Epigenetics of Nucleososmes as Pertaining to Cannabinoids

Using a well-established method of biological age assessment based on arterial stiffness adult patients exposed to cannabis were shown to be have increased arterial stiffness and so to be biologically older [1]. This finding is consistent with pro-inflammatory actions of cannabis [2-7] which are also linked with advancing biological age [8-10]. It was recently shown in advanced cellular senescence that LINE-1 mobile transposable elements, so-called “jumping genes” or retrotransposons, which comprise 17% of the genome, can become mobilized and re-insert into the genome in a random manner using endogenous reverse transcriptases [11]. Not only is this destructive to the genomic sequence with downstream consequences including teratogenesis, carcinogenesis, aging and age-related degenerative disease, but this also activates cytoplasmic cGAS-STING signalling and autocrine and paracrine senescence programs [11-15]. Whilst this novel and fascinating aging mechanism is yet to be evaluated following cannabis exposure several lines of evidence implicate LINE-1 in cannabis-related pathologies including autism [16, 17] and pediatric leukaemias [18] and cancers [19-21] especially germ cell tumours [19] where all four studies to examine the relationship between cannabis use and testicular cancer have found a positive relationship [22-25].

Intriguingly addition of serotonin to the tail of histone 3 (H3) on the glutamine at position 5 (Q5) – right beside the well-known transcription-activating trimethylation post-translational modification (PTM) at H3K4 (lysine 4) – has been shown to be an essential permissive and facilitative histone PTM at many gene promoters to permit proper differentiation of brain and body tissues [26, 27]. This PTM is known as Q5ser. H3K4Q5ser occurs at high density in brain and testes. It is likely that other monoamines such as histamine and dopamine may soon be similarly implicated [26, 27]. The monoamines serotonin and dopamine are well known to be intimately involved in cannabis dependency syndromes [28, 29]. Further thickening the plot the N-terminal tail of H3 was recently shown to be a hot spot for oncomutations amongst histone proteins which allow genes to be made accessible for transcription, often in an activating manner which is independent of SWI/SNF signalling and thus renders it constitutively active [30]. Cannabis use has previously been linked with four pediatric cancers and eight cancers in adults including the germ cell tumours mentioned above [31-33].

Source: Nature Journal 2019

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