Epigenetics in Neurobiology

[Hugo Sanchez-Castillo]

Epigenetics

Is well known, that one of the most important mechanisms to change our system is trough mutations, changes in the DNA itself, however is also know that many of these mutations are so small, irrelevants or that we need to wait thousands of years to have a successful and adaptive mutations. In face of this facts we have to question ourselves, how then we can be prepared to the intempestive changes of the environment?; how genes interact with their environment to produce a phenotype?; how our specie can adapt to fast changes and to inform to the next generations?, is clear that genetics is not enough for explain this phenomena.

Recently we started to answer that questions in the light of the epigenetics. This describes a set of gene regulatory mechanisms that shape how the genome is used in a given cell. This mechanisms and ways to regulate the gene expression includes a broad range of environmental experiences induce epigenetic variation. In the CNS epigenetic studies are advancing understanding of brain development, neuronal plasticity and neuropsychiatric disease.

Now a days, we know that the DNA methylation is literally epigenetic, that the neuronal chromatin is dynamic in posmitotic neurons and orchestrates gene expression during maturation and in response to synaptic activity, and that all the DNA is packed and ordered in a pentameric units called Histones. We know, at least, the existence of five major families of histones H1/5, H2A, H2B, H3 and H4 and that the histone modifications correlated with transcription and the chromatin regulation.

In terms of the chromatin regulation, the intrinsic chromatin landscape determines the structure of regulatory element interactions; extrinsic signals regulates transcription factor expression and function; the functional state of regulatory elements is controlled by biochemical mechanisms; the sum total of these interactions determines gene expression which defines phenotype.

All this knowledge allow us to search how the environment changes the gene expresión, how some behavior can affect the estructure and function of the Central Nervous System. In one experiment showed to us, it was evaluated the maternal care and DNA methylation. It has been  demonstrated that high vs low postnatal licking/grooming is associated with altered hippocampal gene expression of Nr3c1 in adulthood. Postnatal experience is the critical predictor outcome. Low licking/grooming was associated with elevated DNA methylation within the 5’ region of the Nr3c1 gene promotor. But there is more genes involved not only in rats but in different species.

Finally when we work with epigenetics we will have slime methodological considerartions to achieve better and more clear results:

1.- Genteically informed designs: Whitin subject design
2.- Tissue heterogeneity: use of peripheral “proxy” tissue versus target tissue
3.- Experimental manipulations to make causal inferences
4.- Changing resolution and reliability of techniques; genome wide vs candidate gene.

We need to be aware of challenges to study epigenetic as: 
 a) tisssue/cell specific epigenetic profiling of environmentally induced effects. 
b) Plasticity, reversibility and stability. 
c) Establishing causal links between environments, epigeome and outcomes.