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Updated: Jan 21, 2026
Assembly of Nucleosomal Arrays from Recombinant Core Histones and Nucleosome Positioning DNA
Published on: September 10, 2013
Increase in DNA Damage by MYCN Knockdown Through Regulating Nucleosome Organization and Chromatin State in
Xinjie Hu1, Weisheng Zheng1, Qianshu Zhu1
1Institute of Translational Research, Tongji Hospital, the School of Life Sciences and Technology, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, China.
Abstract:
As a transcription factor, MYCN regulates myriad target genes including the histone chaperone FACT. Moreover, FACT and MYCN expression form a forward feedback loop in neuroblastoma. It is unclear whether MYCN is involved in chromatin remodeling in neuroblastoma through regulation of its target genes. We showed here that MYCN knockdown resulted in loss of the nucleosome-free regions through nucleosome assembly in the promoters of genes functionally enriched for DNA repair. The active mark H3K9ac was removed or replaced by the repressive mark H3K27me3 in the promoters of double-strand break repair-related genes upon MYCN knockdown. Such chromatin state alterations occurred only in MYCN-bound promoters. Consistently, MYCN knockdown resulted in a marked increase in DNA damage in the treatment with hydroxyurea. In contrast, nucleosome reorganization and histone modification changes in the enhancers largely included target genes with tumorigenesis-related functions such as cell proliferation, cell migration, and cell-cell adhesion. The chromatin state significantly changed in both MYCN-bound and MYCN-unbound enhancers upon MYCN knockdown. Furthermore, MYCN knockdown independently regulated chromatin remodeling in the promoters and the enhancers. These findings reveal the novel epigenetic regulatory role of MYCN in chromatin remodeling and provide an alternative potential epigenetic strategy for MYCN-driven neuroblastoma treatment.
Insights
MYCN knockdown disrupts chromatin remodeling in neuroblastoma, affecting DNA repair genes and tumorigenesis pathways. This reveals a novel epigenetic role for MYCN, offering potential new treatments for MYCN-driven neuroblastoma.
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Research
Background:
- MYCN is a key transcription factor in neuroblastoma, regulating target genes like FACT.
- A feedback loop exists between MYCN and FACT in neuroblastoma.
- MYCN's role in chromatin remodeling via target gene regulation in neuroblastoma remains unclear.
Purpose of the Study:
- To investigate the role of MYCN in chromatin remodeling in neuroblastoma.
- To determine if MYCN regulates chromatin remodeling through its target genes.
- To explore potential epigenetic therapeutic strategies for MYCN-driven neuroblastoma.
Main Methods:
- MYCN knockdown in neuroblastoma cells.
- Analysis of nucleosome positioning and histone modifications (H3K9ac, H3K27me3) at gene promoters and enhancers.
- Assessment of DNA damage response using hydroxyurea treatment.
- Chromatin immunoprecipitation to identify MYCN-bound regions.
Main Results:
- MYCN knockdown led to nucleosome assembly in promoters of DNA repair genes, loss of H3K9ac, and gain of H3K27me3, specifically at MYCN-bound sites.
- Increased DNA damage was observed upon MYCN knockdown.
- Enhancers showed altered chromatin states affecting tumorigenesis-related genes, irrespective of MYCN binding.
- MYCN independently regulated chromatin remodeling at both promoters and enhancers.
Conclusions:
- MYCN plays a novel epigenetic role in regulating chromatin remodeling in neuroblastoma.
- MYCN's regulation of chromatin remodeling impacts DNA repair and tumorigenesis pathways.
- Targeting MYCN's epigenetic functions presents a potential therapeutic strategy for neuroblastoma.
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