Impaired cell fate through gain-of-function mutations in a chromatin reader

Liling Wan (), Shasha Chong, Fan Xuan, Angela Liang, Xiaodong Cui, Leah Gates, Thomas S. Carroll, Yuanyuan Li, Lijuan Feng, Guochao Chen, Shu-Ping Wang, Michael V. Ortiz, Sara K. Daley, Xiaolu Wang, Hongwen Xuan, Alex Kentsis, Tom W. Muir, Robert G. Roeder, Haitao Li, Wei Li, Robert Tjian, Hong Wen () and C. David Allis ()
Additional contact information
Liling Wan: The Rockefeller University
Shasha Chong: University of California
Fan Xuan: Van Andel Institute
Angela Liang: The Rockefeller University
Xiaodong Cui: Baylor College of Medicine
Leah Gates: The Rockefeller University
Thomas S. Carroll: The Rockefeller University
Yuanyuan Li: Tsinghua University
Lijuan Feng: The Rockefeller University
Guochao Chen: Tsinghua University
Shu-Ping Wang: The Rockefeller University
Michael V. Ortiz: Memorial Sloan Kettering Cancer Center
Sara K. Daley: Princeton University
Xiaolu Wang: Van Andel Institute
Hongwen Xuan: Van Andel Institute
Alex Kentsis: Memorial Sloan Kettering Cancer Center
Tom W. Muir: Princeton University
Robert G. Roeder: The Rockefeller University
Haitao Li: Tsinghua University
Wei Li: Baylor College of Medicine
Robert Tjian: University of California
Hong Wen: Van Andel Institute
C. David Allis: The Rockefeller University

Nature, 2020, vol. 577, issue 7788, 121-126

Abstract: Abstract Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by ‘reader’ proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia1. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour2,3, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatin-reader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.

Date: 2020
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DOI: 10.1038/s41586-019-1842-7

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