Lack of oxygen’s epigenetic effects

This 2016 Finnish review’s subject was the epigenetic effects of hypoxia:

“Ever since the Cambrian period, oxygen availability has been in the center of energy metabolism. Hypoxia stabilizes the expression of hypoxia-inducible transcription factor-1α (HIF-1α), which controls the expression of hundreds of survival genes related to enhanced energy metabolism and autophagy.

There are several other signals, mostly related to stresses, which can increase the expression of HIF factors and thus improve cellular survival. However, a chronic activation of HIF factors can have detrimental effects, e.g. stimulate cellular senescence and tissue fibrosis commonly enhanced in age-related diseases.

Stabilization of HIF-1α increases the expression of histone lysine demethylases (KDM). Hypoxia-inducible KDMs support locally the gene transcription induced by HIF-1α, although they can also control genome-wide chromatin landscape, especially KDMs which demethylate H3K9 and H3K27 sites (repressive epigenetic marks).”

Gene areas where HIF-1α is involved include:

  • “angiogenesis
  • autophagy
  • glucose uptake
  • glycolytic enzymes
  • immune responses
  • embryonic development
  • tumorigenesis
  • generation of miRNAs.”

Figure 1 was instructive in that the reviewers pointed out the lack of a feedback mechanism in HIF-1α signaling. A natural lack of feedback to the HIF-1α signaling source contributed to diseases such as:

  • “age-related macular degeneration
  • cancer progression
  • chronic kidney disease
  • cardiomyopathies
  • adipose tissue fibrosis
  • inflammation
  • detrimental effects which are linked to epigenetic changes.”

The point was similar to a study referenced in The PRice “equation” for individually evolving: Which equation describes your life? that:

“Evolution may preferentially mitigate damage to a biological system than reduce the source of this damage.”


The review was complicated primarily because the subject has many interdependencies and timings within a complex network. Contexts are important:

“The cross-talk between NF-κB [nuclear factor kappa B] and HIF-1α in inflammation might be organized in cell type and context-dependent manner.

It seems that ROS [reactive oxygen species] affect the HIF-1α signaling in a context-dependent manner.

Hypoxia stimulated the expression of KDM3A and KDM4B genes in different cellular contexts. Given that KDM3A and KDM4B are the major histone demethylases which remove the repressive H3K9 sites, their role as transcriptional cofactors seems to be important in the activation of HIF-1α signaling..members of KDM4 subfamily have a crucial role in the DNA repair systems, although the responses seem to be enzyme-specific and appear in a context-dependent manner.

Acute hypoxia can stimulate cell-cycle arrest but does not provoke cellular senescence in all contexts.”

It wasn’t mentioned that hypoxia evokes cellular Adaptations to stress encourage mutations in a DNA area that causes diseases.

The review was tailored for the publishing journal Aging and Disease, and the subject was best summed up by:

“HIF-1α can control cellular fate in adult animals, either stimulating proliferation or triggering cellular senescence, by regulating the expression of different KDMs in a context-dependent manner.”


The review covered hypoxic conditions during human development that are clearly the origins of many immediate and later-life diseases. However, the cited remedies only addressed symptoms.

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 2016?

http://www.aginganddisease.org/article/2016/2152-5250/147502 “Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases”

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The inevitable effects of avoidable wars

“It was like Tom had tried to return home,” says Jacky Sweetnam. “But he didn’t quite make it.”

http://news.nationalpost.com/features/the-ghosts-of-vietnam-the-last-days-of-a-decorated-canadian-vet “The Ghosts of Vietnam”


In memoriam to my father who died twenty years ago last week. World War II ruined his life with undiagnosed PTSD, some of the effects of which affected his children. His brother was a Navy hospital corpsman during the slaughter at Iwo Jima, and was even more afflicted. Neither of them were ever treated.

Using epigenetic outliers to diagnose cancer

This 2016 Chinese/UK human cancer cell study tested five algorithms and found:

“Most of the novel proposed algorithms lack the sensitivity to detect epigenetic field defects at genome-wide significance. In contrast, algorithms which recognise heterogeneous outlier DNA methylation patterns are able to identify many sites in pre-neoplastic lesions, which display progression in invasive cancer.

