Epigenetic similarities between placental and cancer cells

This 2017 New Zealand review compared and contrasted epigenetic evidence from placental and cancer research:

“Placental and cancer cells are globally hypomethylated and share an epigenetic phenomenon that is not well understood – they fail to silence repetitive DNA sequences (retrotransposons) that are silenced (methylated) in healthy somatic cells.

In the placenta, hypomethylation of retrotransposons has facilitated the evolution of new genes essential for placental function. In cancer, hypomethylation is thought to contribute to activation of oncogenes, genomic instability, and retrotransposon unsilencing; the latter, we postulate, is possibly the most important consequence.

Activation of placental retrotransposon-derived genes in cancer underpins our hypothesis that hypomethylation of these genes drives cancer cell invasion.”

http://onlinelibrary.wiley.com/doi/10.1002/bies.201700091/abstract “The Genes of Life and Death: A Potential Role for Placental-Specific Genes in Cancer” (not freely available)


The review cited a 2014 study from the same research group that covered some of the same points and is freely available:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095840 “Retrotransposon Hypomethylation in Melanoma and Expression of a Placenta-Specific Gene”

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A study of perinatal malnutrition where the paradigm excluded epigenetic inheritance

This 2017 New York/Swedish rodent study subject was the epigenetic effects on the F1 children of maternal low protein diet during pregnancy and lactation:

“Male, but not female, offspring of LPD [low protein diet] mothers consistently displayed anxiety- and depression-like behaviors under acute stress.

Our proposed pathway connecting early malnutrition, sex-independent regulatory changes in Egr1 [an Early growth response gene], and sex-specific epigenetic reprogramming of its effector gene, Npy1r [neuropeptide Y receptor Y1 gene], represents the first molecular evidence of how early life risk factors may generate sex-specific epigenetic effects relevant for mental disorders.”


The study was purposely incomplete regarding transgenerational epigenetic effects that may be transmitted from the F1 children to their F2 grandchildren and F3 great-grandchildren. Similar to How one person’s paradigms regarding stress and epigenetics impedes relevant research, the paradigm continued by one of this study’s coauthors restricted inquiry into epigenetic inheritance.

How can the other coauthors respond when a controller of funding publishes the paper referenced in What is epigenetic inheritance? and otherwise makes his narrow views regarding epigenetic inheritance well-known? If the controller’s restricted views won’t allow the funding scope to extend testing to study F2 grandchildren and F3 great-grandchildren, the experiments end, and our understanding of epigenetic inheritance isn’t advanced.

This purposely incomplete study showed that the coauthor only gave lip service to advancing science when he made statements like:

“Further work is needed to understand whether and to what extent true epigenetic inheritance of stress vulnerability adds to the well-established and powerful influence of genetics and environmental exposures.”

The papers of Transgenerational epigenetic inheritance week show the spectrum of opportunities to advance science that were intentionally missed.

https://www.nature.com/articles/s41598-017-10803-2 “Perinatal Malnutrition Leads to Sexually Dimorphic Behavioral Responses with Associated Epigenetic Changes in the Mouse Brain”

Parental lying thwarted both their children and researchers

This 2017 German human study explored the relationship between birth stress and handedness. The authors summarized previous research which, among other points, estimated epigenetic contributions to handedness as great as 75%.

The study hit a snag in its reliance on the sixty participants (average age 24) completing, with the assistance of their parents and medical records, a 24-item questionnaire of maternal health problems during pregnancy, substance use during pregnancy, and birth complications. The subjects didn’t provide accurate information. For example:

  • Only one of the subjects reported maternal alcohol use during pregnancy. An expected number would have been 26.
  • None of the subjects reported maternal mental illness during pregnancy. An expected number would have been at least 7.

The subjects’ parents willingly misled their children about facts of their child’s important earliest development periods. This is unethical to the children in that once it is recognized, it diminishes or destroys the society among family members. This study’s example is also of general interest to anyone who values not being lied to, like me.

