SEC Mediates m6A Deposition and Transcription Pause Release to Drive Cell Identity Transition

Abstract

ABSTRACT Background: Induced pluripotent stem cell (iPSC) reprogramming and embryonic stem cell (ESC) differentiation represent opposite models of cell identity transition, yet their regulatory mechanisms remain incompletely understood. Here, we identify the Super Elongation Complex (SEC), the most pivotal regulators of transcription pause release, as a central driver of cell identity transition in both models. Results: SEC depletion markedly impairs iPSC reprogramming efficiency, particularly during the early stage, by suppressing core reprogramming genes, including Klf4 and Myc, thereby disrupting key reprogramming events, such as cell‐cycle progression and activation of the pluripotency network. Mechanistically, SEC activates the expression of Klf4 and Myc by promoting the release of pre‐established paused RNA polymerase II (RNA Pol II). Moreover, SEC also cooperates with METTL3 to facilitate N6‐methyladenosine (m6A) deposition and transcription pause release at Klf4 and Myc, revealing an additional regulatory layer during iPSC reprogramming. Similarly, during ESC neural induction, SEC upregulates neural gene expression and facilitates ESC transition into the neuroectoderm lineage, via promoting transcription pause release at relevant loci. Conclusions: These findings establish SEC as a shared regulator of cell identity transition in both iPSC reprogramming and ESC differentiation. Elucidating the mechanisms by which SEC drives cell identity transitions provides a foundation for further investigation into diverse cell identity transitions under physiological and pathological conditions.