Epigenetic Mechanisms And Endocannabinoid Signalling

[in vivo]

The endocannabinoid system, composed of endogenous lipids, their target receptors and metabolic enzymes, has been implicated in multiple biological functions in health and disease, both in the central nervous system and in peripheral organs. Despite the exponential growth of experimental evidence on the key role of endocannabinoid signalling in basic cellular processes, and on its potential exploitation for therapeutic interventions, much remains to be clarified about the respective regulatory mechanisms. Epigenetics refers to a set of post-translational modifications that regulate gene expression without causing variation in DNA sequence, endowed with a major impact on signal transduction pathways. The epigenetic machinery includes DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs. Due to the reversibility of epigenetic changes, an emerging field of interest is the possibility of an ‘epigenetic therapy’ that could possibly be applied also to endocannabinoids. Here, we review current knowledge of epigenetic regulation of endocannabinoid system components under both physiological and pathological conditions, as well as the epigenetic changes induced by endocannabinoid signalling.

 

 

 

 

The key role of epigenetic mechanisms in different biological processes [112] and human diseases [113-116] has been clearly demonstrated over the last few years. Among the many genes and signalling pathways regulated by chromatin modification and/or DNA methylation [117], ECS elements are getting more and more attention. The ECS controls lipid signalling pathways by acting both in the central nervous system and in peripheral tissues, and thus a deeper understanding of its regulation might lead to the development of new clinical strategies for different human pathologies [118]. Indeed, epigenetic alterations are reversible and specific interventions that target different epigenetic pathways might have a major impact on health problems, eventually providing a new avenue for innovative therapeutic approaches.

On a final note a few points remain to be addressed. Since CB₁ in the central nervous system is preferentially localized presynaptically, it is of relevance to study how the signal will be translated to the nucleus. Moreover, it is important to understand how CB₁ evokes epigenetic mechanisms, either by directly interacting with the epigenetic machinery or indirectly, for instance by regulating neurotransmitter release. Finally, the involvement of non CB₁/CB₂ receptors should be addressed.

A better understanding of the epigenetic regulation of eCB signalling as well as the eCB regulation of epigenetic mechanisms will be of great value for the possible design of more specific epigenetic drugs, also because those currently FDA approved, although promising, have both a non-specific target (non-chromatin proteins are also affected) and a genome-wide effect.

 

http://onlinelibrary.wiley.com/doi/10.1111/febs.12125/full

 

Abstract | Phenotypic variation is traditionally parsed into components that are

directed by genetic and environmental variation. The line between these two

components is blurred by inherited epigenetic variation, which is potentially

sensitive to environmental inputs. Chromatin and DNA methylation-based

mechanisms mediate a semi-independent epigenetic inheritance system at the

interface between genetic control and the environment. Should the existence

of inherited epigenetic variation alter our thinking about evolutionary change?

 

Inherited epigenetic variation—revisiting soft inheritance

 

Sometimes you've just got to learn to accept the good with the bad. Maybe this time let's not shoot the messenger.

Edited March 27, 2014 by in vivo