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Molecular mechanisms and potential functions of histone demethylases

Key Points

  • The identification of the Lys-specific demethylase (LSD) and the Jumonji C (JMJC) protein families that catalyse the demethylation of methylated Lys residues has led to a new paradigm for how histone methylation is regulated.

  • The histone demethylases are involved in regulating cellular processes such as chromatin structure and transcription. They are important for normal embryonic development and are involved in diseases such as cancer.

  • Both histones and non-histone proteins are targets for the histone demethylases. Examples of non-histone substrates include p53, DNA methyltransferase 1 (DNMT1) and E2F1.

  • Histone demethylase activity is regulated by expression levels, by targeting to specific sites in the genome and by post-translational modifications.

  • Histone demethylases bind to many target genes, where they enable transcriptional competence by ensuring a specific chromatin state.

Abstract

Histone modifications are thought to regulate chromatin structure, transcription and other nuclear processes. Histone methylation was originally believed to be an irreversible modification that could only be removed by histone eviction or by dilution during DNA replication. However, the isolation of two families of enzymes that can demethylate histones has changed this notion. The biochemical activities of these histone demethylases towards specific Lys residues on histones, and in some cases non-histone substrates, have highlighted their importance in developmental control, cell-fate decisions and disease. Their ability to be regulated through protein-targeting complexes and post-translational modifications is also beginning to shed light on how they provide dynamic control during transcription.

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Figure 1: The catalytic mechanisms of histone demethylation.
Figure 2: Histone methylation and the activity of histone demethylase families.
Figure 3: Functions of histone demethylases.
Figure 4: Regulation of demethylase activity.

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Acknowledgements

The authors thank M. T. Pedersen and I. Comet for providing critical and constructive comments on the manuscript and members of the Helin laboratory for discussions. S.M.K is supported by a postdoctoral fellowship from the Netherlands Organization for Scientific Research (NWO). Work in the Helin laboratory is supported by the Danish National Research Foundation, the Danish Cancer Society, the Novo Nordisk Foundation, Denmark, the Danish Medical Research Council, the Lundbeck Foundation, Denmark, the European Union and the Excellence Programme of the University of Copenhagen.

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Comment on Wang, Y. et al. (Cell, 2009)

Glossary

Gastrulate

Gastulation is a phase in early embryonic development of animals during which the embryo is reorganized into the three germ layers — ectoderm, endoderm and mesoderm.

Imprinting

A genomic mechanism for the exclusive expression of certain genes from either the maternal or the paternal allele.

Plant homeodomain

(PHD). A zinc-finger-containing protein domain that is involved in mediating protein–protein interactions. It can recognize differently modified nucleosomes and is often found in chromatin regulators.

Chromatin immunoprecipitation

(ChIP). A method that allows isolation of DNA sequences that are bound to a protein of interest in vivo using specific antibodies to the protein.

Ubiquitin ligase complex

A protein complex that is responsible for the addition of ubiquitin to Lys residues within target proteins. The covalent ubiquitin modification influences the fate and function of its targets.

Proteasome

A large multisubunit protease complex (26S) that selectively degrades polyubiquitylated proteins. It contains a 20S particle that carries the catalytic activity and two regulatory 19S particles.

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Kooistra, S., Helin, K. Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol 13, 297–311 (2012). https://doi.org/10.1038/nrm3327

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