Phase separation drives aberrant chromatin looping and cancer development [ChIP-Seq]
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ABSTRACT:
PROVIDER: PRJNA602701 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Phase separation drives aberrant chromatin looping and cancer development [RNA-Seq]
| PRJNA604380 | ENA
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 elusive how unstructured IDRs contribute to oncogenesis. We show that IDR harbored within NUP98-HOXA9, a homeodomain-containing transcription factor (TF) chimera recurrently detected in leukemias, is essential for establishing liquid-liquid phase separation (LLPS) puncta of chimera and for inducing leukemic transformation. Strikingly, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera TFs but is also required for formation of a broad, ?super-enhancer?-like binding pattern, typically seen at a battery of leukemogenic genes, potentiating their transcriptional activation. Artificial HOX chimera (FUS-HOXA9), created by replacing NUP98?s FG repeats with an unrelated LLPS-forming IDR of FUS, had similar enhancement effects on chimera?s genome-wide binding and target gene activation. Hi-C mapping further demonstrated that phase-separated NUP98-HOXA9 induces CTCF-independent chromatin looping enriched at proto-oncogenes. Together, this report describes a proof-of-principle example wherein cancer acquires mutation to establish oncogenic TF condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumorous transformation. As LLPS-competent molecules are frequently implicated in diseases, this mechanism can potentially be generalized to many malignant and pathological settings.
2021-04-19 | GSE144642 | GEO
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 elusive how unstructured IDRs contribute to oncogenesis. We show that IDR harbored within NUP98-HOXA9, a homeodomain-containing transcription factor (TF) chimera recurrently detected in leukemias, is essential for establishing liquid-liquid phase separation (LLPS) puncta of chimera and for inducing leukemic transformation. Strikingly, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera TFs but is also required for formation of a broad, ?super-enhancer?-like binding pattern, typically seen at a battery of leukemogenic genes, potentiating their transcriptional activation. Artificial HOX chimera (FUS-HOXA9), created by replacing NUP98?s FG repeats with an unrelated LLPS-forming IDR of FUS, had similar enhancement effects on chimera?s genome-wide binding and target gene activation. Hi-C mapping further demonstrated that phase-separated NUP98-HOXA9 induces CTCF-independent chromatin looping enriched at proto-oncogenes. Together, this report describes a proof-of-principle example wherein cancer acquires mutation to establish oncogenic TF condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumorous transformation. As LLPS-competent molecules are frequently implicated in diseases, this mechanism can potentially be generalized to many malignant and pathological settings.
2021-04-19 | GSE144076 | GEO
Project description:Glycogen phase separation drives liver tumor initiation
| PRJNA626580 | ENA
Project description:Components of the transcription machinery can undergo liquid-liquid phase separation, but the functional importance of phase-separated condensates in transcriptional control is not well understood. Here we report that disease-causing mutations in several transcription factors (TFs) alter the phase separation capacity of those TFs. We first demonstrate that the Hoxd13 TF, and its intrinsically disordered N-terminus form phase-separated condensates. Expansions of a polyalanine repeat, which cause hereditary synpolydactyly in humans, facilitate phase separation of Hoxd13, and alter the transcriptional program of several cell types in a cell-specific manner in vivo. Disease-associated expansions of aminoacid repeats in intrinsically disordered regions of other TFs were similarly found to alter phase separation. These results suggest that aberrant phase separation of transcriptional regulators may underlie a spectrum of human pathologies. The paper is available at https://doi.org/10.1016/j.cell.2020.04.018
2020-05-07 | GSE128818 | GEO
Project description: Not available
| S-EPMC8647409 | biostudies-literature
Project description:Aberrant phase separation of transcription factors in human developmental disorders
| PRJNA528953 | ENA
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.
2021-04-22 | PXD023548 | Pride
Project description:Glycogen is the largest soluble cytosolic macromolecule and considered as the principal storage form of glucose. Cancer cells generally increase their glucose consumption and rewire their metabolism towards aerobic glycolysis to promote growth. Here we report that glycogen accumulation is a key initiating oncogenic event and essential for malignant transformation. RNA-sequencing analysis reveals that G6PC, an enzyme catalyzing the last step of glycogenolysis, is frequently downregulated to augment glucose storage in pro-tumor cells. Accumulated glycogen undergoes liquid-liquid phase separation undergoes liquid-liquid phase separation, which results in the assembly of the laforin-Mst1/2 complex and consequently traps Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme PYGL deficiency in both human and mice result in glycogen storage disease with enlarged liver size and cancer development, phenocopying Hippo deficiency. Consistently, elimination of glycogen accumulation abrogates liver enlargement and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that glycogen not only provides nutrition and energy to the cells but also functions as a key initiating oncogenic metabolite, which physically blocks Hippo signaling through glycogen phase separation to augment pro-tumor cell initiation and progression.
2021-10-06 | GSE148933 | GEO
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.
2021-04-19 | GSE143465 | GEO