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”

Advertisements

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”

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

One example of how experience changes the brain

This 2017 California rodent study found:

“Neural representations within the mouse hypothalamus, that underlie innate social behaviours, are shaped by social experience.

In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male versus female conspecifics [members of the same species]. However, in inexperienced adult males, male and female intruders activated overlapping neuronal populations.

Sex-specific neuronal ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not to mount or attack conspecifics, ensemble divergence did not occur. However, 30 minutes of sexual experience with a female was sufficient to promote the separation of male and female ensembles.

These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviours. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a ‘hard-wired’ system.”

Hat tip to Neuroskeptic for both alerting me to the study and simplifying its overly-dense graphics.

http://www.nature.com/nature/journal/v550/n7676/full/nature23885.html “Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex” (not freely available)

Do preventive interventions for children of mentally ill parents work?

The fifth and final paper of Transgenerational epigenetic inheritance week was a 2017 German/Italian meta-analysis of psychiatric treatments involving human children:

“The transgenerational transmission of mental disorders is one of the most significant causes of psychiatric morbidity. Several risk factors for children of parents with mental illness (COPMI) have been identified in numerous studies and meta-analyses.

There is a dearth of high quality studies that effectively reduce the high risk of COPMI for the development of mental disorders.”


I found the study by searching a medical database on the “transgenerational” term. The authors fell into the trap of misusing “transgenerational” instead of “intergenerational” to describe individuals in different generations.

Per the definitions in A review of epigenetic transgenerational inheritance of reproductive disease and Transgenerational effects of early environmental insults on aging and disease, for the term “transgenerational transmission” to apply, the researchers needed to provide evidence in at least the next 2 male and/or 3 female generations of:

“Altered epigenetic information between generations in the absence of continued environmental exposure.”

The meta-analysis didn’t provide evidence for “transgenerational transmission of mental disorders.”


Several aspects of the meta-analysis stood out:

  1. Infancy was the earliest period of included studies, and studies of treatments before the children were born were excluded;
  2. Parents had to be diagnosed with a mental illness for the study to be included;
  3. Studies with children diagnosed with a mental illness were excluded; and
  4. Studies comparing more than one type of intervention were excluded.

Fifty worldwide studies from 1983 through 2014 were selected for the meta-analysis.

Per item 1 above, if a researcher doesn’t look for something, it’s doubtful that they will find it. As shown in the preceding papers of Transgenerational epigenetic inheritance week, the preconception and prenatal periods are when the largest epigenetic effects on an individual are found. There are fewer opportunities for effective “preventive interventions” in later life compared with these early periods.

Science provides testable explanations and predictions. The overall goal of animal studies is to help humans.

Animal studies thus provide explanations and predictions for the consequences of environmental insults to the human fetus – predictable disrupted neurodevelopment with subsequent deviated behaviors and other lifelong damaging effects in the F1 children. The first four papers I curated during Transgenerational epigenetic inheritance week provided samples of which of these and/or other harmful effects may be predictably found in F2 grandchildren, F3 great-grandchildren, and future human generations.

When will human transgenerational epigenetic inheritance be taken seriously? Is the root problem that human societies don’t give humans in the fetal stage of life a constituency, or protection against mistreatment, or even protection against being arbitrarily killed?


The default answer to the meta-analysis title “Do preventive interventions for children of mentally ill parents work?” is No. As for the “dearth of high quality studies” complaint: when treatments aren’t effective, is the solution to do more of them?

No.

The researchers provided an example of the widespread belief that current treatments for “psychiatric morbidity” are on the right path, and that the usual treatments – only done more rigorously – will eventually provide unquestionable evidence that they are effective.

This belief is already hundreds of years old. How much longer will this unevidenced belief survive?

http://journals.lww.com/co-psychiatry/Abstract/2017/07000/Do_preventive_interventions_for_children_of.9.aspx “Do preventive interventions for children of mentally ill parents work? Results of a systematic review and meta-analysis” (not freely available)