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The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains

Artyom A Alekseyenko1, Erica M Walsh2, Xin Wang3

  • 1Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts, 02115, USA;

Genes & Development
|July 30, 2015
PubMed

Insights

NUT midline carcinoma (NMC) involves aggressive cancer driven by BRD4-NUT oncoprotein. This study reveals large, hyperacetylated chromatin "megadomains" that drive tumor growth by altering gene transcription.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • NUT midline carcinoma (NMC) is an aggressive squamous cell cancer driven by the BRD4-NUT oncoprotein.
  • BRD4-NUT disrupts normal cellular differentiation and promotes tumor cell proliferation.
  • BRD4-NUT forms nuclear foci associated with aberrant chromatin structures.

Purpose of the Study:

  • To investigate the nature of chromatin structures associated with BRD4-NUT.
  • To understand how these structures contribute to NMC pathogenesis.
  • To explore the role of large-scale chromatin organization in lineage-specific transcription.

Main Methods:

  • Analysis of patient tumor samples and cell lines.
  • Chromatin immunoprecipitation and sequencing (ChIP-seq) to identify hyperacetylated regions.
  • 3D genome organization analysis to study topologically associating domains (TADs).

Main Results:

  • Identified large, hyperacetylated chromatin expanses ('megadomains') up to 2 Mb in size, associated with BRD4-NUT.
  • Demonstrated that megadomains result from aberrant acetylation-driven feed-forward loops.
  • Showed that megadomains target specific lineage-associated genes, including cMYC and TP63, crucial for tumor growth.
  • Observed that megadomain expansion is constrained by TAD boundaries.

Conclusions:

  • BRD4-NUT drives NMC by creating large-scale, aberrant chromatin megadomains.
  • These megadomains aberrantly regulate lineage-specific gene transcription, promoting tumor growth.
  • Findings provide a framework for understanding the impact of chromatin organization on cancer development.
Keywords:
BRD4chromatin hyperacetylationtopological domains

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