RNA Pol II pausing facilitates phased pluripotency transitions by buffering transcription [Research Papers]

Abderhman Abuhashem1,2,3, Alexandra G. Chivu4,5, Yixin Zhao6, Edward J. Rice4, Adam Siepel6, Charles G. Danko4,7 and Anna-Katerina Hadjantonakis1,3 1Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA; 2Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, New York 10065, USA; 3Biochemistry Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York 10065, USA; 4Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA; 5Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA; 6Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; 7Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA Corresponding author: hadjmskcc.org Abstract

Promoter-proximal RNA Pol II pausing is a critical step in transcriptional control. Pol II pausing has been predominantly studied in tissue culture systems. While Pol II pausing has been shown to be required for mammalian development, the phenotypic and mechanistic details of this requirement are unknown. Here, we found that loss of Pol II pausing stalls pluripotent state transitions within the epiblast of the early mouse embryo. Using Nelfb−/− mice and a NELFB degron mouse pluripotent stem cell model, we show that embryonic stem cells (ESCs) representing the naïve state of pluripotency successfully initiate a transition program but fail to balance levels of induced and repressed genes and enhancers in the absence of NELF. We found an increase in chromatin-associated NELF during transition from the naïve to later pluripotent states. Overall, our work defines the acute and long-term molecular consequences of NELF loss and reveals a role for Pol II pausing in the pluripotency continuum as a modulator of cell state transitions.

Received March 15, 2022. Accepted July 18, 2022.

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