Hi all. This topic is about the word of the week: Methylation.
You will have seen the word being posted a lot lately owing to the recent finding in PFS patients, with study abstracts posted, and “demethylating” mentioned. I regularly say and will reiterate at the outset that for those really wanting to engage with the scientific issue seriously, time spent googling keywords or searching posts with a confirmation or survivorship bias is far more practically used taking basic endocrinology, genetics and epigenetics courses or pursuing a structured self-education with up to date and reputable academic materials on pertinent subjects. However, this is just to give interested members who want to quickly get an idea of what methylation means that in a nutshell. As such you may already know all this. As I have had to explain what it is a few times, I thought I’d make a quick topic I can point to as it’s likely to be relevant in the future.
Something @awor has been talking about for over a decade is that epigenetic mechanisms are involved in PFS. Epigenetics simply means the field of study regarding factors, environmental or endogenous, that alter the expression but not the code of the genes within individual cells. It is likely becoming clear to anyone following the research efforts that evidence is mounting that the pathology involves epigenetic dysregulation of a site-specific nature, differing in severity across patients and affected sites within those patients. Here’s me bringing this up over a year ago:
It is the view of the administrators of this site that persistent changes to gene expression are the only plausible driving factor underlying PFS, which is a manifestation of the broader Post-Endocrine Disruption Syndrome we see occurring after use of diverse antiandrogenic substances in a subset of consumers. In recent years, Di Loreto confirmed significantly higher expression of the androgen receptor in all patients, and Melcangi recently reported methylation of SRD5A2, a gene coding for the 5 alpha reductase type II enzyme, in the cerebrospinal fluid of over half of PFS patients considered. In a poorly reported appendix to a study including assay of nonsymptomatic tissue, Basaria et al. mentioned finding some significant differences in some androgen regulated genes that did not share an identical cluster on hierarchical analysis. We expect further findings in Baylor’s epigenetic investigation which has proceeded with previously validated genital skin. Conclusively, lasting differences in gene expression are observed in controlled study of PFS patients.
Methylation is one way (along with many other factors including ubiquitination, acetylation and phosphorylation) that gene expression is controlled. Methylation patterns are initially set prenatally. Patterns comprising the methylome are (somewhat) stripped from male haploid gamete and replaced by the egg when they together form a zygote, putting the epigenome in a totipotent situation. Sadly, in the context of powerful endocrine disruptors, the sins of the father are not always so escapable. Vinclozolin is an example of this. Finasteride is likewise categorically an endocrine disruptor and exhibits negative effects transgenerationally in animal models, despite the claims to the contrary you’ll find on sites selling it.
A gene is a nucleotide sequence that codes for a functional protein molecule. Chromatin packages DNA up small to fit in the nucleus of ᵘʳ ᵗᶦⁿʸ ᶜᵉˡˡˢ. Chromatin is composed of histones, which DNA wraps around. How tightly closed this is in certain areas is an important determinant of gene expression. Methylation can be acquired in somatic cells, modifies chromatin, and thus alters the access of proteins that bind to DNA (transcription factors). Methylation is what is called a repressive modification. This means that the more methylation there is in a CpG island (an area in most gene promoter regions often denoting the start of a gene), the more repressed the gene. Like a dimmer switch. Additionally, CpG islands can be found in intergenic regions. During cell division and replication, the methyltransferase enzyme DNMT1 maintains existing methylation while the enzymes DMT3a and 3b establish new methylation. To be clear, methylation is crucially important in like…not being a pile of soup…and 80% of mammalian CpG islands are methylated to some degree. Some areas of the genome are shut down entirely. Methylation is also very important to cell differentiation. To be slightly technical, the DNA base 5-methylcytosine is formed through the attachment of a methyl group to the 5th position of the cytosine ring in a CpG dinucleotide. Methylation is therefore by its very nature a question of degrees - the more the merrier - and such degrees of difference provides a compelling explanation for the vast difference in affected sites and severities between patients (e.g. why some have a functional impairment like anesthesia while others will experience severe atrophy), and why additional persistent symptoms are noted to develop in PFS/PSSD/PAS patients following further endocrine disruption.
Proven significant epigenetic differences in pfs patients with genital pain and atrophy (Di Loreto 2014) were on average 5 years after cessation would rule out transient modifications in severe cases and it’s unfortunately the case these changes will be being passed on to daughter cells. Traish’s 2018 paper, The Post-finasteride Syndrome: Clinical Manifestation of Drug-Induced Epigenetics Due to Endocrine Disruption discusses this finding and proposes his idea of how mechanistically epigenetic changes could be occurring and leading to PFS in predisposed patients.
The effects of inhibitors of this process are more significant in the frequent application of cancer, as cancer cells divide much faster than other somatic cells, so are vulnerable to the interruption of DNMT1. In the context of PFS and the use such drugs to address deleteriously methylated loci in somatic cells, it remains to be seen whether something this nonspecific could be taken for a long enough duration without adverse effects in the rest of the organism, a worsening of PFS, and with any positive effects at all. It is also important to consider that adult neurons do not divide, so the usual interruption of enzymatic process is not going to be applicable in the CNS. Although DNMT enzymes are expressed in postmitotic neurons and there is some evidence of HDACis inducing what is referred to as active demethylation, it is not yet clear exactly how they mechanistically regulate neuronal methylation.
Not the most up to date, but this review covers a broad amount if you’d like to read more. http://genesdev.cshlp.org/content/16/1/6.long
For a very readable overview of epigenetics I thoroughly recommend The Epigenetics Revolution by Nessa Carey.
Hope that’s helpful
