[초청강연] Biomolecular condensates in cancer developmen

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
leukaemias, 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 protein, 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 diseases, this mechanism can potentially be
generalized to many malignant and pathological settings.