Here are the most popular of the 65 posts I’ve made so far in 2018, starting from the earliest:
“Although there is an increasing line of evidence from preclinical models of addiction, there are only a few human studies that systematically assessed DNA methylation in addiction. Most of the studies were done on small cohorts and focused on one or a few candidate genes, except in the case of alcohol use where larger studies have been carried out.
A long line of evidence suggests that abnormal patterns of gene expression occur in brain regions related to drug addiction such as the nucleus accumbens, prefrontal cortex, amygdala, and the ventral tegmental area.
Using the “incubation of craving” model in rats trained to self-administer cocaine, and treated with either SAM or RG108, the genome-wide DNA methylation and gene expression landscape in the nucleus accumbens after short (1 day) and long (30 days) abstinence periods and the effects of epigenetic treatments were delineated. The main findings are:
- A long incubation period results in robust changes in methylation;
- Direct accumbal infusion of SAM that is paired with a “cue” after long incubation times increases drug-seeking behavior,
- Whereas a single treatment with RG108 decreases this behavior.
Importantly, the effects of these single administrations of a DNA methylation inhibitor remain stable for 30 more days. These data suggest that DNA methylation might be mediating the impact of “incubation” on the craving phenotype and that this phenotype could be reprogrammed by a DNA demethylation agent.”
The subject has a large scope, and a narrow aspect was presented in this paper. Rodent research by one of the coauthors that was cited, Chronic pain causes epigenetic changes in the brain and immune system, provided some relevant details.
The review covered neither human dimensions of the impacts of unfulfilled needs nor investigations of exactly what pain may impel human drug-seeking behavior. The “Implications for Diagnostic and Therapeutics” were largely at the molecular level.
https://www.sciencedirect.com/science/article/pii/S1877117318300164 “The Role of DNA Methylation in Drug Addiction: Implications for Diagnostic and Therapeutics” (not freely available)
This 2018 Belgian review subject was in part the transgenerational epigenetic effects of maternal obesity during pregnancy. The subject was tailored for the journal in which it appeared, Atherosclerosis, so other transgenerationally inherited epigenetic effects weren’t reviewed:
“The transgenerational impact of these alterations in methylation patterns are only shown in animal studies with HFD [high-fat diet] animals. In this respect the paternal influence also comes forward.
Alterations in methylation at the spermatozoa of male rats fed with a HFD were shown in combination with transgenerational metabolic effects, mainly on the female offspring. Methylation alterations in spermatozoa were also found in the male offspring of dams fed with HFD during their pregnancy. Consequent effects on the phenotype were again only shown in female offspring (until third generation).
A transgenerational inheritance through the female germline by mitochondrial inheritance has been suggested. A recent, small study in humans found altered mitochondrial functioning in the male offspring of overweight woman. A finding that has been confirmed in mice studies with a persistence of this transfer of aberrant oocyte mitochondria into the third generation.
The identification of a number of alterations in active cardiovascular microRNA species in the offspring of animals with obesity offer promising perspectives for the future.”
Evidence for transgenerational aspects of in utero programming included two studies I hadn’t previously curated:
- https://www.cell.com/cell-reports/fulltext/S2211-1247(16)30663-5 “Maternal Metabolic Syndrome Programs Mitochondrial Dysfunction via Germline Changes across Three Generations” (2016)
- https://www.sciencedirect.com/science/article/pii/S221287781500232X “High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring” (2016)
https://www.atherosclerosis-journal.com/article/S0021-9150(18)30328-9/fulltext “In utero programming and early detection of cardiovascular disease in the offspring of mothers with obesity”
The principal way science advances is through the principle Einstein expressed as:
“No amount of experimentation can ever prove me right; a single experiment can prove me wrong.”
Members of the scientific community and of the public should be satisfied that the scientific process is working well when hypotheses are discarded due to nonconfirming evidence. Researchers should strive to develop evidence that rejects paradigms, and be lauded for their efforts.
The opposite took place with this 2018 commentary on two studies where the evidence didn’t confirm current biases. I curated one of these studies in DNA methylation and childhood adversity.
The commentators’ dismissive tone was set in the opening paragraph:
“Is early exposure to adversity associated with a genetic or an epigenetic signature? At first glance, two articles in this issue -..and the other from Marzi et al., who measured genome-wide DNA methylation in a prospective twin cohort assessed at age 18 – appear to say that it is not.”
The two commentators, one of whom was a coauthor of Manufacturing PTSD evidence with machine learning, went on to protect their territory. Never mind the two studies’ advancement of science that didn’t coincide with the commentators’ vested interests.
