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. 2025 Aug 7;85(15):2937-2955.e10.
doi: 10.1016/j.molcel.2025.07.006.

Integrator promotes the association of TFIID and RNA polymerase II to maintain pluripotency during development

Raghu Ram Edupuganti  1 , Felipe Beckedorff  1 , Pradeep Kumar Reddy Cingaram  1 , Saeid Mohammad Parast  2 , Jingyin Yue  1 , Gary LeRoy  1 , Monica Guiselle Valencia  1 , Sadat Dokaneheifard  1 , Helena Gomes Dos Santos  1 , Omar Lopez Ocejo  1 , Mingjiang Xu  3 , Brooke A DeRosa  4 , Derek M Dykxhoorn  4 , Guilherme Miura Lavezzo  5 , Daniel Bilbao  6 , Danny Reinberg  1 , Lluis Morey  1 , Ali Shilatifard  2 , Ramin Shiekhattar  7
Affiliations

Integrator promotes the association of TFIID and RNA polymerase II to maintain pluripotency during development

Raghu Ram Edupuganti et al. Mol Cell. .

Abstract

The mechanisms by which the expression of pluripotency and Polycomb networks are harmonized to allow the transition from pluripotency to a differentiated state have not been fully elucidated. Integrator complex regulates transcription pause release and RNA processing in metazoans. We show that Integrator is required for stemness and plays a critical role as early as day 2 in embryonic development. While the catalytic endonuclease activity enhances cellular reprogramming, Integrator recruits RNA polymerase II (RNAPII) to promoters and super enhancers of pluripotency and Polycomb genes. Integrator coordinates expression of pluripotency and Polycomb networks by fostering the association of RNAPII and basal transcription factors. We pinpoint a critical role for TATA-binding protein-associated factors (TAFs) in Integrator entry into the preinitiation complex. Taken together, beyond its role in RNAPII pause release, Integrator recruitment of RNAPII ensures an orderly cellular differentiation during development.

Keywords: Integrator; RNA polymerase II recruitment; basal transcription factors; cellular differentiation; development; embryonic stem cells; enhancer; pluripotency; promoter; transcription.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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