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PMID: 18682256 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks.

Mutation research ·Vol. 647 ·No. 1-2 ·2008-12-01 ·Pages 3-12

Baker LA, Allis CD, Wang GG

Abstract

Histone covalent modifications regulate many, if not all, DNA-templated processes, including gene expression and DNA damage response. The biological consequences of histone modifications are mediated partially by evolutionarily conserved "reader/effector" modules that bind to histone marks in a modification- and context-specific fashion and subsequently enact chromatin changes or recruit other proteins to do so. Recently, the Plant Homeodomain (PHD) finger has emerged as a class of specialized "reader" modules that, in some instances, recognize the methylation status of histone lysine residues, such as histone H3 lysine 4 (H3K4). While mutations in catalytic enzymes that mediate the addition or removal of histone modifications (i.e., "writers" and "erasers") are already known to be involved in various human diseases, mutations in the modification-specific "reader" proteins are only beginning to be recognized as contributing to human diseases. For instance, point mutations, deletions or chromosomal translocations that target PHD fingers encoded by many genes (such as recombination activating gene 2 (RAG2), Inhibitor of Growth (ING), nuclear receptor-binding SET domain-containing 1 (NSD1) and Alpha Thalassaemia and Mental Retardation Syndrome, X-linked (ATRX)) have been associated with a wide range of human pathologies including immunological disorders, cancers, and neurological diseases. In this review, we will discuss the structural features of PHD fingers as well as the diseases for which direct mutation or dysregulation of the PHD finger has been reported. We propose that misinterpretation of the epigenetic marks may serve as a general mechanism for human diseases of this category. Determining the regulatory roles of histone covalent modifications in the context of human disease will allow for a more thorough understanding of normal and pathological development, and may provide innovative therapeutic strategies wherein "chromatin readers" stand as potential drug targets.

MeSH Terms
Autoimmunity DNA-Binding Proteins/chemistry,metabolism Epigenesis, Genetic Humans Models, Genetic Models, Molecular Mutation Neoplasms/genetics Nervous System Diseases/genetics Polycomb-Group Proteins Syndrome Transcription Factors/chemistry,metabolism
Chemicals
DNA-Binding Proteins PHF1 protein, human Polycomb-Group Proteins Transcription Factors
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Baker Lindsey A
The Rockefeller University, Laboratory of Chromatin Biology & Epigenetics, New York, NY 10065, USA.
Allis C David
Wang Gang G
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Article Info
Journal
Mutation research
Abbr.
Mutat Res
ISSN
0027-5107
DOI
10.1016/j.mrfmmm.2008.07.004
Published
2008-12-01
Epub
2008-00-17
Pages
3-12
Language
English
Region
Netherlands
NLM ID
0400763
PMCID
PMC2656448
Subset
IM
Grants
NIGMS NIH HHS · R37 GM053512-30 · United States
NIGMS NIH HHS · GM 53512 · United States
NCI NIH HHS · T32 CA009673 · United States
NCI NIH HHS · CA09673 · United States
NIGMS NIH HHS · R37 GM053512 · United States
External Links
PubMed source DOI: 10.1016/j.mrfmmm.2008.07.004 PMC Full Text View journal details
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