As I mentioned on the Welcome page, lies and omissions ruin the standard scientific methodology of surveying parents and caregivers. The absence of evidence greatly increased the difficulty for researchers in determining causes of epigenetic effects still present in the subjects’ lives.

The parental lying is again unethical in that it diminished or destroyed the society between the sources of information – the research subjects – and the users of the information. It adversely affected anyone who values evidence-based research. The research hypothesis itself was worthwhile based on the prior studies cited and elsewhere such as Is what’s true for a population what’s true for an individual?.

http://www.tandfonline.com/doi/full/10.1080/1357650X.2017.1377726 “DNA methylation in candidate genes for handedness predicts handedness direction” (not freely available)

How one person’s paradigms regarding stress and epigenetics impedes relevant research

This 2017 review laid out the tired, old, restrictive guidelines by which current US research on the epigenetic effects of stress is funded. The reviewer rehashed paradigms circumscribed by his authoritative position in guiding funding, and called for more government funding to support and extend his reach.

The reviewer won’t change his beliefs regarding individual differences and allostatic load since he helped to start those memes. US researchers with study ideas to develop evidence beyond such memes may have difficulties finding funding.

Here’s one example of the reviewer’s restrictive views taken from the Conclusion section:

Adverse experiences and environments cause problems over the life course in which there is no such thing as “reversibility” (i.e., “rolling the clock back”) but rather a change in trajectory [10] in keeping with the original definition of epigenetics [132] as the emergence of characteristics not previously evident or even predictable from an earlier developmental stage. By the same token, we mean “redirection” instead of “reversibility”—in that changes in the social and physical environment on both a societal and a personal level can alter a negative trajectory in a more positive direction.”

What would happen if US researchers proposed tests of his “there is no such thing as reversibility” axiom? To secure funding, his sphere of influence would probably steer the prospective studies’ experiments toward altering “a negative trajectory in a more positive direction” instead.

An example of his influence may be found in the press release of Familiar stress opens up an epigenetic window of neural plasticity where the lead researcher stated a goal of:

“..not to ‘roll back the clock’ but rather to change the trajectory of such brain plasticity toward more positive directions.”

I found nothing in citation [10] (of which the reviewer is a coauthor) where the rodent study researchers even attempted to directly reverse the epigenetic changes! The researchers under his guidance simply asserted:

“..a history of stress exposure can permanently alter gene expression patterns in the hippocampus and the behavioral response to a novel stressor”

without making any therapeutic efforts to test the permanence assumption!

Never mind that researchers outside the reviewer’s sphere of influence have done exactly that, reverse both gene expression patterns and behavioral responses! In any event, citation [10] didn’t support an “there is no such thing as reversibility” axiom.

The reviewer also implied that humans respond just like lab rats and can be treated as such. Notice that the above graphic conflated rodent and human behaviors. Further examples of this inappropriate merger of behaviors are in the Conclusion section.


What may be a more promising research approach to human treatments of the epigenetic effects of stress now that it’s 2017? I pointed out in The current paradigm of child abuse limits pre-childhood causal research:

“If the current paradigm encouraged research into treatment of causes, there would probably already be plenty of evidence to demonstrate that directly reducing the source of the damage would also reverse the damaging effects. There would have been enough studies done so that the generalized question of reversibility wouldn’t be asked.

Aren’t people interested in human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?”

http://journals.sagepub.com/doi/full/10.1177/2470547017692328 “Neurobiological and Systemic Effects of Chronic Stress”

Epigenetic stress effects in preterm infants

This 2017 Italian review selected 9 human studies on the epigenetic effects of:

“..one of the major adverse events in human development. Preterm infants are hospitalized in the Neonatal Intensive Care Unit where they are exposed to life-saving yet pain-inducing procedures and to protective care.”

