Title

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

Document Type

Article

Publication Date

1-2022

Publication Title

The EMBO journal

Keywords

JMG

JAX Source

EMBO J 2022; 41:e109445

Volume

41

Issue

2

First Page

109445

Last Page

109445

ISSN

1460-2075

PMID

34931323

DOI

https://doi.org/10.15252/embj.2021109445

Grant

CA034196, OD011102, HD007065, GM133724

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 toward neuroectoderm and D2 toward 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.

Comments

We would like to thank all members of the Baker laboratory for comments and discussion. Additionally, we would like to thank Dr. Martin Pera for constructive feedback on the project and reviewing themanuscript; Dr.Martin Ringwald for assisting with approaches to annotate developmental stages of single-cell clusters; and Christopher S. McGinnis and the Gartner Laboratory for providing LMOs for MULTIseq.We recognize contributions fromThe Jackson Laboratory Genome Technologies Services, Flow Cytometry Services, and Single Cell Biology Laboratory for technical assistance and consultation.

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