Phase separation drives aberrant chromatin looping and cancer development

Nature. 2021 Jul;595(7868):591-595. doi: 10.1038/s41586-021-03662-5. Epub 2021 Jun 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis
  • Chromatin / genetics*
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Homeodomain Proteins / genetics*
  • Humans
  • Intrinsically Disordered Proteins / genetics*
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms / genetics
  • Neoplasms / pathology*
  • Nuclear Pore Complex Proteins / genetics*
  • Oncogene Proteins, Fusion / genetics
  • Transcription Factors / genetics
  • Transcriptional Activation
  • Translocation, Genetic*

Substances

  • Chromatin
  • Homeodomain Proteins
  • Intrinsically Disordered Proteins
  • Nuclear Pore Complex Proteins
  • Nup98 protein, human
  • Oncogene Proteins, Fusion
  • Transcription Factors
  • homeobox protein HOXA9