDT-EMBOJ-2021-109445 | biostudies-other |

REPOSITORIES: biostudies-other

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Genetic control of pluripotency epigenome informs differentiation bias in mouse embryonic stem cells

Project description:Genetically diverse pluripotent stem cells (PSCs) display varied, heritable responses to differentiation cues in the culture environment. By harnessing these disparities through derivation of embryonic stem cells (ESCs) from the BXD mouse genetic reference panel, along with C57BL/6J (B6) and DBA/2J (D2) parental strains, we demonstrate genetically determined biases in lineage commitment and identify major regulators of the pluripotency epigenome. Upon transition to formative pluripotency using epiblast-like cells (EpiLCs), B6 quickly dissolves naïve networks adopting gene expression modules indicative of neuroectoderm lineages; whereas D2 retains aspects of naïve pluripotency with little bias in differentiation. Genetic mapping identifies 6 major trans-acting loci co-regulating chromatin accessibility and gene expression in ESCs and EpiLCs, indicating a common regulatory system impacting cell state transition. These loci distally modulate occupancy of pluripotency factors, including TRIM28, P300, and POU5F1, at hundreds of regulatory elements. One trans-acting locus on Chr 12 primarily impacts chromatin accessibility in ESCs; while in EpiLCs the same locus subsequently influences gene expression, suggesting early chromatin priming. Consequently, the distal gene targets of this locus are enriched for neurogenesis genes and were more highly expressed when cells carried B6 haplotypes at this Chr 12 locus, supporting genetic regulation of biases in cell fate. Spontaneous formation of embryoid bodies validated this with B6 showing a propensity towards neuroectoderm differentiation and D2 towards definitive endoderm, confirming the fundamental importance of genetic variation influencing cell fate decisions.

2021-10-05 | GSE164935 | GEO

Genetic control of pluripotency epigenome informs differentiation bias in mouse embryonic stem cells

Project description:Genetic control of pluripotency epigenome informs differentiation bias in mouse embryonic stem cells

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CARM1 is required in embryonic stem cells to maintain pluripotency and resist differentiation.

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