4-5 stars Advanced knowledge

Advanced knowledge

Using salivary microRNA to diagnose autism

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Epigenetics, Hippocampus, Limbic system , , ,

This 2016 New York human study found:

“Measurement of salivary miRNA in this pilot study of subjects with mild ASD [autism spectrum disorder] demonstrated differential expression of 14 miRNAs that are:

  • expressed in the developing brain,
  • impact mRNAs related to brain development, and
  • correlate with neurodevelopmental measures of adaptive behavior.”

Some problems with current diagnostic methods for autism are:

“The first sign of ASD commonly recognized by pediatricians is a deficit in communication and language that does not manifest until 18–24 months of age.

The mean age of diagnosis for children with ASD is 3 years, and approximately half of these are false-positives.

Despite a substantial genetic component, no single gene variant accounts for >1 % of ASD incidence.

Nearly 2000 individual genes have been implicated in ASD, but none are specific to the disorder.”

Study limitations included:

“Aside from the sample size and cross-sectional nature of this pilot study, another limitation is the age of ASD and control subjects it describes (4–14 years) which are not representative of the target population in which ASD biomarkers would ideally be utilized (0–2 years). However, selecting a homogenous group of subjects with mild ASD (as measured by ADOS) that was well-established and diagnosed by a developmental specialist requires subjects with long-standing diagnoses.”

Understanding later-life consequences of disrupted neurodevelopment is critical for tracing symptoms back to their causes, as noted in Grokking an Adverse Childhood Experiences (ACE) score. I wonder how long it will take for researchers in other fields to stop wasting resources and do what this study did: focus on epigenetic biomarkers that have developmental origins.

http://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-016-0586-x “Salivary miRNA profiles identify children with autism spectrum disorder, correlate with adaptive behavior, and implicate ASD candidate genes involved in neurodevelopment”

Contending with epigenetic consequences of violence to women

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Oxytocin, Stress , , ,

This 2016 UK review subject was the interplay of genomic imprinting and intergenerational epigenetic information transfer:

“A range of evolutionary adaptations associated with placentation transfers disproportionate control of this process to the matriline, a period unique in mammalian development in that there are three matrilineal genomes interacting in the same organism at the same time (maternal, foetal, and postmeiotic oocytes).

Genomic imprinting is absent in egg laying mammals and only around 6 imprinted genes have been detected in a range of marsupial species; this is in contrast to eutherian mammals where around 150 imprinted genes have been described.

The interactions between the maternal and developing foetal hypothalamus and placenta can provide a template by which a mother can transmit potentially adaptive information concerning potential future environmental conditions to the developing brain.

In circumstances either where the early environment provides inaccurate cues to the environmental conditions prevailing when adult due to rapid environmental change or when disruptions to normal neural development occur, the mismatch between the environmental predictions made during early development and subsequent reality may mean that an organism may have a poorly adapted phenotype to its adult environment. An appreciation of these underlying evolutionary salient processes may provide a novel perspective on the [causal] mechanisms of a range of health problems.

The concept of a brain that is not pathological in the classical sense but it is simply mismatched to its environment has been most extensively studied in the context of ancestral and early developmental nutrition. However, this concept can be extended to provide insights into the development of a range of alternative neural phenotypes.”

The review’s final sentence was:

“Examination of the adaptive potential of a range of neural and cognitive deficits in the context of evolutionary derived foetocentric brain and placental development, epigenetics and environmental adaptation may provide novel insights into the development and potential treatment of a range of health, neurological, and cognitive disorders.”

One of the reviewers was cited in Epigenetic DNA methylation and demethylation with the developing fetus, which the review cited along with Epigenetic changes in the developing brain change behavior.

Researchers who avoid hypotheses that can’t be proven wrong could certainly test the subject matter of this review if they investigated their subjects’ histories.

For example, let’s say a patient/subject had symptoms where the “150 imprinted genes” were implicated. What are the chances a clinician or researcher would be informed by this review’s material and investigate the mother’s and grandmother’s histories?

