Allergies and epigenetic histone modifications

July 27, 2018December 10, 2018 gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Memory, Stress Control group, DNA methylation, Embryo development, Genetic factors, Infants

This 2018 German review provided short summaries of 44 studies on the contribution of histone modifications to allergies. An overall summary of their search results was:

“There are at least two levels at which the role of histone modifications is manifested.

One is the regulation of cells that contribute to the allergic inflammation (T cells and macrophages) and those that participate in airway remodeling.

The other is the direct association between histone modifications and allergic phenotypes.

Inhibitors of histone-modifying enzymes may potentially be used as anti-allergic drugs. Furthermore, epigenetic patterns may provide novel tools in the diagnosis of allergic disorders.”

This type of search is what’s expected of researchers who will perform either:

A meta-analysis of studies selected from the search results; or
Their own study.

These reviewers didn’t indicate that they were proceeding along either path.

The review was fine for the purpose of presenting current studies of the subject. But this was just the preparatory stage of research.

https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0259-4 “Histone modifications and their role in epigenetics of atopy and allergic diseases”

Epigenetic variations in metabolism

July 25, 2018July 5, 2020 gettingwell4 2-3 stars Required further work, Brain development, Cortisol, Epigenetics, Memory, Neurochemicals, Oxytocin, Stress Control group, Critical period, DNA methylation, Embryo development, Genetic factors, Infants, Neural plasticity

This 2018 German review was comprehensive for its subject, epigenetic control of variation and stochasticity in metabolic disease. I’ll focus on one aspect, phenotypic variation:

“Phenotypic [Mendelian] variation can result both from gain- and loss-of-function mutations. Because of the extreme interconnectivity of cell regulatory networks, even at the cellular level, predicting the impact of a sequence variant is difficult as the resultant variation acts:

In the context of all other variants and

Their potential additive, synergistic and antagonistic interactions.

This phenomenon is known as epistasis.

∼98.5% of our genome is non-protein-coding: it is pervasively transcribed, and its transcripts can support regulatory function. Among the best functionally characterized non-coding RNAs (ncRNAs) arising from these sequences are microRNAs (miRNAs).

Environmental [non-Mendelian] variation or ‘stimuli’ occurring during critical windows of susceptibility can elicit lifelong alterations in an individual’s phenotype. Intergenerational metabolic reprogramming [in fruit flies] results from global alterations in chromatin state integrity, particularly from reduced H3K27me3 and H3K9me3 [histone] domains.

The broad variation of fingerprints in humans is thought to depend to a large degree on stochastic variation in mechanical forces. These clear examples of inducible multi-stable or stochastic variation highlight how little we know about the landscape of potential phenotypic variation itself.

Consensus estimates of heritability for obesity and T2D are ∼70% and ∼35% respectively. The remaining, unexplained component is known to involve gene–environment interactions as well as non-Mendelian players.”

Although the above graphic displays transgenerational inheritance for humans, the reviewers didn’t cite any human studies that adequately demonstrated causes for and effects of transgenerational epigenetic inheritance.

I’ve read the cited Swedish and Dutch studies. Their designs, methods, and “correlate with” / “was associated with” results didn’t provide incontrovertible evidence from the F₀ great-grandparents, F₁ grandparents, F₂ parents, and F₃ children. It’s necessary to thoroughly study each generation to confirm definitive transgenerational epigenetic inheritance causes and effects.

As noted in How to hijack science: Ignore its intent and focus on the 0.0001%, there aren’t any such published studies to cite. Researchers urgently need to do this human research, and stop using these poor substitutes [1] to pretend there are already adequately evidenced transgenerational epigenetic inheritance human results.

I downgraded the review for treating research of this and other subjects as faits accomplis. It’s opposite ends of the evidential spectrum to state “how little we know about the landscape of potential phenotypic variation,” and in the same review, speciously extrapolate animal experiments into putative human results.

https://www.sciencedirect.com/science/article/pii/S2212877818301984 “Epigenetic control of variation and stochasticity in metabolic disease”

[1] As an example of the poor substitutes for evidence, a researcher referred me to the 2013 “Transgenerational effects of prenatal exposure to the 1944–45 Dutch famine” which is freely available at https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/1471-0528.12136 as a study finding human transgenerational epigenetic inheritance.

