Stress Shaping Brains: Higher Order DNA/Chromosome Mechanisms Underlying Epigenetic Programming of the Brain Transcriptome

Abstract

“I believe there is little reason to question the presence of innate systems that are able to restructure a genome. It is now necessary to learn of these systems and to determine why many of them are quiescent and remain so over very long periods of time only to be triggered into action by forms of stress, the consequences of which vary according to the nature of the challenge to be met”. Barbara Mc Clintock, (1978), as cited in (Jorgensen, 2004). Attempts to link specific neurobehavioural phenotypes with causative genes, a necessary step preceding the development of highly specific neuroimaging biomarkers for these phenotypes, have been spectacularly unsuccessful, although numerous significant gene candidates emerged during the process. Various family study approaches, including twin studies, sib pairs, ‘trios’ and so-called ‘pure multiplex pedigrees’ excluding comorbid disorders have been employed in various linkage and association study designs to determine the genes and proteins underlying the relevant disorders. Some genomewide association studies surprised investigators with the information that, when initially promising genomic coding region hotspots were supersaturated with markers at increasingly closer map distances, the results showed weakening of signals in targeted exonic areas, possibly indicating an influence outside these coding areas. The importance of epigenetics (including increasingly complex regulatory region and RNA metabolism gene expression-modifying mechanisms), gradually emerged during the course of molecular genetic ‘brain and behaviour’ studies. “Epigenetics is defined as mitotically or meiotically stable molecular processes that regulate genome activity independent of DNA sequence. The term ‘heritable’ has been included in the definition, but has been omitted recently since this implies generational inheritance by definition and therefore does not include all elements of epigenetics (Skinner, 2011). The brain represents a particular area of interest with regard to epigenetics, where it has been demonstrated that epigenetic modifications are not static, but dynamically change in response to external stimuli including synaptic activity (Crepaldi & Riccio, 2009). The increasing likelihood of the role played by transgenerational epigenetic influences in neurogenetics studies now also impacts on the tracking of neuropsychiatric disorder gene candidates in families, implying a requirement for analyses of both coding as well as noncoding polymorphisms and the manner in which these interact,