Epigenetic effects of microRNA on fetal heart development

This 2017 Australian review’s subject was epigenetic impacts involving microRNA in adverse intrauterine environments, and how these affected fetal heart tissue development:

“We describe how an adverse intrauterine environment can influence the expression of miRNAs (a sub-set of non-coding RNAs) and how these changes may impact heart development. Potential consequences of altered miRNA expression in the fetal heart include; Hypoxia inducible factor (HIF) activation, dysregulation of angiogenesis, mitochondrial abnormalities and altered glucose and fatty acid transport/metabolism.

This feedback network between miRNAs and other epigenetic pathways forms an epigenetics–miRNA regulatory circuit that organizes the whole gene expression profile. The human heart encodes over 700 miRNAs.”


A 2016 review Lack of oxygen’s epigenetic effects also provided a details about hypoxia. Those reviewers importantly pointed out the natural lack of a feedback mechanism to the HIF-1α signaling source, and how this evolutionary lack contributed to diseases.

http://www.mdpi.com/1422-0067/18/12/2628/htm “Adverse Intrauterine Environment and Cardiac miRNA Expression”

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Do you have your family’s detailed medical histories?

Imagine that you were a parent who puzzled over the mystery of your pre-teen daughter’s hyperactive behavior. Without detailed family medical histories, would anyone recognize this as a preprogammed phenotype? Could anyone trace the daughter’s behavior back to her maternal great-grandmother being treated with glucocorticoids near the end of the second trimester of carrying her grandfather?

Such was a finding of a 2017 Canadian guinea pig study that was undertaken to better inform physicians of the transgenerationally inherited epigenetic effects of glucocorticoid treatments commonly prescribed during human pregnancies:

“This study presents the first evidence that prenatal treatment with sGC [synthetic glucocorticoid] results in transgenerational paternal transmission of hyperactivity and altered hypothalamic gene expression through three generations of young offspring. Female offspring appear to be more sensitive than male offspring to the programming effects of sGC, which suggests an interaction between sGC and sex hormones or sex-linked genes. Paternal transmission to F3 strongly implicates epigenetic mechanisms in the process of transmission, and small noncoding RNAs likely play a major role.”


Some details of the study included:

Veh[icle] was the control group initially treated with saline.

The study was informative and conclusive for the aspects studied. From the Methods section:

“Data from same-sex littermates were meaned to prevent litter bias. Sample sizes (N) correspond to independent litters, and not to the total number of offspring across all litters.

Power analyses based on previous studies determined N ≥ 8 sufficient to account for inter-litter variability and detect effects in the tests performed.”

https://www.nature.com/articles/s41598-017-11635-w “Prenatal Glucocorticoid Exposure Modifies Endocrine Function and Behaviour for 3 Generations Following Maternal and Paternal Transmission”

What is a father’s role in epigenetic inheritance?

The agenda of this 2017 Danish review was to establish a paternal role in intergenerational and transgenerational epigenetic inheritance of metabolic diseases:

“There are four windows of susceptibility which have major importance for epigenetic inheritance of acquired paternal epigenetic changes:

  1. paternal primordial germ cell (PGC) development,
  2. prospermatogonia stages,
  3. spermatogenesis, and
  4. during preimplantation.”

The review was a long read as the authors discussed animal studies. When it came to human studies near the paper’s end, though, the tone was of a “we know this is real, we just have to find it” variety. The authors acknowledged:

“To what extent the described DNA methylation changes influence the future health status of offspring by escaping remodeling in the preimplantation period as well as in future generations by escaping remodeling in PGC remodeling has yet to be determined.

These studies have not yet provided an in-depth understanding of the specific mechanisms behind epigenetic inheritance or exact effect size for the disease risk in offspring.

Pharmacological approaches have reached their limits..”

before presenting their belief that a hypothetical series of future CRISPR-Cas9 experiments will demonstrate the truth of their agenda.


The review focused on 0.0001% of the prenatal period for what matters with the human male – who he was at the time of a Saturday night drunken copulation – regarding intergenerational and transgenerational epigenetic inheritance of metabolic diseases. The human female’s role – who she was at conception AND THEN what she does or doesn’t do during the remaining 99.9999% of the prenatal period to accommodate the fetus and prevent further adverse epigenetic effects from being intergenerationally and transgenerationally transmitted  – wasn’t discussed.

