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Inositol pyrophosphates regulate JMJD2C-dependent histone demethylation.

Adam Burton1, Cristina Azevedo, Catia Andreassi

  • 1Medical Research Council Cell Biology Unit and Department of Cell and Developmental Biology, Medical Research Council Laboratory for Molecular Cell Biology, and Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|November 6, 2013
PubMed
Summary

Inositol pyrophosphates (IP7) signaling, regulated by inositol hexakisphosphate kinase 1 (IP6K1), influences chromatin by interacting with JMJD2C. This epigenetic regulation impacts histone modifications and gene transcription.

Keywords:
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Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cell Signaling

Background:

  • Chromatin modifications are crucial for eukaryotic gene regulation in response to environmental stimuli.
  • Intracellular pathways governing epigenetic modifications are not fully understood.

Purpose of the Study:

  • To investigate the role of inositol hexakisphosphate kinase 1 (IP6K1) in epigenetic regulation.
  • To elucidate the interaction between IP6K1, inositol pyrophosphates (IP7), and histone modifications.

Main Methods:

  • RNA interference (RNAi) to reduce IP6K1 levels.
  • Analysis of mouse embryonic fibroblasts from ip6k1 knockout mice.
  • Chromatin association studies of IP6K1 and JMJD2C.
  • Histone modification assays (H3K9me3, H3K9ac).

Main Results:

  • IP6K1 associates with chromatin and interacts with the histone demethylase JMJD2C.
  • Reduced IP6K1 levels lead to decreased IP7, reduced H3K9me3, and increased H3K9ac.
  • IP6K1 catalytic activity is essential for regulating JMJD2C chromatin association and H3K9me3 levels.
  • These epigenetic changes affect the transcription of JMJD2C target genes.

Conclusions:

  • Inositol pyrophosphate signaling directly influences nuclear functions.
  • IP6K1 plays a critical role in regulating histone modifications via JMJD2C.
  • This study reveals a novel link between inositol pyrophosphate metabolism and epigenetic control of gene expression.