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Oct1 cooperates with Smad transcription factors to promote mesodermal lineage specification [single-cell RNA-seq]

ABSTRACT: The pathways used by cells to transition from undifferentiated, pluripotent gene expression programs into cell type-specific gene expression programs are incompletely understood. Here we show that the transcription factor Oct1/Pou2f1 recruits histone lysine demethylase complexes to allow for correct induction of silent, developmental lineage-specific genes and “canalize” developmental progression. Using mesodermal differentiation of inducible-conditional Oct1 knockout embryonic stem cells and single-cell gene expression profiling, we show that the potential to progress efficiently through mesodermal development is impaired in the Oct1 deficient condition. Oct1 deficient cells fail to form late presomitic mesoderm and early somite stage populations, and show “leaky” developmental trajectories with inappropriate lineage branching and accumulation of poorly differentiated cells that retain gene expression and metabolic hallmarks of pluripotency. Oct1 directly binds and regulates genes critical for developmental regulation, including genes encoding mesoderm-specific master regulators and components of chromatin regulatory complexes. Cells lacking Oct1 fail to positively resolve gene bivalency and activate gene expression by removing inhibitory H3K27me3 chromatin marks at mesoderm-specific genes. The Oct1 protein interacts with and recruits UTX to lineage-specific bivalent/poised targets, explaining the failure of Oct1 deficient cells to remove H3K27me3. Ectopic Oct1 expression improves the ability of cells to differentiate accurately under mesoderm lineage-inducing conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE160942 | GEO | 2022/11/26

REPOSITORIES: GEO

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Oct1 cooperates with Smad transcription factors to promote mesodermal lineage specification [BulkRNAseq7221]

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Oct1 cooperates with Smad transcription factors to promote mesodermal lineage specification [HiChIP]

Project description:The pathways used by cells to transition between pluripotent and tissue-specific states are incompletely understood. Here we show that the widely-expressed transcription factor Oct1/Pou2f1 activates silent, developmental lineage-appropriate genes to “canalize” developmental progression. Using Oct1 inducible knockout embryonic stem cells, we show that that Oct1 deficiency impairs mesodermal and terminal muscle differentiation in a manner that can be rescued by Oct1 retroviral expression. We show that mesoderm-specific genes are not correctly induced early in the differentiation timecourse. Oct1-deficient cells lose temporal coherence in the induction of lineage-specific genes and show inappropriate developmental lineage branching, resulting in poorly differentiated cells states retaining epithelial characteristics. In embryonic stem cells, Oct1 co-binds with Oct4 to genes critical for mesoderm induction, and continues to bind these genes during differentiation. Oct1 binding events are enriched at the termini of chromatin loops, including loops gained with differentiation. The Utx/Kdm6a histone lysine demethylase also binds to many of these genes, and using a prototypic Pax3 gene we show that Oct1 recruits Utx to remove inhibitory H3K27me3 marks and activate expression. The specificity of the ubiquitous Oct1 protein for mesodermal genes can be explained by cooperative interactions with lineage-driving Smad transcription factors, as we show that Smad and Oct binding sites frequently coexist mesoderm-specific genes, and that Oct1 and Smad3 act cooperatively at the Myog enhancer. Overall, these results identify Oct1 as a key mediator of the induction of mesoderm lineage-specific genes.

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In vitro cultured H7 human embryonic stem cells (WiCell) and H7-derived downstream early mesoderm progenitors

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