For clinicians or researchers who view histories as irrelevant busywork: How many tens of millions of people alive today have mothers who were fetuses when their grandmothers were adversely affected by violence? Wouldn’t it be appropriate to assess possible historical contributions of:

“The mismatch between the environmental predictions made during early development and subsequent reality”

to the patient’s/subject’s current symptoms?

http://www.hindawi.com/journals/np/2016/6827135/ “Placental, Matrilineal, and Epigenetic Mechanisms Promoting Environmentally Adaptive Development of the Mammalian Brain”

The cerebellum ages more slowly than other body and brain areas

gettingwell4 4-5 stars Advanced knowledge, Cerebellum, Cerebrum, Epigenetics, Hippocampus, Limbic system, Lower brain, Telomeres , , ,

This 2015 UCLA human study used the epigenetic clock methodology to find:

“All brain regions have similar DNAm ages in subjects younger than 80, but brain region becomes an increasingly significant determinant of age acceleration in older subjects. The cerebellum has a lower epigenetic age than other brain regions in older subjects.

To study age acceleration effects in non-brain tissues as well, we profiled a total of 30 tissues of a 112 year old woman. The cerebellum exhibited the lowest (negative) age acceleration effect compared to the remaining 29 other regions. In contrast, bone, bone marrow, and blood exhibit relatively older DNAm ages.”

Limitations included:

  • “While the epigenetic age of blood has been shown to relate to biological age, the same cannot yet be said about brain tissue.
  • Cellular heterogeneity may confound these results since the cerebellum involves distinct cell types.
  • This cross-sectional analysis does not lend itself for dissecting cause and effect relationships.”

The study didn’t determine why the cerebellum was relatively younger. Some hypotheses were:

  • “Our findings suggest that cerebellar DNA is epigenetically more stable and requires less ‘maintenance work.’
  • The cerebellum has a lower metabolic rate than cortex.
  • It has far fewer mitochondrial DNA (mtDNA) deletions than cortex especially in older subjects, and it accumulates less oxidative damage to both mtDNA and nuclear DNA than does cortex.”

http://impactaging.com/papers/v7/n5/full/100742.html “The cerebellum ages slowly according to the epigenetic clock”

Observing pain in others had long-lasting brain effects

gettingwell4 4-5 stars Advanced knowledge, Anterior cingulate cortex, Brain hemispheres, Cerebrum, Limbic system, Memory, Neurochemicals, Oxytocin, Stress , ,

This 2016 Israeli human study used whole-head magnetoencephalography (MEG) to study pain perception in military veterans:

“Our findings demonstrate alterations in pain perception following extreme pain exposure, chart the sequence from automatic to evaluative pain processing, and emphasize the importance of considering past experiences in studying the neural response to others’ states.

Differences in brain activation to ‘pain’ and ‘no pain’ in the PCC [posterior cingulate cortex] emerged only among controls. This suggests that prior exposure to extreme pain alters the typical brain response to pain by blurring the distinction between painful and otherwise identical but nonpainful stimuli, and that this blurring of the ‘pain effect’ stems from increased responses to ‘no pain’ rather than from attenuated response to pain.”

Limitations included:

  • “The pain-exposed participants showed posttraumatic symptoms, which may also be related to the observed alterations in the brain response to pain.
  • We did not include pain threshold measurements. However, the participants’ sensitivity to experienced pain may have had an effect on the processing of observed pain.
  • The regions of interest for the examination of pain processing in the pain-exposed group were defined on the basis of the results identified in the control group.
  • We did not detect pain-related activations in additional regions typically associated with pain perception, such as the anterior insula and ACC. This may be related to differences between the MEG and fMRI neuroimaging approaches.”

The subjects self-administered oxytocin or placebo per the study’s design. However:

“We chose to focus on the placebo condition and to test group differences at baseline only, in light of the recent criticism on underpowered oxytocin administration studies, and thus all following analyses are reported for the placebo condition.”

A few questions:

  1. If observing others’ pain caused “increased responses to ‘no pain’,” wouldn’t the same effect or more be expected from experiencing one’s own pain?
  2. If there’s evidence for item 1, then why aren’t “increased responses to ‘no pain'” of affected people overtly evident in everyday life?
  3. If item 2 is often observed, then what are the neurobiological consequences for affected people’s suppression of “increased responses to ‘no pain’?”
  4. Along with the effects of item 3, what may be behavioral, emotional, and other evidence of this suppressed pain effect?
  5. What would it take for affected people to regain a normal processing of others’ “‘pain’ and ‘no pain’?”

https://www.researchgate.net/publication/299546838_Prior_exposure_to_extreme_pain_alters_neural_response_to_pain_in_others “Prior exposure to extreme pain alters neural response to pain in others” Thanks to one of the authors, Ruth Feldman, for providing the full study

Epigenetic contributions to hypertension

gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Neurochemicals, Stress ,

This 2016 Australian review subject was epigenetic contributions to hypertension:

“Hypertension (HT) affects more than 1 billion people globally and is a major risk factor for stroke, chronic kidney disease, and myocardial infarction.

