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Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
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Ectopic protein interactions within BRD4-chromatin complexes drive oncogenic megadomain formation in NUT midline

Artyom A Alekseyenko1,2, Erica M Walsh3, Barry M Zee1,2

  • 1Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.

Proceedings of the National Academy of Sciences of the United States of America
|May 10, 2017
PubMed

Insights

NUT midline carcinoma (NMC) involves mistargeted chromatin due to BRD4-NUT fusion proteins. This study identifies EP300 and ZNF532 as key interactors, revealing a mechanism driving oncogenic complex propagation in NMC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • NUT midline carcinoma (NMC) is driven by oncogenic fusion proteins.
  • The precise mechanisms of chromatin dysregulation in NMC are not fully understood.

Purpose of the Study:

  • To investigate the protein interactions and molecular mechanisms underlying chromatin mistargeting in NMC.
  • To identify unique interactions of the BRD4-NUT fusion oncoprotein.

Main Methods:

  • Cross-linking, affinity purification, and mass spectrometry were used to identify protein interactions.
  • Chromatin immunoprecipitation (ChIP) sequencing was performed to analyze the localization of key proteins and histone modifications.
  • Biochemical and genetic approaches were employed to study the functional significance of identified interactions.

Main Results:

  • EP300 acetyltransferase was identified as uniquely associated with BRD4 through the NUT fusion.
  • ZNF532 was found associated with BRD4-NUT in NMC patient cells.
  • A ZNF532-NUT translocation fusion was discovered, forming hyperacetylated megadomains analogous to BRD4-NUT.
  • These proteins are implicated in feed-forward regulatory loops propagating the oncogenic chromatin complex.

Conclusions:

  • NMC pathogenesis involves ectopic NUT-mediated interactions between EP300 and BRD4 regulatory complexes.
  • This interaction leads to a cascade of chromatin misregulation and supports a model of NMC dependency on these aberrant complexes.
Keywords:
BRD4BioTAP-XLZNF532–NUThyperacetylationtopological domains

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