Phase separation drives aberrant chromatin looping and cancer development

Jeong Hyun Ahn, Eric S. Davis, Timothy A. Daugird, Shuai Zhao, Ivana Yoseli Quiroga, Hidetaka Uryu, Jie Li, Aaron J. Storey, Yi-Hsuan Tsai, Daniel P. Keeley, Samuel G. Mackintosh, Ricky D. Edmondson, Stephanie D. Byrum, Ling Cai, Alan J. Tackett, Deyou Zheng, Wesley R. Legant, Douglas H. Phanstiel () and Gang Greg Wang ()
Additional contact information
Jeong Hyun Ahn: University of North Carolina at Chapel Hill School of Medicine
Eric S. Davis: University of North Carolina at Chapel Hill
Timothy A. Daugird: University of North Carolina at Chapel Hill School of Medicine
Shuai Zhao: University of North Carolina at Chapel Hill School of Medicine
Ivana Yoseli Quiroga: University of North Carolina at Chapel Hill
Hidetaka Uryu: University of North Carolina at Chapel Hill School of Medicine
Jie Li: University of North Carolina at Chapel Hill School of Medicine
Aaron J. Storey: University of Arkansas for Medical Sciences
Yi-Hsuan Tsai: University of North Carolina at Chapel Hill School of Medicine
Daniel P. Keeley: University of North Carolina at Chapel Hill
Samuel G. Mackintosh: University of Arkansas for Medical Sciences
Ricky D. Edmondson: University of Arkansas for Medical Sciences
Stephanie D. Byrum: University of Arkansas for Medical Sciences
Ling Cai: University of North Carolina at Chapel Hill School of Medicine
Alan J. Tackett: University of Arkansas for Medical Sciences
Deyou Zheng: and Neuroscience, Albert Einstein College of Medicine
Wesley R. Legant: University of North Carolina at Chapel Hill School of Medicine
Douglas H. Phanstiel: University of North Carolina at Chapel Hill School of Medicine
Gang Greg Wang: University of North Carolina at Chapel Hill School of Medicine

Nature, 2021, vol. 595, issue 7868, 591-595

Abstract: Abstract The development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human haematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains the nucleoporin IDR—tandemly dispersed repeats of phenylalanine and glycine residues1,2. However, how unstructured IDRs contribute to oncogenesis remains unclear. Here we show that IDRs contained within NUP98–HOXA9, a homeodomain-containing transcription factor chimera recurrently detected in leukaemias1,2, are essential for establishing liquid–liquid phase separation (LLPS) puncta of chimera and for inducing leukaemic transformation. Notably, LLPS of NUP98–HOXA9 not only promotes chromatin occupancy of chimera transcription factors, but also is required for the formation of a broad ‘super-enhancer’-like binding pattern typically seen at leukaemogenic genes, which potentiates transcriptional activation. An artificial HOX chimera, created by replacing the phenylalanine and glycine repeats of NUP98 with an unrelated LLPS-forming IDR of the FUS protein3,4, had similar enhancing effects on the genome-wide binding and target gene activation of the chimera. Deeply sequenced Hi-C revealed that phase-separated NUP98–HOXA9 induces CTCF-independent chromatin loops that are enriched at proto-oncogenes. Together, this report describes a proof-of-principle example in which cancer acquires mutation to establish oncogenic transcription factor condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumourous transformation. As LLPS-competent molecules are frequently implicated in diseases1,2,4–7, this mechanism can potentially be generalized to many malignant and pathological settings.

Date: 2021
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DOI: 10.1038/s41586-021-03662-5

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