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Phase separation of phospho-HDAC6 drives aberrant chromatin architecture in triple-negative breast cancer [Hi-C]

ABSTRACT: To investigate the Nexturastat A effects on chromatin structure which disrupt phospho-HDAC6 LLPS in triple-negative breast cancer (TNBC), we conducted the analysis of Hi-C in TNBC cells treated with or without Nexturastat A.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254213 | GEO | 2024/05/09

REPOSITORIES: GEO

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Project description:Development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human hematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains nucleoporin’s IDR, tandemly dispersed phenylalanine-and-glycine (FG) repeats. However, it remains largely elusive how unstructured IDRs contribute to oncogenesis. We here show that IDR or FG repeats harbored within NUP98-HOXA9, a HOX transcription factor (TF) chimera recurrently detected in acute leukemia patients, is essential for establishing nuclear liquid-liquid phase separation (LLPS) puncta and for inducing leukemic transformation of primary hematopoietic cells in vitro and in vivo. Strikingly, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera TF oncoproteins but is also required for formation of a broad, ‘super-enhancer’-like binding pattern, typically seen at a battery of leukemia-related loci exemplified by HOX, MEIS and PBX genes, potentiating their transcriptional activation. An artificial HOX chimera, created by replacing NUP98’s FG repeats with an unrelated LLPS-forming IDR of FUS, had similar enhancement effects on chimera’s chromatin binding and target gene activation. Via Hi-C mapping, we further demonstrated that the phase-separated NUP98-HOXA9 protein assembly is able to induce de novo formation of CTCF-independent chromatin looping enriched at leukemic oncogenes. Together, this report describes a proof-of-principle example wherein cancer acquires mutation to establish multi-molecule assemblies of oncogenic TFs via a phase separation mechanism, which simultaneously enhances their chromatin targeting and induces organization of aberrant three-dimensional chromatin structure during tumorous transformation. As a range of LLPS-competent molecules are implicated in various human cancers, this mechanism can potentially be generalized to many malignant and diseased settings.

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Phase separation of phospho-HDAC6 drives aberrant chromatin architecture in triple-negative breast cancer [Hi-C]

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