Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Super-enhancer Driven Core Regulatory Circuitry in MYCN-amplified Neuroblastoma [ATAC-Seq]

ABSTRACT: Transcriptional dysregulation plays a major role in the development and progression of human tumors such as pediatric neuroblastoma. Therefore, we sought to elucidate the relationship between genes required for neuroblastoma cell growth and survival and the transcriptional core regulatory circuitry (CRC) that controls the gene expression program. A genome-scale CRISPR-Cas9 screen for oncogenic dependencies revealed that 143 genes are essential for cell survival and growth in neuroblastoma relative to other cancers, including many super-enhancer (SE) regulated transcription factors. Genome-wide occupancy analysis of transcription factor binding demonstrated that at least six of these transcription factors were both dependency genes and components of the CRC in MYCN-amplified neuroblastoma including: HAND2, ISL1, PHOX2B, GATA3, TBX2, and MEIS2. Binding sites for these transcription factors were clustered within a few hundred base pairs in their own enhancers and the enhancers of downstream target genes, which surprisingly included 40% of the independently determined neuroblastoma dependency genes. This profound level of transcriptional control of oncogenesis through self-reinforcing transcriptional circuits led us to test combinatorial pharmacological inhibition of transcriptional initiation and elongation, which synergistically induced tumor cell death, supporting Òdrugging transcriptionÓ as a means to advance the treatment of high risk neuroblastoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94823 | GEO | 2018/05/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Super-enhancer Driven Core Regulatory Circuitry in MYCN-amplified Neuroblastoma [array]

Project description:Transcriptional dysregulation plays a major role in the development and progression of human tumors such as pediatric neuroblastoma. Therefore, we sought to elucidate the relationship between genes required for neuroblastoma cell growth and survival and the transcriptional core regulatory circuitry (CRC) that controls the gene expression program. A genome-scale CRISPR-Cas9 screen for oncogenic dependencies revealed that 143 genes are essential for cell survival and growth in neuroblastoma relative to other cancers, including many super-enhancer (SE) regulated transcription factors. Genome-wide occupancy analysis of transcription factor binding demonstrated that at least six of these transcription factors were both dependency genes and components of the CRC in MYCN-amplified neuroblastoma including: HAND2, ISL1, PHOX2B, GATA3, TBX2, and MEIS2. Binding sites for these transcription factors were clustered within a few hundred base pairs in their own enhancers and the enhancers of downstream target genes, which surprisingly included 40% of the independently determined neuroblastoma dependency genes. This profound level of transcriptional control of oncogenesis through self-reinforcing transcriptional circuits led us to test combinatorial pharmacological inhibition of transcriptional initiation and elongation, which synergistically induced tumor cell death, supporting drugging transcription as a means to advance the treatment of high risk neuroblastoma.

2018-05-22 | GSE108914 | GEO

Super-enhancer Driven Core Regulatory Circuitry in MYCN-amplified Neuroblastoma [ChIP-Seq]

Project description:Transcriptional dysregulation plays a major role in the development and progression of human tumors such as pediatric neuroblastoma. Therefore, we sought to elucidate the relationship between genes required for neuroblastoma cell growth and survival and the transcriptional core regulatory circuitry (CRC) that controls the gene expression program. A genome-scale CRISPR-Cas9 screen for oncogenic dependencies revealed that 143 genes are essential for cell survival and growth in neuroblastoma relative to other cancers, including many super-enhancer (SE) regulated transcription factors. Genome-wide occupancy analysis of transcription factor binding demonstrated that at least six of these transcription factors were both dependency genes and components of the CRC in MYCN-amplified neuroblastoma including: HAND2, ISL1, PHOX2B, GATA3, TBX2, and MEIS2. Binding sites for these transcription factors were clustered within a few hundred base pairs in their own enhancers and the enhancers of downstream target genes, which surprisingly included 40% of the independently determined neuroblastoma dependency genes. This profound level of transcriptional control of oncogenesis through self-reinforcing transcriptional circuits led us to test combinatorial pharmacological inhibition of transcriptional initiation and elongation, which synergistically induced tumor cell death, supporting Òdrugging transcriptionÓ as a means to advance the treatment of high risk neuroblastoma.

