Ontology highlight
ABSTRACT:
PROVIDER: PRJNA778966 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16889121_1.fastq.gz | Fastqsanger.gz | |||
| SRR16889121_2.fastq.gz | Fastqsanger.gz |
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Project description:In precursor B-cell acute lymphoblastic leukemia (ALL), whole chromosome uniparental isodisomy (wUPD) occurs almost uniquely in the high hyperdiploid (51-67 chromosomes) (HH) subtype. Comparison of 26 HH with wUPD with 31 with noUPD, showed a higher modal number of chromosomes and gains of 5+ in wUPD. Mutations in genes within epigenetic pathways with upregulation of genes involved in cellular response to stress and stimuli, and mutations in RAS/RTK pathways and upregulation of genes in RNA Polymerase III pathway were seen in wUPD and noUPD respectively. Though overall outcomes were similar in patient with and without wUPD, those with noUPD were more likely to have residual disease after treatment. Differential gene expression between the two groups showed upregulation of genes involved in thiopurine drug resistance in wUPD. Genome-wide differences between HH ALL with and without UPD identified plausible biological explanations for the heterogeneity in therapeutic response in HH ALL.
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Project description:Paracrine Hedgehog (Hh) signaling regulates growth and patterning in many Drosophila organs. We mapped chromatin binding sites for Cubitus interruptus (Ci), the transcription factor that mediates outputs of Hh signal transduction, and we analyzed transcription profiles of control and mutant embryos to identify genes that are regulated by Hh. Putative targets we identified include several Hh pathway components, most previously identified targets, and many targets that are novel. Analysis of expression patterns of pathway components and target genes gave evidence of autocrine Hh signaling in the optic primordium of the embryo. And, every Hh target we analyzed that is not a pathway component appeared to be regulated by Hh in a tissue-specific manner. We present evidence that Hh-dependent tissue specificity is dependent upon transcription factors that are Hh-independent, suggesting that “pre-patterns” of transcription factors partner with Ci to make Hh-dependent gene expression position-specific. We utilized the DamID method to identify regions of CiRep methylated genomic DNA in stage 10-11 Drosophila embryos.
2010-11-03 | GSE24024 | GEO
Project description:Paracrine Hedgehog (Hh) signaling regulates growth and patterning in many Drosophila organs. We mapped chromatin binding sites for Cubitus interruptus (Ci), the transcription factor that mediates outputs of Hh signal transduction, and we analyzed transcription profiles of control and mutant embryos to identify genes that are regulated by Hh. Putative targets we identified include several Hh pathway components, most previously identified targets, and many targets that are novel. Analysis of expression patterns of pathway components and target genes gave evidence of autocrine Hh signaling in the optic primordium of the embryo. And, every Hh target we analyzed that is not a pathway component appeared to be regulated by Hh in a tissue-specific manner. We present evidence that Hh-dependent tissue specificity is dependent upon transcription factors that are Hh-independent, suggesting that “pre-patterns” of transcription factors partner with Ci to make Hh-dependent gene expression position-specific. We utilized the DamID method to identify regions of CiAct methylated genomic DNA in stage 10-11 Drosophila embryos.
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Project description:Aberrant activation of Hedgehog (Hh) signaling pathway plays important roles in both oncogenesis and targeted therapy of many cancers. The clinical application of FDA-approved Hh-targeted Smoothened inhibitor (SMOi) drugs is hindered due to the emergence of various primary or acquired drug resistance, indicating the need of novel anti-Hh therapies. Our previous studies demonstrate that epigenetic/transcriptional targeted therapies represent a promising direction for anti-Hh drug development. In this study, we identified CDK9 and CDK12, two transcription elongation regulators, as novel therapeutic targets for antagonizing the aberrant Hh pathway and overcoming SMOi resistance. CDK9 inhibition and CDK12 inhibition exhibited similarly potent anti-Hh activities when treating various SMOi responsive or resistant Hh-driven tumor models as previously reported BET inhibition or CDK7 inhibition. We also utilized SHH-subtype medulloblastoma (SHH-MB) as the representative Hh-driven cancer model to perform Super-enhancer (SE) analysis and elucidate the crucial roles of SE in Hh-driven oncogenesis and above-mentioned anti-Hh epigenetic/transcriptional targeted therapies. Furthermore, we identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the IGF pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target of multiple Hh-driven tumor models, including the SMOi-resistant ones. Collectively, our study demonstrates that the SE-driven transcriptional dependencies represent promising therapeutic vulnerabilities for suppressing the aberrant Hh pathway and overcoming the SMOi resistance. As CDK9 inhibitor and IRS inhibitor drugs have already entered human clinical trials for cancer treatment, our study provides comprehensive preclinical support for expanding their trials to Hh-driven cancers in near future.