Essential hypertension (EH) is a complex, polygenic condition with no single causative agent. There is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of EH.

Many epigenetic studies are, however, limited by the fact that only blood is studied rather than the effector tissues. The utility of blood methylation status in epigenetic research is yet to be determined. Furthermore, the polygenic complexity of HT and the limited knowledge on some of the non-coding RNAs makes it more challenging to decipher the exact mechanisms involved.”

The review had sections for hypertension studies on DNA methylation, histone modification, and microRNA/other non-coding RNA types. Here’s a sample of the findings:

“HSD11B2-mediated degradation of cortisol to cortisone is disrupted when the promoter region of the HSD11B2 gene is hypermethylated. The resulting imbalance in the active metabolites of cortisol and cortisone, tetrahydrocortisol, and tetrahydocortisone, respectively, promotes the onset of HT.

Histone modification affecting arterial pressure levels has been documented in a variety of human and animal tissues, including vascular smooth muscle. Vascular oxidative stress can contribute to endothelial dysfunction—a hallmark of HT—and the development of HT.

Two miRNAs (has-miR-181a and has-miR-663) with the ability to bind to the 3′ UTR of renin mRNA were found to be under-expressed in EH. These miRNAs were able to regulate the expression of a reporter gene and renin-mRNA itself, which explains over-expression of renin mRNA seen in EH kidney.”

The publisher, International Journal of Molecular Sciences, makes ALL of its articles open access. Another of its requirements is:

“The full experimental details must be provided so that the results can be reproduced.”

There also aren’t artificial limitations on either the length of the study or the number of supplementary files.

http://www.mdpi.com/1422-0067/17/4/451/htm “Epigenetic Modifications in Essential Hypertension”

A followup study of DNA methylation and age

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Hypothalamus, Limbic system ,

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”

Oxytocin research null findings come out of the file drawer

gettingwell4 4-5 stars Advanced knowledge, Neurochemicals, Oxytocin

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.

 

Beneficial epigenetic effects of mild stress with social support during puberty

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Serotonin, Stress , , , ,

This 2016 Pennsylvania rodent study found:

“Stress in the context of social support experienced over the pubertal window can promote epigenetic reprogramming in the brain to increase resilience to age-related cognitive decline in females.

These findings are actually consistent with previous studies showing that some amount of adversity, or adversity under more favorable circumstances such as social support or a protective gene polymorphism, provides a measure of ‘grit’ in coping with later life challenges.

Our findings provide a unique perspective on this relationship, as they highlight the important link between experience during the pubertal window and cognitive health during aging.”

These researchers made efforts to further investigate causes of unexpected results, such as:

“Peripubertal stress alone did not significantly alter Barnes maze performance in aging compared to aged Controls. Mice that had experienced stress with concurrent social support (CVS + SI) actually performed better than Control aged mice, specifically in learning the reversal task faster.

Peripubertal stress had no effect on corticosterone levels in response to an acute restraint stress or in sensorimotor gating and baseline startle reactivity.”

Their investigations led to epigenetic findings:

“Consistent with our behavioral findings, stress in the context of social interaction resulted in long-term reprogramming of gene expression in the PFC [prefrontal cortex]. While there were no differentially expressed genes between Control and CVS females, there were 88 genes that were significantly different between Control and CVS + SI groups. Of genes that were downregulated, a large portion (23 genes; 35%) were microRNAs.

We found that the PFC transcriptome of CVS + SI aged females was significantly enriched for predicted targets of the 23 microRNAs that were downregulated in the PFC in these mice. This suggests that microRNAs represent a mode of regulation capable of enacting far-reaching programmatic effects, and are a critical epigenetic gene expression regulatory mechanism.”

Applicability to humans was suggested by associations such as:

“A single microRNA can target more than a hundred different mRNA targets, and more than 45,000 conserved microRNA binding sites have been annotated in the 3′ UTR of 60% of human genes.”

A few limitations were noted:

“Given that mice at this age (1 year) are commonly compared to ‘late middle aged’ humans, later aging time points may yield differences in this group. Alternatively, it is possible that there was an effect of peripubertal stress that was not long-lasting due to the mild nature of our chronic stress model.

To include early neglect as a part of the stressor experience, CVS females were weaned one week earlier (PN21) than Control and CVS + SI mice. Addition of stress of this earlier weaning likely poses a significant contribution to programming of the PFC.”

