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

EMBO J. 2022 Dec 17;41(2):e109445. doi: 10.15252/embj.2021109445. Epub 2021 Dec 21.


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.

Keywords: BXD mice; KRAB zinc-finger proteins; cell fate; epigenetic variability; mESCs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Lineage
  • Chromatin Assembly and Disassembly
  • Epigenome*
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks
  • Mice
  • Mice, Inbred DBA
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • Regulatory Sequences, Nucleic Acid