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Mol. Cell, Jul 03 2026, S1097-2765(26)00410-7 | https://doi.org/10.1016/j.molcel.2026.06.021 Thyroid cancer-associated EZH1 Q571R mutation drives chromatin compaction and H3K27me3 invasion into active chromatin

Hanbyeol Kim ^1,2,14, Do-Gyun Kim ^3,14, Seongyun Ha ^4,14, Jun-Young Jang ³, Francisca N. de L. Vitorino ⁵, Joanna M. Gongora ⁵, Woochul Kim⁶, Yoonji Oh^1,2, Gyeongsik Park ⁷, Hyeji Kang ^1,2, Soo-Hyun Im ⁸, Chan Kwon Jung ⁹, Seon-Young Kim⁸, Inkyung Jung ⁷, Jae-Kyung Won ¹⁰, Benjamin A. Garcia ⁵, Su-jin Kim ^6,11, Kyu Eun Lee ^6,11, Je-Kyung Ryu ³, Chul-Hwan Lee^{1,2,11,12,13,15}

¹Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea
²Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
³Department of Physics and Astronomy, Seoul National University, Seoul, Republic of Korea
⁴Interdisciplinary Program of Cancer Biology, Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
⁵Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA
⁶Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Republic of Korea
⁷Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
⁸Korea Bioinformation Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon 34141, Republic of Korea
⁹Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
¹⁰Department of Pathology, Seoul National University Hospital and College of Medicine, Seoul, Republic of Korea
¹¹Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
¹²Ischemic/hypoxic Disease Institute, Neuroscience Research Institute, The Institute of Molecular Biology & Genetics, Seoul National University, Seoul, Republic of Korea
¹³Wide River Institute of Immunology, Seoul National University, Hongcheon, Republic of Korea
¹⁴These authors contributed equally
¹⁵Lead contact

Corresponding authors: Kyu Eun Lee, Je-Kyung Ryu, Chul-Hwan Lee

Abstract

Dysregulation of Polycomb Repressive Complex 2 (PRC2) contributes to cancer. Of its catalytic subunits, Enhancer of Zeste (EZH) 1 and EZH2, EZH2 mutations are extensively studied, but the role of EZH1 in cancer remains largely unexplored. Here, we investigate the thyroid cancer-associated EZH1^Q571R mutation and uncover a mechanism that extends beyond catalytic gain of function. Using biochemical, single-molecule, epigenomic, and transcriptomic analyses, we demonstrated that EZH1^Q571R significantly enhances chromatin compaction and stimulates PRC2-EZH1 catalytic activity, thereby rewiring PRC2-chromatin interactions. This altered engagement enables PRC2 activity within H3K36me2-marked chromatin typically refractory to H3K27 methylation, leading to widespread epigenetic and transcriptional reprogramming. Notably, enhanced chromatin compaction is observed with EZH1^Q571R but not with the corresponding EZH2^Q570R mutation, indicating an EZH1-specific mechanism. Functionally, EZH1^Q571R accelerated tumor growth in vivo and induced pronounced micronuclei formation ex vivo, reflecting aberrant chromatin compaction and genome instability. Together, our study demonstrates that EZH1^Q571R promotes a permissive epigenomic landscape for the progression of follicular thyroid cancer.

논문정보

형식Research article
게재일2026년 07월 (BRIC 등록일 2026-07-06)
연구진국내(교신)+국외 연구진
분야 생명과학 > 유전자발현

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