My main concern with the study was that although the children had been studied at ages 5, 7, 10, 12, and 18, the parents had never been similarly evaluated! The researchers passed up an opportunity to develop the parents as a F0 generation for understanding possible human transgenerational inherited epigenetic causes and effects.
The study focused on the children’s intergenerational epigenetic effects. However, animal studies have often demonstrated transgenerational effects that skip over the F1 generation children!
- Transgenerational pathological traits induced by prenatal immune activation found a F2 grandchild and F3 great-grandchild phenotype of impaired sociability, abnormal fear expression and behavioral despair – effects that weren’t present in the F1 children;
- A self-referencing study of transgenerational epigenetic inheritance found histone modifications in the F3 generation that weren’t found in the F1 and F2 generations; and
- A study not cited in – but completely appropriate for – The lack of oxygen’s epigenetic effects on a fetus found heart disease effects in the F1 generation that were different from the heart disease effects found in the F2 and F3 generations.
https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2018.18020156 “Considering the Genetic and Epigenetic Signature of Early Adversity Within a Biopsychosocial Framework” (not freely available)
This 2018 Loma Linda review subject was gestational hypoxia:
“Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue.
An understanding of the specific hypoxia-induced environmental and epigenetic adaptations linked to specific organ systems will enhance the development of target-specific inhibition of DNA methylation, histone modifications, and noncoding RNAs that underlie hypoxia-induced phenotypic programming of disease vulnerability later in life.
A potential stumbling block to these efforts, however, relates to timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.
With future developments, it may even become possible to intervene before conception, before the genetic determinants of the risk of developing programmed disease are established.”
Table 3 “Antenatal hypoxia and developmental plasticity” column titles were Species | Offspring Phenotypes of Disorders and Diseases | Reference Nos.
This review was really an ebook, with 94 pages and 1,172 citations in the pdf file. As I did with Faith-tainted epigenetics, I read it with caution toward recognizing the influence of the sponsor’s biases, and any directed narrative that ignored evidence contradicting the narrative, and any storytelling.
See if you can match the meaning of the review’s last sentence quoted above with the meaning of any sentence in its cited reference Developmental origins of noncommunicable disease: population and public health implications.
One review topic that was misconstrued was transgenerational epigenetic inheritance of hypoxic effects. The “transgenerational” term was used inappropriately by several of the citations, and no cited study provided evidence for gestational hypoxic effects through the F2 grandchild and F3 great-grandchild generations.
One omitted topic was gestational hypoxic effects of caffeine. The first paper that came up for my PubMed search of “caffeine pregnancy hypoxia” was an outstanding 2017 Florida rodent review Long-term consequences of disrupting adenosine signaling during embryonic development that had this paragraph and figure:
“One substance that fetuses are frequently exposed to is caffeine, which is a non-selective adenosine receptor antagonist. We discovered that in utero alteration in adenosine action leads to adverse effects on embryonic and adult murine hearts. We find that cardiac A1ARs [a type of adenosine receptor] protect the embryo from in utero hypoxic stress, a condition that causes an increase in adenosine levels.
After birth in mice, we observed that in utero caffeine exposure leads to abnormal cardiac function and morphology in adults, including an impaired response to β-adrenergic stimulation. Recently, we observed that in utero caffeine exposure induces transgenerational effects on cardiac morphology, function, and gene expression.”
Why was this review and its studies omitted? It was on target for both gestational hypoxia and transgenerational epigenetic inheritance of hypoxic effects!
It was alright to review smoking, cocaine, methamphetamine, etc., but the most prevalent drug addiction – caffeine – couldn’t be a review topic?
The Loma Linda review covered a lot, but I had a quick trigger due to the sponsor’s bias. I started to lose “faith” in the reviewers after reading the citation for the review’s last sentence that didn’t support the statement.
My “faith” disappeared after not understanding why a few topics were misconstrued and omitted. Why do researchers and sponsors ignore, misrepresent, and not continue experiments through the F3 generation to produce evidence for and against transgenerational epigenetic inheritance? Where was the will to follow evidence trails regardless of socially acceptable beverage norms?
The review acquired the taint of storytelling with the reviewers’ assertion:
“..timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.”
Contradictory evidence was in the omitted caffeine study’s graphic above which described two gestational periods where an “intervention” had opposite effects, all of which were harmful to the current fetus’ development and/or to following generations. Widening the PubMed link’s search parameters to “caffeine hypoxia” and “caffeine pregnancy” returned links to human early life studies that used caffeine in interventions, ignoring possible adverse effects on future generations.
