Punctuating DNA

The epigenome controls the differential expression of genes in a cell-, tissue-, or time-specific manner via inheritance without associated DNA sequence alterations. Epigenetic control involves several mechanisms, including DNA methylation, histone modifications and variants, and chromatin structural alterations. DNA methylation is the most stable type of currently identified epigenetic modification. Methylation of CpG islands within promoter regions is associated with transcriptional repression (silencing) of associated genes. Histone acetylation, phosphorylation, and methylation play roles in the positioning of nucleosomes on DNA, affecting gene expression by controlling access of the transcription machinery to genes.

Inappropriate epigenetic programming has been associated with human diseases, including cancer, neuro-developmental disorders, aging-related conditions, and autoimmunity. Interaction of the epigenome with the environment, including pollutants, infections, stress, and nutrition can alter patterns of gene expression and may lead to late onset diseases. Although heritable, at least in somatic cells, agents capable of reversing epigenetic changes are being identified and used clinically [e.g., DNA demethylating drugs and histone deacetylase (HDAC) inhibitors].

A Role in Cancer

“It's a very exciting time now in the epigenetics of cancer biology,” says Stephen Baylin, Professor of Oncology and Medicine, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD. “The results with demethylating drugs and HDAC inhibitors in hematopoietic malignancies are astounding. It looks as if many more genes are epigenetically silenced in cancer than mutated, although the importance is not yet known.” Candidate silenced genes include tumor suppressor genes. DNA methylation in aberrant gene silencing and alterations affecting chromatin architecture are leading to more and more legitimate therapeutic targets for reversal of this silencing as a strategy for cancer prevention and/or therapy.

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Moshe Szyf, Professor, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada, refers to methylation as the “punctuation mark of DNA that over- and under-rides what genes are expressed and what not.” His laboratory is interested in understanding the links between chromatin, DNA methylation, and cancer therapy, what mechanisms define DNA methylation patterns, and why these patterns are tightly correlated with chromatin structure. One question he'd like to answer is how to activate tumor suppressor genes without activating meta-static genes. For example, treating breast cancer cells with hypomethylating drugs increases their potential to metastasize. It's not yet known how to target hypomethylating drugs to specific sequences to activate desirable genes without activating undesirable ones. The cross-talk between chromatin and DNA methylation has therapeutic potential, Szyf observes. “If you change chromatin, you could change methylation. It's a dynamic world that offers potential. We're still scratching the surface.”

Learning Process

Xinyu Zhao, Assistant Professor, Department of Neurosciences, University of New Mexico, Albuquerque, AZ, says, “epigenetics is pretty new for the neurosciences. Even 3 years ago I had problems finding reviewers for my papers.” Her work focuses on identifying genetic and epigenetic factors that regulate postnatal neurogenesis and neural stem cell functions, including how DNA methylation functions in neuro development. She is studying mouse models with mutations in methylated-CpG binging proteins (MeCP2 and MBD1) that exhibit phenotypes similar to human neurodevelopmental syndromes.

She believes a lot of neurodevelopmental and complex mental disorders result not from classic genetic mutations but from epigenetic changes. “It's very exciting, especially in the neuroscience field, now that we are past the genomic era. We know the blueprint, beyond that, what can we learn? However, there may be a limit to how far we can understand our own brain. Neurodevelopmental studies will require crossing fields, including stem cell research, epigenetics, and neurosciences. It's a learning process.”

Karen Usdin, Chief, Gene Structure and Disease Section, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD, studies Repeat Expansion Diseases, conditions with neurodevelopmental implications resulting from gene silencing. One of these diseases resulting from expansion is Friedreich ataxia (FA), caused by the expansion of a GAAoTTC repeat in the frataxin gene, leading to reduced levels of frataxin messenger RNA (mRNA), which in turn causes sensory motor neuron degeneration, diabetes, and cardiomyopathy. The second disease involves expansion of a CGGoCCG repeat in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene, and the consequences depend upon the number of repeats in the expanded allele. Premutation alleles with 59 to 200 repeats are at risk of fragile X-associated tremor and ataxia syndrome (FXTAS). Female carriers of this allele are also at risk for fragile X-associated premature ovarian failure and can transmit an FMR1 allele with greatly expanded repeats to offspring.Carriers with full mutation alleles, those with over 200 repeats, are at very high risk of fragile X syndrome (FXS), a developmental disorder, characterized by moderate to severe mental retardation. Usdin's group is looking at a mouse model of permutation FXS, with 120 CGG-CGG repeats in the murine Fmr1 gene.