Advances in chromatin remodeling and human disease

doi:10.1016/j.gde.2004.04.015

Current Opinion in Genetics & Development

Volume 14, Issue 3, June 2004, Pages 308-315

https://doi.org/10.1016/j.gde.2004.04.015 Get rights and content

Abstract

Epigenetic factors alter phenotype without changing genotype. A primary molecular mechanism underlying epigenetics is the alteration of chromatin structure by covalent DNA modifications, covalent histone modifications, and nucleosome reorganization. Remodeling of chromatin structure regulates DNA methylation, replication, recombination, and repair as well as gene expression. As these functions would predict, dysfunction of the proteins that remodel chromatin causes an array of multi-system disorders and neoplasias. Insights from these diseases suggest that during embryonic and fetal life, environmental distortions of chromatin remodeling encode a ‘molecular memory’ that predispose the individual to diseases in adulthood.

Introduction

Within the context of human disease, phenotypic variation has typically been attributed to differences in genetic background and the influences of environment on that genetic background. In isogenic populations of model organisms, however, phenotypic variations persist 1., 2.••. These studies of isogenic organisms showed that changes in chromatin structure and DNA methylation, arising stochastically or in response to physiologic stress, account for this variation and can be transmitted through mitosis and meiosis 1., 2.••, 3.. Medically, these observations suggest a role for epigenetics in complex diseases and a mechanism by which exposure of a gamete or embryo to stresses can predispose that individual to adult disease [4].

The human genome is assembled into chromatin, which consists of DNA and protein condensed into nucleoprotein complexes [5]. The fundamental packaging unit of chromatin is the nucleosome, 147 base pairs of DNA wound twice around an octamer core of histones (two each of the H2A, H2B, H3 and H4 histones). The position and density of histone octamers along the DNA are mediated by ATP-dependent chromatin remodeling complexes that bind DNA and use the energy from ATP hydrolysis to move the histone octamers among and along DNA molecules 6., 7.. The affinity of histones for DNA and chromatin-associated proteins is controlled by acetylation, methylation, phosphorylation, poly-ADP ribosylation, and ubiquitination of histone amino termini [8]. These modifications and the positioning of histones organize the genome into either open or condensed chromatin and thus regulate the accessibility of DNA for transcription, methylation, recombination, replication, and repair. The positioning and modification of the histones form a histone code or epigenetic ‘memory’ that is passed from mother cell to daughter cells [9].

Mutations affecting the function and targeting of chromatin-remodeling complexes generally cause cancers or multi-system developmental disorders. The multi-system nature of these single-gene disorders can be explained by deregulation of chromatin structure at many loci. In this review, we focus on the recent advances in our understanding of cancers and Mendelian disorders ascribed to defects of ATP-dependent chromatin remodeling and histone acetylation and deacetylation.

Section snippets

ATPase-dependent chromatin remodeling and disease

ATP-dependent chromatin remodeling complexes contain several subunits, one of which is a SWI/SNF-related ATPase (Table 1). The amino and carboxyl domains flanking the ATPase domain of the SWI/SNF-related proteins allow association with other proteins in the complex. The SWI/SNF-related ATPase derives specificity for chromatin domains through these interactions. Structural modification of chromatin is essential for all processes requiring access to nuclear DNA (Figure 1, Figure 2, Figure 3).

Histone acetylation and disease

Generally, SWI/SNF-related ATPases and histone acetyltransferases (HATs) and deacetylases (HDACs) cooperate in chromatin remodeling; at some promoters, a SWI/SNF-related ATPase recruits a HAT or a HDAC, whereas at other promoters, a HAT or a HDAC recruits a SWI/SNF-related ATPase. Like SWI/SNF-related ATPases, HATs and HDACs are members of multiprotein complexes; the interacting proteins such as methyl-CpG-binding proteins (MECPs) target these complexes to genomic loci (Figure 1iii).

Histone

Conclusions

The studies of chromatin structure in model organisms are the foundation for our investigation of the role of chromatin structure and epigenetics in human biology and disease. Such studies have illustrated the critical roles of chromatin remodeling in sequential gene activation and inactivation during development, differentiation, apoptosis, and homeostasis. Consistent with these observations in non-primates, the multi-system disorders and neoplasias discussed above implicate chromatin

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

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of special interest
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of outstanding interest

Acknowledgements

We thank Pawel Stankiewicz, Millan Patel, Hamed Jafar-Nejad, R Grace Zhai, Amy Lossie and Jennifer Northrop for critical reading of this manuscript. We apologize to those whose work could not be cited directly due to reference limitations and the scope of the review.

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View full text

Advances in chromatin remodeling and human disease

Abstract

Introduction

Section snippets

ATPase-dependent chromatin remodeling and disease

Histone acetylation and disease

Conclusions

References and recommended reading

Acknowledgements

Bioessays

Cancer Biol Ther

Oncogene

Cell

Annu Rev Genomics Hum Genet

Genomics

Am J Med Genet

Nat Genet

Histol Histopathol

Genes Dev

Hum Mol Genet

Hsp90 as a capacitor of phenotypic variation

Nature

Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution

Nat Genet

Hsp90 as a capacitor for morphological evolution

Nature

Quantitative epigenetics

Nat Genet

Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome

Cell

Recent advances in understanding chromatin remodeling by Swi/Snf complexes

Curr Opin Genet Dev

Yeast heterochromatin: regulation of its assembly and inheritance by histones

Cell

Role for BRG1 in cell cycle control and tumor suppression

Mol Cell Biol

P16INK4a is required for hSNF5 chromatin remodeler-induced cellular senescence in malignant rhabdoid tumor cells

J Biol Chem

BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer

Cell

Identification of the WBSCR9 gene, encoding a novel transcriptional regulator, in the Williams-Beuren syndrome deletion at 7q11.23

Cytogenet Cell Genet

WSTF-ISWI chromatin remodeling complex targets heterochromatic replication foci

EMBO J

Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS)

Nat Genet