One of the study coauthors was also a coauthor of:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870871/ “Peripubertal stress with social support promotes resilience in the face of aging”

Using an epigenetic clock with older adults

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Memory, Telomeres ,

This 2016 German human study found:

“Epigenetic age acceleration is correlated with clinically relevant aging-related phenotypes through pathways unrelated to cellular senescence as assessed by telomere length.

The current work employed the frailty index, a multi-dimensional approach that combines [34] parameters of multiple physiological systems and functional capacities. The present findings were based on [1,820] study participants aged 50 to 75 years.

Innovative approaches like Mendelian randomization will be needed to elucidate whether epigenetic age acceleration indeed plays a causal role for the development of clinical phenotypes.”

The study had an informative “Age acceleration and telomere length are not correlated” section with references. It was another step toward establishing the Horvath epigenetic clock for widespread usage.

http://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-016-0186-5 “Frailty is associated with the epigenetic clock but not with telomere length in a German cohort”

Using an epigenetic clock with children

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics , ,

This 2015 UK human study by many of the coauthors of What’s the origin of the problem of being fat? applied the Horvath epigenetic clock method to the same UK mother-child pairs and a Danish cohort:

“There has been no investigation on prenatal and antenatal factors that affect AA [age acceleration] in children. It is possible that the detrimental consequences of a higher AA may accrue over time, initiating in childhood. Conversely, it could be postulated that having a positive AA during early life and childhood is developmentally advantageous. To reflect this, we could refer to AA as an epigenetic measure of development in children.

We found associations between AA and sex, birth weight, caesarean section delivery and several maternal characteristics, namely smoking in pregnancy, weight, BMI, selenium and cholesterol level.

Offspring of non-drinkers had higher AA on average at birth, but this appeared to resolve during childhood. Offspring of smokers had higher AA on average and this difference became larger during childhood and adolescence.

The lack of correlation between AA and several clinical variables may also indicate that AA reflects an ‘intrinsic’ aging rate that is independent of various aging factors.

The observation that the estimated genetic component of AA increased in older study participants may indicate that the AA measure is more biologically meaningful in adults rather than children, though alternatively it could be a reflection of a decreasing environmental influence on DNA methylation patterns over time.

This accords with our finding of strengthening within subject correlation over time, which suggests the period of rapid early life changes in methylation affects epigenetic age during development to a greater extent than adulthood changes in methylation.”

The heritability of age acceleration was analyzed:

“The heritability estimate from our study (h = 0.37) is lower than that reported Horvath (h = 1.0), which was based on a small number of cord blood samples from twin pairs. Both of these heritability estimates were based on relatively few samples. Future large scale studies will be needed to arrive at precise estimates of the heritability of AA in newborns and minors.

While our heritability estimate may seem low, empirical evidence has suggested that fitness related traits tend to have lower heritability than morphological traits because selection acts to purify deleterious genetic variation, and one might consider age accelerated residuals in the former category.”

Like the coauthors’ follow-on study, causality couldn’t be definitively determined:

“Assessing the causal relationship between exposures and AA (through Mendelian randomization) is underpowered in our current data.”

Epigenetic age acceleration at birth seemed to be overall “developmentally advantageous” for offspring of non-drinking mothers. That age acceleration continued for the offspring of smokers at the second and third measurement times (ages 7 and 15-17) seemed to have “detrimental consequences.” I’d guess that the methylation state of specific CpG sites would be more informative than the overall rate in these cases.

The point about “AA..is independent of various aging factors” was similar to one made in Using an epigenetic clock to distinguish cellular aging from senescence:

“Cellular ageing is distinct from cellular senescence and independent of DNA damage response and telomere length.”

The study was a step toward establishing the Horvath epigenetic clock for widespread usage. The Hannum method was also compared and contrasted.

http://hmg.oxfordjournals.org/content/25/1/191.full “Prenatal and early life influences on epigenetic age in children: a study of mother-offspring pairs from two cohort studies”

What’s the origin of the problem of being fat?

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics , , ,

This 2016 UK human study attempted to replicate the DNA methylation and adiposity associations found by studies on a long-term longitudinal UK cohort:

“We tested for replication of associations between previously identified CpG sites at HIF3A [the hypoxia inducible factor 3 alpha subunit gene] and adiposity in ∼1,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children.”

