Wednesday, July 7, 2010

My histones made me do it!

Unraveling the biochemistry of behavior is one of the most difficult ongoing scientific ventures. The brain develops nearly continuously from shortly after implantation to early adulthood. Much of the molecular biology of normal brain development remains elusive; even less is known how genetic and environmental cues could potentially interact to cause psychopathology later in life.

A news focus appears in this month's Science, discussing the work that has been done to date on the role of epigenetics in human behavior and the promise of future research in that field. (link to abstract)

For those of you unfamiliar with molecular biology, epigenetics is the term used to describe the correlation between gene regulation and phenotype. (methinks I'll add a glossary page)

Individual chromosomes are LARGE molecules--stretched end to end, the 46 chromosomes in a single human cell would be roughly two meters long. Obviously, this is an inconvenient way for cells to store genetic data--cells get around this problem by compactly packaging DNA around proteins called histones.

With the exception of certain types of blood cells, every cell in the human body contains a complete copy of the host genome. As cells differentiate throughout development and adult life, each cell type only needs to actively use a minority of the genes it its genome. Mechanically, genes that are packaged around histones cannot be actively expressed--therefore histone modification allows the "unpacking" and "repacking" of genes according to developmental and physiological need.

The important thing to remember regarding the role of epigenetics in development is that development is not a static program. Owing to environmental factors, even identical twins can manifest markedly different physical phenotypes (e.g. I'm an inch taller than my own identical twin). Based on environmental and physiological cues, expression level of any given gene in a particular tissue can vary widely from individual to individual. The variability of development is known as phenotypic plasticity.

Inappropriate epigenetic regulation of gene expression has been implicated in several human diseases ranging from cancer to metabolic disorders to autism. As the age of monogenic disease gene hunting draws to a close, scientists are increasingly coming to understand the role of differential gene regulation in human disease.

Regarding the role of epigenetics in human behavior and psychopathology, there was a more complete review published in Frontiers of Neuroendocrinology last year.

Much of the work that has been done to date in behavioral epigenetics has focused on the role of epigenetic factors in creating brain sex differences and favoring sex-specific behaviors in rodent animal models.

The potential link between autism and epigenetics is tantalizing. Gregory et al. (2009) found a significantly higher rate of histone methylation (silencing) within the oxytocin receptor (OXTR) promoter region in samples taken from the temporal lobe of autistic patients versus age and sex matched controls.

Polymorphisms within the regulatory region of the OXTR gene have been previously correlated with autism. Additionally, exogenous administration of oxytocin to autistic patients has been shown to temporarily attenuate many of its outward behavioral signs.

These finding, coupled with the recent correlation of gene copy number of various genes with autism, imply that autism could conceivably be a disorder of transcriptional regulation rather than the direct result of one or more "broken" genes.

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