PT  - JOURNAL ARTICLE
AU  - Jelena Perovanovic
AU  - Yifan Wu
AU  - Zuolian Shen
AU  - Erik Hughes
AU  - Mahesh B. Chandrasekharan
AU  - Dean Tantin
TI  - Oct1 recruits the histone lysine demethylase Utx to canalize lineage specification
AID  - 10.1101/2020.12.01.406488
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2020.12.01.406488
4099  - http://biorxiv.org/content/early/2021/07/18/2020.12.01.406488.short
4100  - http://biorxiv.org/content/early/2021/07/18/2020.12.01.406488.full
AB  - The pathways used by cells to transition between undifferentiated, pluripotent state and tissue-specific states are incompletely understood. Here we show that the transcription factor Oct1/Pou2f1 activates silent, developmental lineage-appropriate genes to “canalize” developmental progression. Using inducible knockout embryonic stem cells and single-cell gene expression profiling, we show that Oct1 deficiency impairs mesodermal differentiation. Oct1-deficient cells show inappropriate developmental lineage branching and display a poorly differentiated state with hallmarks of pluripotency. Like Oct4, Oct1 directly binds genes critical for mesoderm induction and chromatin modification. Oct1 recruits the Utx/Kdm3a histone lysine demethylase to remove inhibitory H3K27me3 marks and activate their expression. The specificity of the ubiquitous Oct1 protein for mesodermal genes is explained by cooperative interactions with the Smad3 transcription factor. We also show that ectopic Oct1 expression improves the ability of cells to differentiate accurately under mesoderm lineage-inducing conditions. Overall, these results identify Oct1 as a key regulator of mesoderm differentiation.HIGHLIGHTSOct1 “canalizes” gene expression to promote developmentally accurate gene expression and differentiationOct1 is necessary for proper bivalency resolutionOct1 recruits Utx to demethylate H3K27me3 at mesoderm lineage-appropriate targetsCompeting Interest StatementThe authors have declared no competing interest.