The researchers had sufficient data to test the unidirectional and causal findings of previous studies:

“Availability of methylation and adiposity measures at multiple time points, as well as genetic data, allowed us to assess the temporal associations between adiposity and methylation and to make inferences regarding causality and directionality.”

The analyses didn’t replicate the previous studies’ findings, and a new finding was indicated:

“Our results were discordant with those expected if HIF3A methylation has a causal effect on BMI [body mass index, derived from height and weight] and provided more evidence for causality in the reverse direction i.e. an effect of BMI on HIF3A methylation.

These results are based on robust evidence from longitudinal analyses and were also partially supported by Mendelian randomization analysis, although this latter analysis was underpowered to detect a causal effect of BMI on HIF3A methylation.

Our results also highlight an apparent long-lasting inter-generational influence of maternal BMI on offspring methylation at this locus, which may confound associations between own [offspring] adiposity and HIF3A methylation.”

A person’s parents contributed all of their genetic material and the prenatal environment, and usually almost all of their postnatal and childhood development environment. If a person has a health problem that may have genetic and developmental origins, this is where to look for causes and preventive actions.

That these distant causes can no longer be addressed is a hidden assumption of research and treatment of effects of health problems. Aren’t such assumptions testable here in the current year?

http://diabetes.diabetesjournals.org/content/early/2016/02/01/db15-0996.long (pdf) “DNA methylation and body mass index: investigating identified methylation sites at HIF3A in a causal framework”

The mystery of humans’ evolved capability for adults to grow new brain cells

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Hippocampus, Limbic system, Memory , ,

This 2016 German review discussed the evolution of human adult neurogenesis:

“Mammalian adult hippocampal neurogenesis is a trait shaped by evolutionary forces that have contributed to the advantages in natural selection that are associated with the mammalian dentate gyrus. Adult hippocampal neurogenesis in mammals originates from an ectopic precursor cell population that resides in a defined stem-cell niche detached from the ventricular wall.

Neurogenesis in the adult olfactory bulb generates a diverse range of interneurons, and is involved in the processing of sensory input. In contrast, adult hippocampal neurogenesis produces only one type of excitatory principal neuron and plays a role in flexible memory formation.

A surplus of new neurons is generated first from which only a subset survives. And it is exactly these new neuronal nodes that, at least for a transient period, are the carriers of synaptic plasticity.

For a number of weeks after they were born, the new neurons have a lower threshold for long-term potentiation. This directs the action to the new cells and results in a bias toward the most plastic cells in the local circuitry.

It is a highly polygenic trait, and numerous genes have already been identified to ultimately have essentially identical effects on net neurogenesis.

Adult neurogenesis is also an individualizing trait. Even before an identical genetic background, subtle individual differences in starting conditions and differential behavioral trajectories result in an increase in phenotypic variation with time.”

The author continued the penultimate paragraph above to pose a question about adult neurogenesis that’s incompletely answered by evolutionary biology theory and evidence todate:

“How genetic variation in single genes (or many genes) would be able to exert a phenotypic change in neurogenesis that can provide a large enough advantage to be selected for.”

The development of new brain cells throughout our lives helps us continually adapt and learn. The “increase in phenotypic variation with time” helps us maintain the unique individual that each of us is.

The review emphasized to me how “individual differences” should neither be viewed as a mystery, nor explained away, nor treated as an etiological factor as researchers often do. Focusing on what caused the differences may provide clearer information.

http://cshperspectives.cshlp.org/content/8/2/a018986.full “Adult Neurogenesis: An Evolutionary Perspective”

Epigenetic memories of stress as therapeutic targets

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Memory, Stress

This 2015 Swedish rodent study found:

“Histone modifications induced by glucose are associated with activation of TXNIP gene [a proinflammatory gene involved in diabetic kidney disease] transcription.

Glucose-stimulated TXNIP gene expression can be

  • reversed by inhibition of histone acetyltransferase (HAT), or
  • enhanced by inhibition of histone deacetylase (HDAC).”

A 2016 Japanese commentary expounded on the study:

“Epigenetic changes accumulate as cell memory, and this epigenetic memory plays a crucial role in the long-term consequences of adult-onset diseases and aging.

The first stimulus, which might be high glucose levels or hypoxia, changes the condition of histone modification or chromosomal conformations. The changes are then memorized as epigenetic memory in the cells, which could help to maintain epigenetic status in response to the first stimulus.

Consequently, when a second stimulus occurs, cells with epigenetic memory respond to the stimulus promptly by the upregulation of downstream genes through binding transcriptional factors. The cells without epigenetic memory take longer to upregulate the expression of downstream target genes.

