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Published on: August 25, 2023
Unveiling MYCN regulatory networks in neuroblastoma via integrative analysis of heterogeneous genomics data
Chia-Lang Hsu1, Hsin-Yi Chang1, Jen-Yun Chang1
1Department of Life Science, Institute of Molecular and Cellular Biology, Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 106, Taiwan.
Abstract:
MYCN, an oncogenic transcription factor of the Myc family, is a major driver of neuroblastoma tumorigenesis. Due to the difficulty in drugging MYCN directly, revealing the molecules in MYCN regulatory networks will help to identify effective therapeutic targets for neuroblastoma therapy. Here we perform ChIP-sequencing and small RNA-sequencing of neuroblastoma cells to determine the MYCN-binding sites and MYCN-associated microRNAs, and integrate various types of genomic data to construct MYCN regulatory networks. The overall analysis indicated that MYCN-regulated genes were involved in a wide range of biological processes and could be used as signatures to identify poor-prognosis MYCN-non-amplified patients. Analysis of the MYCN binding sites showed that MYCN principally served as an activator. Using a computational approach, we identified 32 MYCN co-regulators, and some of these findings are supported by previous studies. Moreover, we investigated the interplay between MYCN transcriptional and microRNA post-transcriptional regulations and identified several microRNAs, such as miR-124-3p and miR-93-5p, which may significantly contribute to neuroblastoma pathogenesis. We also found MYCN and its regulated microRNAs acted together to repress the tumor suppressor genes. This work provides a comprehensive view of MYCN regulations for exploring therapeutic targets in neuroblastoma, as well as insights into the mechanism of neuroblastoma tumorigenesis.
Insights
MYCN drives neuroblastoma; this study maps its regulatory network, identifying co-regulators and microRNAs (miRNAs) that could be therapeutic targets for this cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- MYCN is a key driver of neuroblastoma, a challenging cancer.
- Directly targeting MYCN is difficult, necessitating exploration of its regulatory network for therapeutic strategies.
Purpose of the Study:
- To construct a comprehensive MYCN regulatory network in neuroblastoma.
- To identify MYCN co-regulators and microRNAs (miRNAs) involved in neuroblastoma pathogenesis.
- To explore the interplay between MYCN's transcriptional and miRNA-mediated regulations.
Main Methods:
- ChIP-sequencing and small RNA-sequencing were performed on neuroblastoma cells.
- Genomic data integration was used to build the MYCN regulatory network.
- Computational approaches identified MYCN co-regulators and associated miRNAs.
Main Results:
- MYCN-regulated genes are implicated in diverse biological processes and can predict prognosis in MYCN-non-amplified neuroblastoma.
- MYCN primarily functions as a transcriptional activator.
- 32 MYCN co-regulators were identified, and specific miRNAs (e.g., miR-124-3p, miR-93-5p) were linked to neuroblastoma pathogenesis.
- MYCN and its regulated miRNAs cooperate to suppress tumor suppressor genes.
Conclusions:
- This study provides a detailed map of MYCN regulatory networks in neuroblastoma.
- Identified co-regulators and miRNAs represent potential therapeutic targets for neuroblastoma.
- The findings offer insights into the molecular mechanisms driving neuroblastoma tumorigenesis.