The Methods section showed:

The study’s non-statistical data was almost all unverified self-reports by a self-selected sample of the F₂ generation, average age 37.
No detailed physical measurements or samples were taken of them, nor of the F₁ generation, nor of the F₀ generation, all of which are required as baselines for any transgenerational epigenetic inheritance findings.
No detailed physical measurements or samples were taken of the F₃ generation, which is the generation that may provide transgenerational evidence if the previous generations also have detailed physical baselines.

The study’s researchers drew enough participants (360) such that their statistics package allowed them to impute and assume into existence a LOT of data. But the scientific method constrained them to make factual statements of what the evidence actually showed. They admitted:

“In conclusion, we did not find a transgenerational effect of prenatal famine exposure on the health of grandchildren in this study.”

Yet this study is somehow cited for evidence of human transgenerational epigenetically inherited causes and effects!

Group statistics don’t necessarily describe an individual

July 22, 2018December 27, 2022 gettingwell4 2-3 stars Required further work, Primal Therapy, Stress Antidepressants, Control group, Dr. Arthur Janov

I’m curating this 2018 UC Berkeley/Drexel/Netherlands analysis of human studies via its press coverage. The authors:

“Collaborated to analyze data on hundreds of adults – some mentally or physically sound, others suffering from various conditions such as depression, anxiety, or post-traumatic stress disorder. Participants had completed surveys about their mental health and had their heart rates monitored via electrocardiogram.

Researchers used the data to conduct six different experiments. They sought to find out whether the conclusions of each study would successfully apply to participants individually.

One study that focused on how frequently depression sufferers reported feeling worried. Results tallied from the pool of participants showed that depressed people worry a significant amount.

But when the analysis was applied individually, the results were all over the map. Some participants worried hardly at all, while others were notably beyond the group average.

Another experiment that centered around the link between fear and avoidance showed a strong correlation when measured as a group. Yet a significant number of participants who experienced fear had no issues with avoiding various activities.

Across all six experiments, the authors could not show that what was concluded for the group applied to most individuals.”

http://www.pnas.org/content/early/2018/06/15/1711978115.full “Lack of group-to-individual generalizability is a threat to human subjects research”

Other studies such as the below have addressed problems with statistical analysis techniques. These issues aren’t limited to human studies:

Is what’s true for a population what’s true for an individual?

“The probability of turning right averaged across all individuals within each line was statistically indistinguishable from 50%. However, an individual fly’s probability of turning right often diverged markedly from the population average.”
Genetic statistics don’t necessarily predict the effects of an individual’s genes

“Epigenomic analyses are limited by averaging of population-wide dynamics and do not inform behavior of single cells. We observe dynamics at the single-cell level not predicted by epigenomic analysis.”
A review of biological variability

“It is critical to obtain a measurement of variability that is independent of the mean to ensure to not confound changes in variability with shifts in mean.”
Obtaining convictions with epigenetic statistics?

“16 of the 18 individual age acceleration estimates of the control group subjects aren’t close to the median value!”

The current study highlighted the fact that people aren’t interchangeable. Assuming ergodicity is a statistical analysis flaw that produces individually inapplicable results for many measurements of fruit flies, cells, humans, you name the organism.

When this presumption makes a study’s statistics useless for an individual, researchers can’t cure the analysis by invoking an “individual differences” meme. Neither is the flaw fixed by spinning a tale about “This is how we can truly personalize medicine.”

The current study needed to provide evidence for its proposed solution.

Regarding worrying, Dr. Arthur Janov said it best as I quoted in How well can catastrophes be predicted?:

“Worrying is not a problem, it is the symptom of something that is occurring physiologically within the brain. What causes worrying is the problem.

Constant worry is anticipating catastrophe. But what we don’t realize is that the catastrophe already has happened; we simply have no access to it.

We are actually worried about the past, not the future.”

A study of our evolutionary remnants

July 22, 2018October 5, 2019 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system DNA methylation, Genetic factors

This 2018 Michigan human cell study subject was factors affecting the expression of human endogenous retroviruses:

“We provide a comprehensive genomic and epigenomic map of the more than 500,000 endogenous retroviruses (ERVs) and fragments that populate the intergenic regions of the human genome.

The repressive epigenetic marks associated with the ERVs, particularly long terminal repeats (LTRs), show a remarkable switch in silencing mechanisms, depending on the evolutionary age of the LTRs:

Young LTRs tend to be CpG-rich and are mainly suppressed by DNA methylation, whereas

Intermediate age LTRs are associated predominantly with histone modifications, particularly histone H3 lysine 9 (H3K9) methylation.

