Connections between epigenetic gene silencing and human disease

Timothy J. Moss, Lori L. Wallrath

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

Alterations in epigenetic gene regulation are associated with human disease. Here, we discuss connections between DNA methylation and histone methylation, providing examples in which defects in these processes are linked with disease. Mutations in genes encoding DNA methyltransferases and proteins that bind methylated cytosine residues cause changes in gene expression and alterations in the patterns of DNA methylation. These changes are associated with cancer and congenital diseases due to defects in imprinting. Gene expression is also controlled through histone methylation. Altered levels of methyltransferases that modify lysine 27 of histone H3 (K27H3) and lysine 9 of histone H3 (K9H3) correlate with changes in Rb signaling and disruption of the cell cycle in cancer cells. The K27H3 mark recruits a Polycomb complex involved in regulating stem cell pluripotency, silencing of developmentally regulated genes, and controlling cancer progression. The K9H3 methyl mark recruits HP1, a structural protein that plays a role in heterochromatin formation, gene silencing, and viral latency. Cells exhibiting altered levels of HP1 are predicted to show a loss of silencing at genes regulating cancer progression. Gene silencing through K27H3 and K9H3 can involve histone deacetylation and DNA methylation, suggesting cross talk between epigenetic silencing systems through direct interactions among the various players. The reversible nature of these epigenetic modifications offers therapeutic possibilities for a wide spectrum of disease.

Original languageEnglish (US)
Pages (from-to)163-174
Number of pages12
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume618
Issue number1-2
DOIs
StatePublished - May 1 2007

Bibliographical note

Funding Information:
We apologize to the many investigators whose research could not be cited due to space limitations. We would like to thank Al Klingelhutz and members of the Wallrath Lab for comments on the manuscript, and Judith Kassis for discussions. Research is supported by an NIH grant (GM61513) to L.L.W., a grant from the Department of Defense Breast Cancer Research Foundation (DAMD17-02-1-0424) to L.L.W. and a Susan G. Komen Dissertation Research Award (DISS0403121) to T.J.M.

Keywords

  • Chromatin
  • DNA methylation
  • Epigenetic gene silencing
  • Histone methylation
  • Human disease

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