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CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex [ATAC-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235299 | GEO | 2023/10/01

REPOSITORIES: GEO

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CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex [CUT&RUN]

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.

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CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex [ChIP-seq]

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Genomic studies controvert the existence of the CUX1 p75 isoform

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

CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex

Project description:CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex

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CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex [ChIP-seq]

Project description:CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex [ChIP-seq]

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CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex [ATAC-seq]

Project description:CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex [ATAC-seq]

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CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex [CUT&RUN]

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Next generation sequencing following CUX1 knockdown in erythroblasts

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

Functional genomic analysis of the haploinsufficient tumor suppressor, CUX1

Project description:CUX1 is a homeodomain-containing transcription factor that is conserved, ubiquitous, and essential in vertebrates and invertebrates. CUX1 is mutated or deleted in high-risk myeloid neoplasms and solid tumors, resulting in haploinsufficiency and tumor growth. Here we provide the first analysis of endogenous, whole genome, CUX1 DNA binding. We demonstrate that CUX1 binds with transcriptional activators and cohesin at distal enhancers across three different human cell types. Haploinsufficiency of CUX1 altered the expression of a large number of genes, including cell cycle regulators, with concomitant increased cellular proliferation. Surprisingly, CUX1 occupancy decreased genome-wide in the haploinsufficient state, and binding site affinity did not correlate with differential gene expression. Instead, differentially expressed genes had multiple, low-affinity CUX1 binding sites, consistent with an analog model for CUX1 gene regulation. A machine-learning algorithm determined that chromatin accessibility, enhancer activity, and distance to the transcription start site are features of functional CUX1 DNA binding. Moreover, CUX1 is enriched at sites of DNA looping, and these loops connect CUX1 to the promoters of target genes. We propose that CUX1 is an analog transcription factor that regulates target genes through higher order genome architecture.

2017-03-29 | GSE92882 | GEO

Transcriptomic analysis of neuroblastoma cells in response to stable over-expression of circular RNA derived from CUX1 gene (circ-CUX1)

Project description:Circular RNAs (circRNAs), a subclass of noncoding RNAs characterized by covalently closed continuous loops, play emerging roles in tumorigenesis and aggressiveness. However, the functions and underlying mechanisms of circRNAs in regulating neuroblastoma progression still remain elusive. We identify one circRNA derived from CUX1 (circ-CUX1) as a novel driver of neuroblastoma progression. To investigate the mechanisms underlying the oncogenic functions of circ-CUX1, we employed the Illumina HiSeq X Ten as a discovery platform to analyze the transcriptome profiling changes of human neuroblastoma IMR32 cells in response to stable over-expression of circ-CUX1. The results showed that stable over-expression of circ-CUX1 led to altered expression of 1215 human mRNAs, including 781 up-regulated genes and 434 down-regulated genes. Furthermore, we validated the RNA-seq results by real-time RT-PCR with high identity. Overall, our results provided fundamental information about the transcriptomic changes in response to circ-CUX1 over-expression in human tumor cells, and these findings will help us understand the pathogenesis of tumor progression.

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