The evolutionarily old LTRs are more likely inactivated by the accumulation of loss-of-function genetic mutations.

Because the expression of ERVs is potentially dangerous to the host cell, understanding the repressive mechanisms is important. Earlier studies have implicated the aberrant expression of ERVs in autoimmune disease pathogenesis. However, this “enemy within” may also play a beneficial role in cancer therapy.

The same kinds of chromatin dynamics appear to be used both by LTRs and genes.”

I wasn’t going to curate this study before I saw the above graphic of our Boreoeutherian ancestor. Evolutionary subjects seem very abstract until an artist reconstructs the data visually.

https://genome.cshlp.org/content/early/2018/07/03/gr.234229.118.full.pdf “Switching roles for DNA and histone methylation depend on evolutionary ages of human endogenous retroviruses” (not freely available)

This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.

Preventing prostate cancer with a broccoli sprouts diet

July 21, 2018August 28, 2020 gettingwell4 0-1 star Wasted resources, Epigenetics Control group, DNA methylation, Genetic factors

This 2018 Oregon rodent study fed a 15% broccoli sprout diet beginning at four weeks of age to a mouse strain with a near-100% chance of developing prostate cancer:

“Broccoli sprouts reduced prostate cancer incidence and progression to invasive cancer. Broccoli sprout consumption also decreased histone H3 lysine 9 trimethylation in the ventral lobe (age 12 wk), and decreased histone H3 lysine 18 acetylation in all prostate lobes (age 28 wk).

The TRAMP model of prostate cancer was utilized because the tumors occur in the prostate epithelium and the tumor tissue histopathology closely mimics human disease. Additional advantages include that the tumors arise spontaneously and appear in ∼100% of mice.”

Like in utero prevention of breast cancer by a broccoli sprouts diet, this study had a problem measuring sulforaphane dosage. The relevant statements were:

“This 15% broccoli sprout diet had 400 mg SFN [sulforaphane]/kg diet, which was chosen because it is equivalent to 1 mg SFN/d which has been used in previous studies.

Food consumption was measured over the course of the study and no difference was found in the intake of food between the control and broccoli sprout–fed groups.”

To be “equivalent to 1 mg SFN/d” at a .4 mg sulforaphane/gram rate, the animals would eat 2.5 grams per day. That’s half of a normal intake. “Food consumption was measured” but not disclosed.

The study for the “1 mg SFN/d” dosage cited at http://cancerpreventionresearch.aacrjournals.org/content/early/2015/02/21/1940-6207.CAPR-14-0386.full-text.pdf was actually:

“4 week old male TRAMP mice were treated with PBS [phosphate-buffered saline] (control) or 1 mg SFN in PBS three times/week for 15-18 weeks.”

not “1 mg SFN/d which has been used in previous studies.”

The researchers didn’t sufficiently quantify their findings to help humans, which is the basic purpose of any animal study.

https://academic.oup.com/cdn/article/2/3/nzy002/4803105 “Broccoli Sprouts Delay Prostate Cancer Formation and Decrease Prostate Cancer Severity with a Concurrent Decrease in HDAC3 Protein Expression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) Mice”

Starving awakens ancient parasite DNA within us

July 21, 2018February 2, 2020 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress, Telomeres Control group, DNA methylation, Genetic factors

This 2018 Italian human cell study conducted a series of experiments on the effects of nutrient deprivation:

“Reduced food intake, and in particular protein or amino acid (AA) restriction, extends lifespan and healthspan.

We have previously shown that, in mammalian cells, deprivation of essential AAs (methionine/cysteine or tyrosine) leads to the transcriptional reactivation of integrated silenced transgenes by a process involving epigenetic chromatic remodeling and histone acetylation.

Here we show that the deprivation of methionine/cysteine also leads to the transcriptional upregulation of endogenous retroviruses [ERVs], suggesting that essential AA starvation affects the expression not only of exogenous non-native DNA sequences, but also of endogenous anciently-integrated and silenced parasitic elements of the genome.

ERVs, comprising 8% of the human genome, represent the remnants of past infections of germ cells by exogenous retroviruses, and are mostly unable to retrotranspose in the human genome. However, they can reactivate during physiological development, or in pathological conditions like cancer, and regulate the expression of nearby genes by their LTR elements, leading to general transcriptional reprogramming.

