Role of ETS-Transcription Factors in Regulating Cell Fate

Division Of Basic Sciences - Nci

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Abstract

During FY2021 we have made great progress in this project, and we have this work accepted for publication in Sciences Advances. We have established the role of the transcriptional repressor ERF as the MAPK dependent switch that controls the exit from the naive state of pluripotency. For this, we have used inducible ESCs to genetically eliminate all RAS proteins and determined that, while differentiated RAS deficient cells remain trapped in an intermediate state of pluripotency, further absence of ERF overcomes the developmental blockage of RAS deficient cells from this intermediate state. We also performed RNAseq data and observed that deletion of ERF restored the overall gene expression profile to a wild type level in differentiated Ras deficient cells. Mechanistically, we have demonstrated that ERF ensures naive pluripotency by strengthen naive pluripotent transcription factor binding and accessibility at specific ESC enhancers. Moreover, we have also determined that ERF regulates negatively the expression of the de novo methylase DNMT3, essential for the extinction of the naive transcriptional program. Our data has revealed an essential role for ERF in the exit from rosette pluripotency as a regulator of the progression to primed pluripotency.