CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex [ATAC-seq]
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ABSTRACT:
PROVIDER: PRJNA985674 | ENA |
REPOSITORIES: ENA
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Project description:CUX1 is a HOX-family transcription factor that is essential for development and differentiation of multiple tissues. CUX1 is recurrently mutated or deleted in cancer, particularly in myeloid malignancies. However, the mechanism by which CUX1 regulates gene expression and differentiation remains poorly understood, creating a barrier to understanding the tumor suppressive functions of CUX1. Herein, we demonstrate that CUX1 directs the BAF chromatin remodeling complex to DNA to increase chromatin accessibility in hematopoietic cells. CUX1 preferentially regulates lineage-specific enhancers, and CUX1 target genes are predictive of cell fate in vivo. These data indicate that CUX1 functions as a pioneer factor to epigenetically regulate hematopoietic lineage commitment and homeostasis, and CUX1 deficiency disrupts these processes in stem and progenitor cells, facilitating transformation.
2023-10-01 | GSE235303 | GEO
Project description:CUX1 is a HOX-family transcription factor that is essential for development and differentiation of multiple tissues. CUX1 is recurrently mutated or deleted in cancer, particularly in myeloid malignancies. However, the mechanism by which CUX1 regulates gene expression and differentiation remains poorly understood, creating a barrier to understanding the tumor suppressive functions of CUX1. Herein, we demonstrate that CUX1 directs the BAF chromatin remodeling complex to DNA to increase chromatin accessibility in hematopoietic cells. CUX1 preferentially regulates lineage-specific enhancers, and CUX1 target genes are predictive of cell fate in vivo. These data indicate that CUX1 functions as a pioneer factor to epigenetically regulate hematopoietic lineage commitment and homeostasis, and CUX1 deficiency disrupts these processes in stem and progenitor cells, facilitating transformation.
2023-10-01 | GSE235301 | GEO
Project description:CUX1 is a HOX-family transcription factor that is essential for development and differentiation of multiple tissues. CUX1 is recurrently mutated or deleted in cancer, particularly in myeloid malignancies. However, the mechanism by which CUX1 regulates gene expression and differentiation remains poorly understood, creating a barrier to understanding the tumor suppressive functions of CUX1. Herein, we demonstrate that CUX1 directs the BAF chromatin remodeling complex to DNA to increase chromatin accessibility in hematopoietic cells. CUX1 preferentially regulates lineage-specific enhancers, and CUX1 target genes are predictive of cell fate in vivo. These data indicate that CUX1 functions as a pioneer factor to epigenetically regulate hematopoietic lineage commitment and homeostasis, and CUX1 deficiency disrupts these processes in stem and progenitor cells, facilitating transformation.
2023-10-01 | GSE235299 | GEO
Project description:CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex
| PRJNA985668 | ENA
Project description:CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex [CUT&RUN]
| PRJNA985679 | ENA
Project description:CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex [ChIP-seq]
| PRJNA985672 | ENA
Project description:In order to study the genomic regions undergoing chromatin accessibility changes when BAF chromatin remodelling complex is inhibited, ATAC-Seq of SK-N-BE(2) neuroblastoma cells was performed after silencing of BAF structural subunits ARID1A and ARID1B.
2022-11-01 | GSE202306 | GEO
Project description:Loss-of-function mutations in genes coding for subunits of the large, multifarious BRG1/BRM associated factor (BAF) chromatin remodeling complexes are frequently causative for cancer or developmental diseases1-5. Cells lacking the most frequently mutated subunits like the ATPase SMARCA4 typically exhibit drastic chromatin accessibility changes, especially of important regulatory regions6-12. However, so far it remains unknown how these changes are established over time, and whether they are causative for intra-complex synthetic lethalities abrogating the formation (SMARCC1-SMARCC2)8,13,14 or activity (SMARCA4-SMARCA2)15-17 of BAF complexes. Here, we utilize the dTAG system18 to induce acute degradation of BAF subunits in wild-type and BAF mutant backgrounds and analyze the resulting chromatin accessibility changes with high kinetic resolution. We observe that chromatin alterations are established faster than the duration of one cell cycle and that maintaining genome accessibility requires constant ATP-dependent remodeling. Completely abolishing BAF complex function by acute degradation of a synthetic lethal subunit in a paralog-deficient background results in a near-complete loss of chromatin accessibility at BAF-controlled sites, especially at super-enhancers, providing a mechanism for intra-complex synthetic lethalities.
2020-12-23 | PXD018381 | Pride
Project description:Anemia is a significant cause of morbidity and mortality in myeloid malignances. Cytogenetic changes are recurrent within malignant hematopoietic stem and progenitor cells, yet their role in anemia pathogenesis remains unknown. One recurrent karyotypic abnormality in myeloid neoplasms is the deletion of part or all of chromosome 7 [-7/del(7q)], which harbors the transcription factor and tumor suppressor gene, CUX1. CUX1 knockdown mouse models develop myeloid disease similar to that seen in humans, including a spontaneous, cell intrinsic, and lethal anemia that develops with age. Here, we elucidate the cellular and molecular mechanisms by which CUX1 regulates erythropoiesis. We demonstrate CUX1 knockdown mice have an aberrant stress erythropoiesis response and decreased survival after acute anemia induction. CUX1 insufficient erythroblasts undergo accelerated cell cycling and increased apoptosis. In line with these phenotypes, transcriptome profiling indicates that CUX1-knockdown elicits increased proliferation and decreased erythroid differentiation gene signatures. ATAC-sequencing demonstrated dramatic, global chromatin opening in CUX1-knockdown erythroblasts. As measured by fluorescence lifetime imaging, this increased chromatin accessibility is concomitant with a disruption in nuclear condensation, which is normally requisite in mammalian erythroblasts for nuclear eviction and terminal differentiation. Finally, we show that CUX1 mediates chromatin compaction by promoting histone deacetylation. Thus, rather than a transcriptional role, our data implicate in an epigenetic regulatory role for CUX1 in erythropoiesis. Furthermore, these results suggest therapeutic targeting of epigenetic regulators, such as histone acetyl transferases, may have clinical benefit for the anemias associated with loss of CUX1.
2021-08-10 | GSE181626 | GEO
Project description:CUX1, a homeodomain-containing transcription factor, is recurrently deleted or mutated in multiple tumor types. In myeloid neoplasms, CUX1 deletion or mutation carries a poor prognosis. We have previously established that CUX1 functions as a tumor suppressor in hematopoietic cells across multiple organisms. Others, however, have described oncogenic functions of CUX1 in solid tumors, often attributed to truncated CUX1 isoforms, p75 and p110. Given the clinical relevance, it is imperative to clarify these discrepant activities. Herein, we sought to determine the CUX1 isoforms expressed in hematopoietic cells, and find that they express the full-length p200 isoform. Through the course of this analysis, we found no evidence of the p75 alternative transcript in any cell type examined. Using an array of orthogonal approaches, including biochemistry, proteomics, CRISPR/Cas9 genomic editing, and analysis of functional genomics datasets across a spectrum of normal and malignant tissue types, we found no data to support the existence of the CUX1 p75 isoform generated by an alternative transcriptional start site. Based on these results, prior studies of p75 require reevaluation, including the interpretation of oncogenic roles attributed to CUX1.
2022-02-17 | PXD027527 | Pride