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Mol. Cell, Feb 04 2025, S1097-2765(24)01067-0 | https://doi.org/10.1016/j.molcel.2024.12.026
The phenylalanine-and-glycine repeats of NUP98 oncofusions form condensates that selectively partition transcriptional coactivators
Jeong Hyun Ahn,6,7 Yiran Guo,2,7 Heankel Lyons,3,7 Samuel G. Mackintosh,4 Benjamin K. Lau,2 Ricky D. Edmondson,4 Stephanie D. Byrum,4 Aaron J. Storey,4 Alan J. Tackett,4 Ling Cai,1,5,* Benjamin R. Sabari,3,* and Gang Greg Wang 1,2,5,8,*
1Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA
2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA
3Laboratory of Nuclear Organization, Cecil H. and Ida Green Center for Reproductive Biology Sciences, Division of Basic Research, Department of Obstetrics and Gynecology, Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
4Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
5Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
6Institute for Molecular Biology and Genetics, Seoul National University, Seoul, South Korea
7These authors contributed equally
8Lead contact
2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA
3Laboratory of Nuclear Organization, Cecil H. and Ida Green Center for Reproductive Biology Sciences, Division of Basic Research, Department of Obstetrics and Gynecology, Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
4Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
5Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
6Institute for Molecular Biology and Genetics, Seoul National University, Seoul, South Korea
7These authors contributed equally
8Lead contact
*Corresponding authors: correspondence to Ling Cai, Benjamin R. Sabari or Gang Greg Wang
Abstract
Recurrent cancer-causing fusions of NUP98 produce higher-order assemblies known as condensates. How NUP98 oncofusion-driven condensates activate oncogenes remains poorly understood. Here, we investigate NUP98-PHF23, a leukemogenic chimera of the disordered phenylalanine-and-glycine (FG)-repeat-rich region of NUP98 and the H3K4me3/2-binding plant homeodomain (PHD) finger domain of PHF23. Our integrated analyses using mutagenesis, proteomics, genomics, and condensate reconstitution demonstrate that the PHD domain targets condensate to the H3K4me3/2-demarcated developmental genes, while FG repeats determine the condensate composition and gene activation. FG repeats are necessary to form condensates that partition a specific set of transcriptional regulators, notably the KMT2/MLL H3K4 methyltransferases, histone acetyltransferases, and BRD4. FG repeats are sufficient to partition transcriptional regulators and activate a reporter when tethered to a genomic locus. NUP98-PHF23 assembles the chromatin-bound condensates that partition multiple positive regulators, initiating a feedforward loop of reading-and-writing the active histone modifications. This network of interactions enforces an open chromatin landscape at proto-oncogenes, thereby driving cancerous transcriptional programs.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-10)
- 국내+국외 연구진
- 생명과학 > 분자생물학
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