Genomics

Dataset Information

45

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. Overall design: ATAC-Seq in neuroblastoma cell types

INSTRUMENT(S): Illumina NextSeq 500 (Homo sapiens)

SUBMITTER: Richard A Young  

PROVIDER: GSE94823 | GEO | 2018-05-22

REPOSITORIES: GEO

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Publications


Childhood high-risk neuroblastomas with MYCN gene amplification are difficult to treat effectively<sup>1</sup>. This has focused attention on tumor-specific gene dependencies that underlie tumorigenesis and thus provide valuable targets for the development of novel therapeutics. Using unbiased genome-scale CRISPR-Cas9 approaches to detect genes involved in tumor cell growth and survival<sup>2-6</sup>, we identified 147 candidate gene dependencies selective for MYCN-amplified neuroblastoma cell l  ...[more]

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