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Nucleic Acids Res., 01 November 2023 | https://doi.org/10.1093/nar/gkad908 Molecular basis for SOX2-dependent regulation of super-enhancer activity

Wanki Yoo ¹, Yi Wei Song¹, Jihyun Kim², Jihye Ahn², Jaehoon Kim ², Yongdae Shin ³, Je-Kyung Ryu⁴ and Kyeong Kyu Kim ^1,*

¹Department of Precision Medicine, Graduate School of Basic Medical Science (GSBMS), Institute for Antimicrobial Resistance Research and Therapeutics, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea

²Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea

³Department of Mechanical Engineering, Seoul National University, Seoul 08826, Republic of Korea 4Department of Physics & Astronomy, Seoul National University, Seoul 08826, Republic of Korea

^*To whom correspondence should be addressed.: Kyeong Kyu Kim

Abstract

Pioneer transcription factors (TFs) like SOX2 are vital for stemness and cancer through enhancing gene expression within transcriptional condensates formed with coactivators, RNAs and mediators on super-enhancers (SEs). Despite their importance, how these factors work together for transcriptional condensation and activation remains unclear. SOX2, a pioneer TF found in SEs of pluripotent and cancer stem cells, initiates SE-mediated transcription by binding to nucleosomes, though the mechanism isn’t fully understood. To address SOX2’s role in SEs, we identified mSE078 as a model SOX2-enriched SE and p300 as a coactivator through bioinformatic analysis. In vitro and cell assays showed SOX2 forms condensates with p300 and SOX2-binding motifs in mSE078. We further proved that SOX2 condensation is highly correlated with mSE078’s enhancer activity in cells. Moreover, we successfully demonstrated that p300 not only elevated transcriptional activity but also triggered chromatin acetylation via its direct interaction with SOX2 within these transcriptional condensates. Finally, our validation of SOX2-enriched SEs showcased their contribution to target gene expression in both stem cells and cancer cells. In its entirety, this study imparts valuable mechanistic insights into the collaborative interplay of SOX2 and its coactivator p300, shedding light on the regulation of transcriptional condensation and activation within SOX2-enriched SEs.

논문정보

형식Research article
게재일2023년 11월 (BRIC 등록일 2023-11-06)
연구진국내 연구진
분야 생명과학 > 유전자발현

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