Highlights of the referenced studies included:

  • “..early exposure to adverse events during the third trimester of pregnancy is capable to alter the epigenetic status of imprinted and placenta-related genes which have relevant implications for fetal development and preterm infants’ HPA [hypothalamic–pituitary–adrenal] stress reactivity during infancy.”
  • “..there was an association between DNAm [DNA methylation] and white matter tract tissue integrity and shape inferred from dMRI [diffusion MRI], suggesting that epigenetic variation may contribute to the cerebral phenotype of preterm birth.”

Limitations of the referenced studies included:

  • “A multiple sampling design that includes parental samples, placental tissue, cord blood and extends across the life-course would be required to investigate the relative contributions of in utero and postnatal exposures to changes in DNAm, and the extent to which preterm birth leaves a legacy on the methylome.”
  • Saliva, blood, and other tissues’ DNA methylation may not produce valid links to brain tissue DNA methylation of the same gene, which may hamper conclusive inferences about behavior, etc.

http://www.sciencedirect.com/science/article/pii/S0149763417302117 “Preterm Behavioral Epigenetics: A systematic review” (not freely available)

http://www.nature.com/tp/journal/v6/n1/full/tp2015210a.html “Epigenomic profiling of preterm infants reveals DNA methylation differences at sites associated with neural function” (one of the studies selected, quoted above)

Epigenetic effects on genetic diseases

This 2017 review provided evidence for epigenetic effects on a disease widely considered to be of genetic origins:

“..for a T1D [type 1 diabetes] identical twin the concordance rate (both twins affected)..is consistently less than 100%, which implies a non-genetically determined effect. However, the concordance rate declines with age at diagnosis of the index twin, indicating that in adult-onset T1D the genetic impact is limited, and certainly lower than that in childhood-onset disease.

Genes associated with T1D are well-established and have four broad functions..However, T1D is unlikely to be a single disease since there is disease heterogeneity..the incidence of T1D has even increased several-fold in the last 30 years-a timeframe which rules out genetic evolution. In addition, studies of the incidence of T1D in migrant populations have shown a convergence towards the risk of the host population.

Alongside histone modifications and transcription factors, several cis-regulatory elements, including enhancers, promoters, silencers and insulators, are crucial to the function of the genome..There are more than a million enhancers; therefore, many more than there are genes, so that a number of genes are regulated by the same enhancer, which may co-localise with CpGs. Gene enhancers can be found upstream or downstream of genes and do not necessarily act on the closest promoter..Enhancers may be accompanied by insulators, which are located between the enhancers and promoters of adjacent genes and can limit phenotypic gene expression despite genetic activation.”


The review was weak in a few areas. The authors repeated a laughable claim for gross national product as a non-genetic effect for Type 1 diabetes. They also made other hyperbolic statements such as “..this observation illustrates the power of epigenetic analysis to identify those cells which are actively using the genes associated with a given tissue, given that all cells contain every gene..” that were out of place with the review’s evidential bases.

https://link.springer.com/article/10.1007/s11892-017-0916-x “The Role of Epigenetics in Type 1 Diabetes”

Epigenetics account for two-thirds of Alzheimer’s disease

The genetics percentage from a 2017 summary of Alzheimer’s disease research caught my eye:

“Although numerous single nucleotide polymorphisms (SNPs) have now been robustly associated with AD via genome-wide association studies and subsequent meta-analyses, collectively these common SNPs are believed to only account for 33% of attributable risk and the mechanism behind their action remains largely unknown.”

This citation aligned with other studies’ findings per Using twins to estimate the extent of epigenetic effects that on cellular levels, our experiences account for two-thirds of who we are.


The promise of this category of epigenetics research?

“One of the most exciting aspects of identifying disease-associated epigenomic dysfunction is that these mechanisms are potentially reversible.”

Let’s make research on reversing epigenetic changes a priority for funding, and get studies underway here in 2017!

https://www.epigenomicsnet.com/users/27784-katie-lunnon/posts/14634-robust-evidence-for-dna-methylomic-variation-in-alzheimer-s-disease “Robust evidence for DNA methylomic variation in Alzheimer’s disease” (Registration required)