What is epigenetic inheritance?

This 2016 review by Eric Nestler, a well-known and well-funded researcher, entitled Transgenerational Epigenetic Contributions to Stress Responses: Fact or Fiction? concluded:

“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 in determining an individual’s susceptibility versus resilience to stress throughout life.

There is growing evidence for at least some contribution of epigenetic regulation – perhaps achieved by miRNAs – in mediating part of the ability of parental behavioral experience to influence stress vulnerability in their offspring.”

The reviewer applied the terms involved to exclude behavioral inheritance mechanisms. The extent of what is “epigenetic inheritance” seemed to be lost in the process.

For example, his own 2011 research Paternal Transmission of Stressed-Induced Pathologies was cited for evidence that:

“Adult male mice subjected to chronic social defeat stress generate offspring that are more vulnerable to a range of stressful stimuli than the offspring of control mice.”

Yet that finding was dismissed in the review and in that study as behavioral:

“While epigenetic changes in sperm might be a small factor in transgenerational transmission of stress vulnerability, a large portion of the observed transmission may be behavioral.

The fact that most of the transgenerational transmission of stress vulnerability observed in our experiments was not seen with IVF argues against the preponderance of epigenetic mechanisms. Rather, our data would suggest that the bulk of the vulnerabilities are passed on to subsequent generations behaviorally.”

A few questions:

  1. If the experimental subjects had no more control over their behavioral stress-response effects than they had over their DNA methylation, histone modification, or microRNA stress-response effects, then why was such behavior not included in the “epigenetic mechanisms” term?
  2. How do behavioral inheritance mechanisms fall outside the “true epigenetic inheritance” term when behavioral stress-response effects are shown to be reliably transmitted generation after generation?
  3. Wouldn’t the cessation of behavioral inheritance mechanisms confirm their status by falsifiability? This was done with studies such as the 1995 Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress.


I ain’t got a heart of stone
I’m hurting more now than I’ve ever known
If you mean the things you said
I’m gonna wind up out of my head

Can’t sleep alone at night
I just can’t seem to get it right
Damned if I do
Damned if I don’t
But I love you

I don’t wanna tie you down
Don’t need a reason to have you around
But each time you walk away
Don’t be surprised if I ask you to stay

Can’t sleep alone at night
I just can’t seem to get it right
Damned if I do and I’m damned if I don’t
But I love you
I said I’m damned if I do and I’m damned if I don’t
But I love you

I ain’t got a heart of stone
You haven’t left me a mind of my own
But it’s got such a hold on me
I don’t think I could ever be free

How can I survive?
I’m fighting to keep myself alive
I’m damned if I do
Damned if I don’t
But I love you

Can’t seem to see the light
I’ve done everything but I can’t get it right
Damned if I do
Damned if I don’t
But I love you

A followup study of DNA methylation and age

This 2016 Finnish human study was a followup to A study of DNA methylation and age:

“At the 2.55-year follow-up, we identified 19 mortality-associated CpG sites that mapped to genes functionally clustering around the nuclear factor kappa B (NF-κB) complex. None of the mortality-associated CpG sites overlapped with the established aging-associated DNAm sites.

Our results are in line with previous findings on the role of NF-κB in controlling animal life spans and demonstrate the role of this complex in human longevity.”

I was again impressed with the researchers’ frankness in the Discussion section:

“Our data do not provide a mechanistic link between the hypomethylation of these CpG sites and the risk of mortality.

Our data do not allow us to determine whether disrupted regulation of chromatin permissiveness underlies the increased mortality risk.

None of our top 250 mortality-associated methylomic sites were among the 525 common age-associated CpG sites that have been observed in more than one study.”

Regarding the lack of confirmation at the 4-year followup:

“The number of mortality-associated CpG sites was markedly reduced from the 2.55-years follow-up to the 4-years follow-up.

A substantial part of the genomic CpG sites might be constantly remodeled, and during 4 years, their methylation levels are likely to change to an extent that their predictive ability in our population is reduced. The longer follow-up time also allows more time for stochastic mortality determinants, such as trauma, to operate, which may thus weaken the role of the genomic predictors.”

The epigenetic clock method was investigated:

“The DNAm age has also been recently demonstrated to predict all-cause mortality in four different cohorts of elderly individuals and in Danish twins. However, the DNAm age was not predictive of mortality in our study.

One reason for the negative finding might be that individuals in our cohort were all very old at baseline (90 years), and death at this age likely has different underpinnings than at younger old ages and when assessed in cohorts with wider age spectra.”

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=8278&path[]=24504 “Methylomic predictors demonstrate the role of NF-κB in old-age mortality and are unrelated to the aging-associated epigenetic drift”

A study of how genetic factors determined diet-induced epigenetic changes

This 2016 California rodent study found:

“HF [high fat] diet leads to persistent alterations of chromatin accessibility that are partially mediated by transcription factors and histone post-translational modifications. These chromatin alterations are furthermore strain specific, indicating a genetic component to the response.

These results suggest that persistent epigenetic modifications induced by HF diet have the potential to impact the long-term risk for metabolic diseases.”

The experimental procedure was that 7-8 week old subjects of two mice strains “were placed on three diet regimens:

  1. control diet for sixteen weeks,
  2. HF diet for sixteen weeks, or
  3. HF diet for an initial eight weeks followed by control diet for eight weeks (diet reversal).”