This is my final curation of any paper sponsored by this institution.
https://www.physiology.org/doi/abs/10.1152/physrev.00043.2017 “Gestational Hypoxia and Developmental Plasticity” (not freely available) Thanks to coauthor Dr. Xiang-Qun Hu for providing a copy.
This 2018 Michigan review subject was cancer evolution:
“Based on the fact that cancer typically represents a complex adaptive system, where there is no linear relationship between lower-level agents (such as each individual gene mutation) and emergent properties (such as cancer phenotypes), we call for a new strategy based on the evolutionary mechanism of aneuploidy [abnormal number of chromosomes] in cancer, rather than continuous analysis of various individual molecular mechanisms.
Cancer evolution can be understood by the dynamic interaction among four key components:
- Internal and external stress;
- Elevated genetic and non-genetic variations (either necessary for cellular adaptation or resulting from cellular damages under stress);
- Genome-based macro-cellular evolution (genome replacement, emergent as new systems); and
- Multiple levels of system constraint which prevent/slow down cancer evolution (from tissue/organ organization to the immune system interaction).
Since the sources of stress are unlimited and unavoidable (as they are required by all living systems), there are large numbers of gene mutations / epigenetic events / chromosomal aberrations, such as aneuploidy, that can be linked to stress-mediated genomic variants. Furthermore, as environmental constraints are constantly changing, even identical instances of aneuploidy will have completely different outcomes in the context of cancer evolution, as the results of each independent run of evolution will most likely differ.
Most current research efforts are focusing on molecular profiles based on an average population, and outliers are eliminated or ignored, either by the methods used or statistical tools. The traditional view of biological research is to identify patterns from “noise,” without the realization that the so-called “noise” in fact is heterogeneity, which represents a key feature of cancer evolution by functioning as the evolutionary potential.
Understanding the molecular mechanism (both cause and effect) of aneuploidy is far from enough. A better strategy is to monitor the evolutionary process by measuring evolutionary potential. For example, the overall degree of CIN [chromosome instability] is more predictive than individual gene mutation profile.”
Although I read many abstracts of cancer research papers every week, I usually don’t curate them. I curated this paper because the reviewers emphasized several themes of this blog, including:
- Further examples of how stress may shape one’s life.
- How researchers miss information when they ignore or process away variation:
“Studies have demonstrated the importance of outliers in cancer evolution, as cancer is an evolutionary game of outliers. While this phenomenon can provide a potential advantage for cellular adaptation, it can also, paradoxically, generate non-specific system stress, which can further produce more genetic and non-genetic variants which favor the disease condition.”
Epigenetics researchers may benefit from evolutionary viewpoints that incorporate the interactions of stress and “genetic and non-genetic variants.”
Since epigenetic changes require inheritance in order to persist, it would be a step forward to see researchers start “measuring evolutionary potential” of these inheritance processes.
https://molecularcytogenetics.biomedcentral.com/articles/10.1186/s13039-018-0376-2 “Understanding aneuploidy in cancer through the lens of system inheritance, fuzzy inheritance and emergence of new genome systems”
This 2018 French review subject was mechanisms of autoimmunity:
“Autoimmune diseases (AIDs) encompass more than 80 distinct chronic disorders characterized by inflammatory reactions that can either be systemic or organ specific. In all cases, the disease development is the consequence of the effects of environmental factors in predisposed individuals.
Most of the genes identified by genome-wide association studies (GWAS) on AIDs are related to immunity. However, functional immune parameters that are commonly dysregulated in AIDs do not necessarily stem from these genetic variants. Rather than performing even larger GWAS, understanding complex traits, such as human diseases, may require meticulous analysis or cell-specific gene networks and take into account not only core genes but also seemingly irrelevant genes that may overall have an impact on the disease.
Treg cell defects have been considered a primary cause of AIDs. However, one could ask whether the Treg cell dysfunction exists before the onset of the disease or is provoked by the inflammatory event induced by the triggering components. The defect of Treg cells generally coexists with the inflammatory processes, suggesting several hypotheses:
- The inflammation might develop because of a poor regulation of the immune system,
- The Treg cells could become inefficient because of the inflammatory environment, or
- A common factor concomitantly leads to both effects.
It is likely that autoimmunity results from a chronic imbalance involving both environmental and intrinsic factors. It is now clear that polygenic explanations did not fulfill expectations and that more efforts are needed to understand how the interplay of environmental clues may have a phenotypic impact.”
https://nyaspubs.onlinelibrary.wiley.com/doi/full/10.1111/nyas.13560 “Pathophysiological mechanisms of autoimmunity” (not freely available) Thanks to Dr. Julien Verdier for providing a copy.