Who benefits from this agenda’s narrow focus?

If the review authors sincerely want to:

“..raise societal awareness of behavior to prevent a further rise in the prevalence of metabolic diseases in future generations..”

then earn it! Design and implement human studies to test what’s already known from epigenetic inheritance animal studies per Experience-induced transgenerational programming of neuronal structure and functions.

http://jme.endocrinology-journals.org/content/early/2017/12/04/JME-17-0189.full.pdf “DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line”

An update on brain zapping

This 2017 general-audience article entitled Ultrasound for the brain provided a hyped update on brain zapping:

“Ultrasound could potentially treat other movement disorders, as well as depression, anxiety and a host of intract­able neuropsychiatric disorders..

This could be a breakthrough..

Researchers hope one day to help people with neuropsychiatric conditions by repairing or resetting the relevant neural pathways..

The potential advantages, especially for deep brain areas, are huge..”

Though not the main thrust of the article, another potential use of ultrasound would be to activate drugs delivered to a specific area, as this image portrays:


Vanderbilt University was again at the forefront of brain zapping, as noted in What’s an appropriate control group for a schizophrenia study? for example. I hope the disclaimers for subjects participating in Vanderbilt’s brain-zapping studies made it clear that:

“At high intensities, such as those used to relieve essential tremor, ultrasound’s effects are largely thermal: the tissue heats up and cells die.”

Epigenetic mechanisms regulate bone growth

This 2017 Baltimore/China rodent study found:

“MSPC [Mesenchymal stem/progenitor cell] senescence is epigenetically controlled by the polycomb histone methyltransferase enhancer of zeste homolog 2 (Ezh2) and its trimethylation of histone H3 on Lysine 27 (H3K27me3) mark. Ezh2 maintains the repression of key cell senescence inducer genes through H3K27me3.

Our work establishes the role of Ezh2-H3K27me3 as a key epigenetic regulator that controls the onset and progression of MSPC senescence during the transition of fast- to slow-growing phase of long bones.

The self-renewal and proliferative capacity of cells in primary spongiosa of fast-growing bones are maintained by a high level of Ezh2-H3K27me3, whereas loss of Ezh2-H3K27me3 during late puberty leads to cell senescence.”

One of the experiments led to this note in the Discussion section:

“An epidemiologic study demonstrated that 60% of the risk of osteoporosis can be explained by the bone mineral acquired by early adulthood.

Our finding that deletion of Ezh2 in nestin+ cells during early puberty increases the risk of osteoporosis in later adulthood suggests that premature cellular senescence in the primary spongiosa region during the prepubertal or early pubertal phase may also be a major cause of osteoporosis/bone loss in later life.”


The study was short of explanations in several areas. For example, causes for the effect of “loss of Ezh2-H3K27me3 during late puberty” weren’t specified.

In another example, this statement referenced nestin-positive cells:

“Because these cells are likely no longer required in this particular region during adulthood, they stop proliferating and undergo senescence during late puberty.”

but what caused the cells to be “no longer required” wasn’t specified.

The “programmed” and “fate” words were used in the Abstract:

“Our data reveals a programmed cell fate change in postnatal skeleton..”

but not explained until the Discussion section:

“The senescence process is program[m]ed by a conserved mechanism because it restricts in a particular region of long bone and follows a specific time course.”

https://www.nature.com/articles/s41467-017-01509-0 “Programmed cell senescence in skeleton during late puberty”

Beliefs about genetic and environmental influences in twin studies

This 2017 Penn State simulation found:

“By taking advantage of the natural variation in genetic relatedness among identical (monozygotic: MZ) and fraternal (dizygotic: DZ) twins, twin studies are able to estimate genetic and environmental contributions to complex human behaviors.

In the standard biometric model when MZ or DZ twin similarity differs from 1.00 or 0.50, respectively, the variance that should be attributed to genetic influences is instead attributed to nonshared environmental influences, thus deflating the estimates of genetic influences and inflating the estimates of nonshared environmental influences.

Although estimates of genetic and nonshared environmental influences from the standard biometric model were found to deviate from “true” values, the bias was usually smaller than 10% points indicating that the interpretations of findings from previous twin studies are mostly correct.”

The study model’s input was five phenotypes that varied the degrees of:

  1. Genetic and epigenetic heritability;
  2. Shared environmental factors; and
  3. Nonshared environmental factors.

Item 1 above was different than the standard model’s treatment of heritable factors, which considers only additive genetic influences.