On diet regimen 3, one of the mouse strains wasn’t able to reverse the epigenetic changes caused by eight weeks of a high-fat diet. The symptoms included:

  • Elevated lipid accumulation and triglyceride levels
  • 15% of chromatin sites were more accessible, with the HNF4α transcription factor implicated
  • 6% of chromatin sites were less accessible due to H3K9 methylation
  • Persistently up-regulated genes were more likely to be in the vicinity of a persistently accessible site
  • A set of persistently up-regulated genes enriched for mitochondrial genes was present only with diet regimen 3 subjects.

A second mouse strain “known to display differences in metabolic dysfunction under HF diet” compared to the first strain didn’t experience the same symptoms on diet regimen 3:

  • Lipid accumulation and triglyceride levels weren’t elevated
  • The majority of diet-induced chromatin remodeling [was] reversible
  • Little overlap with the first strain in the set of genes that changed expression.

The study didn’t suggest any specific human applicability.

http://www.jbc.org/content/early/2016/03/22/jbc.M115.711028.long (pdf) “Persistent chromatin modifications induced by high fat diet”


A skin study that could have benefited from preregistration

This 2016 German human skin study found:

“An age-related erosion of DNA methylation patterns that is characterized by a reduced dynamic range and increased heterogeneity of global methylation patterns. These changes in methylation variability were accompanied by a reduced connectivity of transcriptional networks.”

The study could have benefited from preregistration using an approach such as Registered Reports. As it was, the study gave the impression of a fishing expedition.

For example, the initial subjects were 24 women ages 18-27 and 24 women ages 61-78. The barbell shape of the subjects’ age distribution wouldn’t make sense if the researchers knew they were going to later use the epigenetic clock method.

The researchers did so, although the method’s instructive study noted:

“The standard deviation of age has a strong relationship with age correlation”

and provided further details in “The age correlation in a data set is determined by the standard deviation of age” section.

A second round of subjects were recruited, 60 women aged 20-79, “that also included intermediate ages.” No discrete numbers were provided, but from eyeballing Figure S1 in the supplementary material, the ages of the second group appeared to be evenly distributed.

The subject groups were lumped together to make findings such as:

“We observed a significant age-related hypermethylation of CpG island-associated probes. This effect was strongly enriched during two specific age windows, at 40–45 and 50–55 years.

Considering that our samples were exclusively derived from female volunteers, it seems reasonable to link the latter window to menopause, which is also known to distinctly accelerate skin aging.”

The study didn’t state that the second group of subjects were screened for menopause, or for use of hormone therapies or skin creams.

If the ages of the second group of subjects were evenly distributed, 6 of the 108 subjects would be ages 50-55. It wasn’t “reasonable to link” a small number of subjects to conditions for which they hadn’t been screened.

http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12470/ “Reduced DNA methylation patterning and transcriptional connectivity define human skin aging”

Mechanisms of stress memories in plants

This 2016 Australian review’s subject was plant memory mechanisms:

“Plants are adept at rapidly acclimating to stressful conditions and are able to further fortify their defenses by retaining memories of stress to enable stronger or more rapid responses should an environmental perturbation recur.

The recovery process entails a balancing act between resetting and memory formation. During recovery, RNA metabolism, posttranscriptional gene silencing, and RNA-directed DNA methylation have the potential to play key roles in resetting the epigenome and transcriptome and in altering memory.”

Many of the principles applied to animals, and several animal studies were cited for illustration. Here’s one of the graphics:


I disagreed with the Summary statement:

“Memory, in particular epigenetic memory, is likely a relatively rare event.”

The reviewers cited a 2015 Australian study Stress induced gene expression drives transient DNA methylation changes at adjacent repetitive elements which found the opposite conclusion with rice:

“Despite 21 days of starvation, resupplying phosphate for just 1 day reversed expression of 40% of induced genes, further increasing to 80% after 3 days and corresponding with a reestablished internal root phosphate concentration. Interestingly though, 80 genes remained differentially regulated even after 31 days of resupply.”

The cited study’s researchers attributed their epigenetic memory finding to several factors, including their study design:

“The majority of DNA methylation analyses performed in plants to date have focused on Arabidopsis, despite being relatively depleted of TEs [transposable elements] (15–20% of the genome) and being poorly methylated compared to other plant genomes.

To date, only a limited number of studies have comprehensively investigated the involvement of DNA methylation in response to adverse environmental conditions. Several studies have reported that changes in the environment can affect the methylation status of some regions of the genome, using low resolution and non-quantitative techniques. These studies have lacked the resolution to provide the specific context and genomic location of the changes in DNA methylation, thus offering limited insights into the potential role of stress-induced changes in DNA methylation.”

So, the current review judging “memory, in particular epigenetic memory” to be “a relatively rare event” probably had more to do with study designs rather than what actually occurs in nature. See one of the coauthor’s response below.

http://advances.sciencemag.org/content/2/2/e1501340.full “Reconsidering plant memory: Intersections between stress recovery, RNA turnover, and epigenetics”

Oxytocin research null findings come out of the file drawer

In 2016 Belgian researchers released their previously unpublished studies:

“Is there a file drawer problem in intranasal oxytocin research?

We submitted several studies yielding null-findings to different journals but they were rejected time and time again.

The aggregated effect size was not reliably different from zero [including all of the researchers’ previously unpublished intranasal oxytocin studies].”

Neuroskeptic comments:

“By publishing these results, Lane et al. have ensured that future meta-analysts will be able to include the full dataset in their calculations.”

http://blogs.discovermagazine.com/neuroskeptic/2016/03/17/open-the-file-drawer/ “Psychologists Throw Open the File Drawer”

See Testing the null hypothesis of oxytocin’s effects in humans for more on the topic.