High glucose levels that are sustained for long periods appear to change histone modification, resulting in the prompt response of TXNIP gene upregulation. Considering that TXNIP is an important proinflammatory gene, this prompt response increases the likelihood of diabetic complications. TXNIP is reported to be augmented by high glucose levels and to promote oxidative stress.”

The study and commentary provided specific examples of the wide-ranging forms of physiological memory induced by stress.

http://www.sciencedirect.com/science/article/pii/S0085253815000927 “Epigenetic regulation of the thioredoxin-interacting protein (TXNIP) gene by hyperglycemia in kidney”

The purpose of many epigenetic processes is to control virus-like material

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics ,

This 2016 Swiss human review’s subject was:

“Transposable elements (TEs) may account for up to two-thirds of the human genome, and as genomic threats they are subjected to epigenetic control mechanisms engaged from the earliest stages of embryonic development.

TEs are present in all organisms from bacteria to humans, and they constitute essential motors of evolution. TEs are phylogenetically and biologically related to viruses.

TEs can disrupt genes, provide novel coding activities, exert a wide range of transcriptional influences, and, because of their repetitive nature, create grounds for recombination events leading to genomic deletions and duplications, yet only a very small minority of TEs present in the human genome are still transposition-competent, accounting for one new germline integrant in 20 to 50 human births, and none is capable of horizontal transfer.

A vast majority of these DNA-binding proteins, including many of those expressed in human differentiated cells, primarily recognize sequences contained within TEs..controlling the transcriptional potential of their TE targets well beyond the early embryonic period..modulating the transcriptional impact of TE-residing sequences that are co-opted to regulate the expression of cellular genes.

A large fraction of the recognizable mobile elements in our genome are unique to humans or close relatives. The impact of this phenomenon on speciation might be particularly pronounced in organs subjected to environmental constraints that are not overly coercive, such as the brain..the central nervous system.”

The author presented evidence that the purpose of many ongoing epigenetic processes is to silence or otherwise “tame” TEs “to regulate the expression of cellular genes.” The author contrasted his view with the view that:

“Beyond this early embryonic period, TEs become permanently silenced, and that the evolutionary selection of TE controllers is the result of a simple evolutionary arms race between the host and these genetics invaders.”

http://symposium.cshlp.org/content/early/2016/01/13/sqb.2015.80.027573.long “Transposable Elements, Polydactyl Proteins, and the Genesis of Human-Specific Transcription Networks”

Treating prenatal stress-related disorders with an oxytocin receptor agonist

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Oxytocin, Stress , , ,

This 2015 French/Italian rodent study found:

“Chronic systemic treatment with carbetocin [unavailable in the US] in PRS [prenatally restraint stressed] rats corrected:

  • the defect in glutamate release,
  • anxiety– and depressive-like behavior,

and abnormalities:

  • in social behavior,
  • in the HPA response to stress, and
  • in the expression of stress-related genes in the hippocampus and amygdala.

These findings disclose a novel function of oxytocin receptors in the hippocampus, and encourage the use of oxytocin receptor agonists in the treatment of stress-related psychiatric disorders in adult life.”

carbetocin

The adult male subjects were:

“PRS rats..the offspring of dams exposed to repeated episodes of restraint stress during pregnancy.

These rats display anxiety- and depressive-like behaviors and show an excessive glucocorticoid response to acute stress, which is indicative of a dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis caused by an impaired hippocampal glucocorticoid negative feedback.

PRS rats show a selective reduction in glutamate release in the ventral hippocampus.”

The researchers cited several other studies they have performed with the PRS phenotype. In the current study:

“Carbetocin treatment had no effect on these behavioral and neuroendocrine parameters in prenatally unstressed (control) rats, with the exception of a reduced expression of the oxytocin receptor gene in the amygdala.

Carbetocin displayed a robust therapeutic activity in PRS rats, but had no effect in unstressed rats, therefore discriminating between physiological and pathological conditions.”

The PRS phenotype showed the ease with which a child can be epigenetically changed – even before they’re born – to be less capable over their entire life. Just stress the pregnant mother-to-be.

https://www.sciencedirect.com/science/article/abs/pii/S0306453015002395 “Activation of presynaptic oxytocin receptors enhances glutamate release in the ventral hippocampus of prenatally restraint stressed rats” (not freely available) Thanks to coauthor Dr. Eleonora Gatta for providing the full study.