The authors cited studies for moderate and significant shared environmental influences in child and adolescent psychopathology and parenting to support the model’s finding that overall, item 2 above wasn’t underestimated.


I wasn’t satisfied with the simulation’s description of item 1 above. With environmental influences accounted for elsewhere, and no references to transgenerational epigenetic inheritance, randomness seemed to be the only remaining explanation for an epigenetic heritability factor.

Inserting the model’s non-environmental randomness explanation for epigenetic heritability into the abstract’s statement above exposes the non sequitur:

In the standard biometric model when MZ or DZ twin similarity differs from 1.00 or 0.50, respectively, the variance that should be attributed to genetic [and non-environmental stochastic heritability] influences is instead attributed to nonshared environmental influences, thus deflating the estimates of genetic [and non-environmental stochastic heritability] influences and inflating the estimates of nonshared environmental influences.

Why did the researchers design their model with an adjustment for non-environmental epigenetic heritability? Maybe it had something to do with:

“..estimates of genetic and nonshared environmental influences from the standard biometric model were found to deviate from “true” values.”

Empirical rather than simulated findings in human twin study research are more compelling, such as The primary causes of individual differences in DNA methylation are environmental factors with its finding:

“Differential methylation is primarily non-genetic in origin, with non-shared environment accounting for most of the variance. These non-genetic effects are mainly tissue-specific.

The full scope of environmental variation remains underappreciated.”

In any event, I didn’t see that this simulation was much more than an attempt to reaffirm a belief that:

“..the interpretations of findings from previous twin studies are mostly correct.”

https://link.springer.com/article/10.1007/s10519-017-9875-x “The Impact of Variation in Twin Relatedness on Estimates of Heritability and Environmental Influences” (not freely available)

Does a societal mandate cause DNA methylation?

This 2017 worldwide meta-analysis of humans of recent European ancestry found:

“Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study [EWAS] meta-analysis of EA based on data from 27 cohort studies with a total of 10,767 individuals.”

No association was found between the societal mandate of educational attainment and the most widely studied epigenetic mark found in individuals.


The authors preregistered the analysis plan. This discouraged the fishing expeditions that researchers are so often tempted to go on when the study data find for the null hypothesis, as this meta-analysis did.

I was puzzled that the researchers described part of the preregistered analysis plan to be:

“..hypothesis-free as it is performed genome-wide without an expected direction of effect for individual CpG loci.”

The abstract, though, declared:

“If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.”

Was the meta-analysis “hypothesis-free” or did it have “the hypothesis that such factors have large effects on the epigenome”?


Society mandates year after year of school attendance. The mandate continues on to require a four-year degree just to get an entry-level job in many lines of work.

The researchers stated:

“..our EWAS associations are small in magnitude relative to the EWAS associations reported for more biologically proximal environmental factors.”

These factors – BMI, smoking, alcohol consumption, and maternal smoking – all had detrimental effects. What about the effects of educational attainment?

Would a study categorize it as detrimental when an individual breaks from expectations about what they should do, and terminates their educational attainment? One individual I know – who didn’t go to graduate school after Princeton although they were capable of quality graduate and doctorate work – wouldn’t benefit if they stopped working after three years of a career that pays several hundred thousands of dollars a year, and went back to school.

Would a study evaluate it as beneficial when an individual lengthens their educational attainment past society’s thirteen-year educational requirement? Would the extra four years still be considered beneficial when they – after foregoing four years of income, and accumulating tens of thousands of dollars of nondischargeable debt – achieve the expected outcome of an entry-level job, and then can’t unassistedly provide for their basic needs?

Are further epigenetic studies of educational attainment as an environmental factor really worthwhile? How about using research funds and efforts on more promising topics like human transgenerational epigenetic inheritance? Suitable subjects may already be selected for the researcher, as several of the “27 cohort studies” that provided data for this meta-analysis included at least three human generations.

http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2017210a.html “An epigenome-wide association study meta-analysis of educational attainment”


Here’s 48 minutes of Brian Nosek, a co-founder of the Open Science Framework (where this meta-analysis was preregistered), explaining why science needs openness like the coordination displayed here:

http://rationallyspeakingpodcast.org/show/rs-172-brian-nosek-on-why-science-needs-openness.html