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Nuclear Pores provide a scaffold for induced enhancer promoter contacts

ABSTRACT: We found that in addition to promoters, multiple Nups bind enhancers and insulators in the Drosophila genome. We identified a functional role for Nup98 in mediating enhancer-promoter looping at ecdysone-inducible genes. These genes were found to be stably associated with nuclear pores before and after activation. Interestingly, although changing the levels of Nup98 disrupted induced enhancer-promoter contact, it did not affect transcriptional activation. Instead, loss of Nup98-mediated enhancer-promoter contact affected the primed response to subsequent transcriptional activation or transcriptional memory. In support of the enhancer-looping role, we found Nup98 to gain and retain physical interactions with several architectural proteins upon stimulation with ecdysone.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE94922 | GEO | 2017/03/30

SECONDARY ACCESSION(S): PRJNA374851

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-andglycine (FG) repeats1-3. However, it remains largely elusive how unstructured IDRs contribute to oncogenesis. We here show that IDR or FG repeats harbored within NUP98-HOXA9, a homeodomain-containing transcription factor (TF) chimera recurrently detected in acute leukemia patients1,4,5, 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 LLPSforming IDR of FUS6,7, 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 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 condensates 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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Nuclear Pores provide a scaffold for induced enhancer promoter contacts

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