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Project description:Misactivation of the Hedgehog (Hh) pathway can cause cancers such as medulloblastomas, the most common malignant brain tumor in children, and basal cell carcinomas, the most common cancer in the United States. Hedgehog signals are transmitted through primary cilia, where Hedgehog ligands bind to Patched1 and activate Smoothened through interactions with cilia-associated sterol lipids. The gene expression programs driving cellular responses to ciliary Hh signals are incompletely understood. Thus, to define Hh target genes, we performed RNA sequencing of cells after treatment with Hh ligands (Shh, Dhh, Ihh), cilia-associated lipids (7b,27-dihydroxycholesterol, 24(S),25-epoxycholesterol), or synthetic lipids or small molecules that activate Smoothened (20(S)-hydroxycholesterol, SAG). Treatment with Hh pathway agonists identified a core gene expression program comprised of 155 genes driving lipid synthesis, metabolism, signaling, adhesion, or angiogenesis. These datasets were integrated with RNA sequencing of Hh-human medulloblastomas (n=?), a Math1-Cre SmoM2 mouse genetic model of Hh-associated medulloblastoma (n=?), and human basal cell carcinomas (n=10) to ascertain how malignant Hh signaling differs from canonical Hh signaling. We discover a conserved response to ciliary Hh signals in human or mouse medulloblastomas, including known target genes such as Gli1 or Ptch1, and novel target genes such as Hsd11b1 or Retnla. Importantly, mechanistic studies reveal Hsd11b1 to be a putative negative regulator of Hh signaling that is dysregulated in malignancies. We further demonstrate Retnla to be a positive regulator of Hh signaling that drives expression of Hsd11b2, a druggable dependency underlying Hedgehog-associated medulloblastoma. Orthotopic implantation of neuroepithelial stem cells that overexpress either Hsd11b1 and Retnla demonstrate that tumors derived Hsd11ß1 overexpression are more primitive and less aggressive whereas Retnla overexpression forms tumors that are more differentiated and behave more aggressively. In sum, we illuminate the first comprehensive transcriptome of Hh signaling and highlight the intricate interplay between Hh signaling and lipid metabolism that Hh-dependent malignancies dysregulate to drive tumor progression.
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Project description:In this study, we used ATAC sequencing to compare the chromatin landscape of esophageal cells in which hedgehog (HH) pathway has been activated (K5SmoM2), to control esophageal cells (WT). We identified more than 50% of the peaks differentially opened in both conditions. Among these differentially opened peaks in EpHI cells, we identified chromatin regions in key columnar markers. Taken together these results show that HH pathway activation triggers chromatin landscape remodeling to facilitate transcommitment.
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Project description:X-chromosome inactivation (XCI) is the process that leads to silencing of one X-chromosome in female mammals. XCI is essential to peri-implantation development and is thought to be cell-autonomous, with all factors required to execute silencing being produced within each cell. Nevertheless, external cues to time XCI must exist in vivo, but such developmental signals have yet to be identified. Using multiple approaches to identify developmental regulators of XCI, we identify Indian Hedgehog (IHH) signaling as critical to this process. We demonstrate that IHH signaling keeps XCI in check in pluripotent cells. HH signal transduction through GLI transcription factors regulates XCI by directly binding control elements at the 5’ end of Tsix, the antisense repressor of XCI. GLI binding potentiates Tsix expression and thereby impedes XCI. In vivo, mutating Ihh results in a sex ratio bias against females. Importantly, this female-specific lethality is rescued by a second-site mutation in Tsix. We propose that XCI in the epiblast is regulated by IHH expressed from the visceral endoderm. Our data connect the HH and XCI pathways and support a role of cell-to-cell communication in the developmental timing of XCI.
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