2018-05-22 | GSE94822 | GEO

Heterogeneity of neuroblastoma cell identity revealed by transcriptional circuitries

Project description:Neuroblastoma is a tumor of the peripheral sympathetic nervous system, derived from multipotent neural crest cells (NCCs). To define Core Regulatory Circuitries (CRCs) controlling the gene expression program of neuroblastoma, we established and analyzed the neuroblastoma super-enhancer landscape. We discovered three types of identity in neuroblastoma cell lines: a sympathetic noradrenergic identity defined by a CRC module including the PHOX2B, HAND2 and GATA3 transcription factors (TFs); an NCC-like identity, driven by a CRC module containing AP-1 family TFs; a mixed type further deconvoluted at the single cell level. Treatment of the mixed type with chemotherapeutic agents resulted in enrichment of NCC-like cells. The noradrenergic module was validated by ChIP-seq. Functional studies demonstrated dependency of neuroblastoma with noradrenergic identity on PHOX2B, evocative of lineage addiction. Most neuroblastoma primary tumors express TFs from the noradrenergic and NCC-like modules. Our data demonstrate a novel aspect of tumor heterogeneity relevant for neuroblastoma treatment strategies.

2017-07-01 | GSE90683 | GEO

Retinoic acid rewires the adrenergic core regulatory circuitry of neuroblastoma but can be subverted by enhancer hijacking of MYC or MYCN (CUT&RUN-Seq)

Project description:Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that incorporate MYCN to drive the oncogenic gene expression program. For neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation in both primary neuroblastomas and cell lines; however, the underlying mechanisms remain unclear. Here we show that when MYCN-amplified neuroblastomas cells are treated with all-trans retinoic acid (ATRA), they undergo modifications of histone H3K27 acetylation and methylation that decommission super-enhancers driving the expression of PHOX2B and GATA3, together with the activation of new super-enhancers that drive high levels of expression of MEIS1, HIC1 and SOX4. These findings indicate that treatment with ATRA can reprogram the enhancer landscape to collapse the adrenergic CRC, which downregulates MYCN expression, while upregulating a new “retino-sympathetic” CRC that causes proliferative arrest and sympathetic differentiation. Thus, we provide mechanisms that account for the beneficial effects of retinoids against high-risk neuroblastoma and explain the rapid downregulation of expression of MYCN despite massive levels of gene amplification.

2021-10-25 | GSE169616 | GEO

Retinoic acid rewires the adrenergic core regulatory circuitry of neuroblastoma but can be subverted by enhancer hijacking of MYC or MYCN (RNA-Seq)

2021-10-25 | GSE155000 | GEO

Retinoic acid rewires the adrenergic core regulatory circuitry of neuroblastoma but can be subverted by enhancer hijacking of MYC or MYCN (ChIP-Seq)

2021-10-25 | GSE154999 | GEO

KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [ChIP-seq]

Project description:A small set of interconnected lineage-specific transcription factors (TFs) form a core regulatory circuitry (CRC) that establishes and maintains cell identity and grants selective dependencies of distinct cancer types. However, effective therapies to targeting CRC TFs remain lacking. Here, we show that the best-in-class KDM4 inhibitor QC6352 has a potent anticancer activity in MYCN-driven high-risk neuroblastoma and significantly represses the CRC TFs including MYCN, HAND2, ASCL1, PHOX2B by disrupting the super-enhancers that dominate the expression of CRC TFs. Furthermore, we have developed a combination therapy by integrating QC6352 into cytotoxic chemotherapy, which leads to a complete response of MYCN amplified tumors and a better animal survival. This study reveals that targeting histone lysine demethylase 4 family may transform into a therapeutic strategy in clinic for cancers driven by CRC TFs.

2024-03-04 | GSE164451 | GEO

KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [ATAC-seq]

2024-03-04 | GSE164450 | GEO

KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [RNA-seq]

2024-03-04 | GSE164455 | GEO

KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [Cut&Tag]

2024-03-04 | GSE164454 | GEO