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 naive networks adopting gene expression modules indicative of neuroectoderm lineages; whereas D2 retains aspects of naive 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.

中文翻译：

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多能表观基因组的遗传控制确定小鼠胚胎干细胞的分化偏向。

遗传多样性的多能干细胞（PSC）对培养环境中的分化线索显示出多种可遗传的反应。通过利用BXD小鼠遗传参考小组的胚胎干细胞（ESC）以及C57BL / 6J（B6）和DBA / 2J（D2）亲本菌株衍生出的这些差异，我们证明了遗传确定的血统偏倚并确定了主要的多能表观基因组的调节者。使用上皮细胞样细胞（EpiLCs）转变为形成性多能性后，B6迅速溶解幼稚网络，采用指示神经外胚层谱系的基因表达模块。而D2保留了幼稚的多能性方面，几乎没有分化偏见。遗传图谱鉴定了6个主要的交易位点，它们共同调节ESC和EpiLC中的染色质可及性和基因表达，表明影响细胞状态转换的通用调控系统。这些基因座在远端调节数百个调节元件上的多能性因子（包括TRIM28，P300和POU5F1）的占有率。Chr 12上的一个反式基因座主要影响ESCs中的染色质可及性。而在EpiLC中，相同的基因座随后会影响基因表达，这提示了染色质的早期启动。因此，该基因座的远端基因靶点富含神经发生基因，并且当细胞在此Chr 12基因座上携带B6单倍型时，其表达更高，从而支持了细胞命运偏向的遗传调控。胚状体的自发形成证明了这一点，B6表现出对神经外胚层分化的倾向，D2表现出对定形内胚层的倾向，