Dissection of the underlying mechanism ruled out a role for the main AA-deficiency sensor GCN2 and pointed to the ribosome as the possible master controller.”

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200783 “Amino acid deprivation triggers a novel GCN2-independent response leading to the transcriptional reactivation of non-native DNA sequences”

The study found that reality is sometimes stranger than what fiction writers dream up. 🙂

The authors cited a 2016 Danish review I hadn’t previously curated:

https://www.nature.com/articles/nrendo.2016.87 “The role of diet and exercise in the transgenerational epigenetic landscape of T2DM” (not freely available)

Contrary to what’s implied by its title, though, and as I noted in How to hijack science: Ignore its intent and focus on the 0.0001%, those reviewers didn’t cite any human studies that adequately demonstrated transgenerational epigenetic inheritance causes and effects. They admitted:

“Direct evidence that epigenetic factors drive the inheritance of T2DM [type 2 diabetes mellitus] in humans is lacking.”

The Danish reviewers then continued on as if proof of human transgenerational epigenetic inheritance was a foregone conclusion! It didn’t serve any valid scientific purpose to assume such evidence into existence.

A dietary supplement that trains the innate immune system

July 21, 2018December 26, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Glutamate, Immune system, Memory, Neurochemicals, Stress DNA methylation

This 2018 Netherlands review topic was long-term epigenetic programming of the innate immune system:

“Immunological memory has been classically described for the adaptive immune system, in which naive B and T lymphocytes develop antigen-specific, long-lasting memory cells after encountering a new antigen.

Immunological memory is not an exclusive trait of lymphocytes. The function of cells from the innate immune system, such as monocytes, macrophages, dendritic cells, and NK cells, is also influenced by contact with different stimuli, undergoing functional reprogramming.

β-glucan, the prototypical trained immunity-inducing agonist:

Modulates hematopoietic stem and progenitor cells, influencing behavior and responsiveness of peripheral myeloid cells;

Leads to a shift of cellular metabolism from oxidative phosphorylation toward aerobic glycolysis.

Analysis of transcriptional data from macrophages stimulated with β-glucan revealed that the cholesterol synthesis pathway is highly up-regulated in trained immunity. A follow-up of this study showed that activation of the cholesterol synthesis pathway, but not its synthesis itself, is crucial for innate memory. In agreement with this, inhibition of cholesterol synthesis in mice reduced induction of trained immunity by β-glucan.

β-glucan-induced changes in trimethylation of histone 3 lysine 4 (H3K4me3) and acetylation of histone 3 lysine 27 (H3K27ac) in human monocytes 7 days after the first stimulation in vitro were associated with a switch to glycolysis, suggesting a deep, long lasting reprogramming of cells.

Inducers of cellular reprogramming such as β-glucan have shown potential as a treatment or adjuvant for osteosarcoma, influenza, or skin lesions, among others.”

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1002/JLB.MR0318-104R “Long-term reprogramming of the innate immune system”

A seasonal epigenetic effect of conception on BMI

July 12, 2018September 13, 2018 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Stress Control group, DNA methylation

This 2018 Swiss human/rodent study found:

“The presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring.

Adipose tissue functions as a dynamic endocrine organ, and its ‘quality’ is considered to be an important factor in the development of obesity-associated comorbidities. Adipose tissue can be divided into the functionally and morphologically distinct white adipose tissue (WAT) and BAT. The main function of BAT is energy dissipation via nonshivering thermogenesis, which is enabled by the presence of uncoupling protein (UCP1) in the inner mitochondrial membrane.

In humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.

We performed a retrospective study of FDG-PET/CT scans from 2007–2015 that were collected from the University Hospital of Zurich (n = 8,440 individuals). Individuals with active BAT were 3.2% more likely to have been conceived in the colder period of the year, for example, between October and February (mean temperature estimate 2° C), whereas individuals without active BAT were more likely to have been conceived in the warmer months, for example, between April and September (mean temperature estimate 13° C).”

The study provided another example of how stressful experiences of parents – even those before offspring conception – affected their offspring.

Edit 8/13/2018: I substituted the authors’ corrected graphic where the calendar month started with April vs. January.

A review of this study was made in The imperative of human transgenerational studies.

https://www.nature.com/articles/s41591-018-0102-y “Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring” (not freely available)