Many DNA methylation outliers are not technical artefacts, but define epigenetic field defects which are selected for during cancer progression.”

The usual method of epigenetic studies involves:

“Identify genomic sites where the mean level of DNAm [DNA methylation] differs as much as possible between the two phenotypes. As we have seen however, such an approach is seriously underpowered in cancer studies where tissue availability is a major obstacle.

In addition to allelic frequency, we also need to take the magnitude of the alteration into consideration. As shown here, infrequent but bigger changes in DNAm (thus defining outliers) are more likely to define cancer field defects, than more frequent yet smaller DNAm changes.”

A similar point was made in 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.”

One of the five tested algorithms was made freely available by the researchers. The limitations on its use were discussed, and included:

“Studies conducted in a surrogate tissue such as blood are scenarios where DNAm outliers are probably not of direct biological relevance to cancer development.”

http://bmcbioinformatics.biomedcentral.com/articles/10.1186/s12859-016-1056-z “Stochastic epigenetic outliers can define field defects in cancer”

Using salivary microRNA to diagnose autism

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.”


Regarding other later-life consequences of disrupted neurodevelopment, an understanding of these processes 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

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 casual [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”

A human study of pain avoidance

This 2016 UK human study found:

“People differ in how they learn to avoid pain, with some individuals refraining from actions that resulted in painful outcomes, whereas others favor actions that helped prevent pain.

Learning in our task was best explained as driven by an outcome prediction error that reflects the difference between expected and actual outcomes. Consistent with the expression of such a teaching signal, blood-oxygen level-dependent (BOLD) responses to outcomes in the striatum were modulated by expectation.

Positive learners showed significant functional connectivity between the insula and striatal regions, whereas negative learners showed significant functional connectivity between the insula and amygdala regions.

The degree to which a participant tended to learn from success in avoiding than experiencing shocks was predicted by the structure of a participants’ striatum, specifically by higher gray matter density where the response to shocks was consistent with a prediction error signal. Higher gray matter density in the putamen (and lower gray matter density in the caudate) predicted better learning from shocks and poorer learning from success in avoiding shocks.”

The researchers termed the subjects’ pain responses “learning” instead of conditioning. The experiments presented no 100%-certain choices to avoid pain. The experiments were also rigged to force choices at similar rates among subjects because:

“Participants who learned more from painful outcomes developed a propensity to avoid gambling, whereas participants who learned more from success in preventing pain developed a propensity to gamble.”


Human responses to pain don’t arise out of nowhere. The subjects’ pain histories were clearly relevant, but weren’t investigated. The closest the study came to considering the subjects’ histories was:

“Before the experiment, participants completed an 80-item questionnaire composed of several measures of different mood and anxiety traits. Age, sex and mood and anxiety traits did not differ between participants later classified as positive and negative learners.”

Emotional content was neither included nor solicited. Emotions were inferred:

“Participants biased in favor of passive avoidance learning (i.e., learning what gambles should be avoided), striatal response to painful outcomes was consistent with an aversive prediction error, as seen in fear conditioning.”

As a result, there weren’t causal explanations for the subjects’ differing pain responses. How, when, and why did the behavioral, functional, and structural differences develop?


I didn’t see the level of detail needed to characterize striatal regions into the Empathy, value, pain, control: Psychological functions of the human striatum segments. I’d guess that the findings of “higher gray matter density in the putamen (and lower gray matter density in the caudate)” applied to the posterior putamen and the anterior caudate nucleus.

Two of the coauthors were also coauthors of If a study didn’t measure feelings, then its findings may not pertain to genuine empathy. The technique of Why do we cut short our decision-making process? was referenced.

http://www.pnas.org/content/early/2016/04/06/1519829113.full “Striatal structure and function predict individual biases in learning to avoid pain”

A one-sided review of stress

The subject of this 2016 Italian/New York review was the stress response:

“The stress response, involving the activation of the hypothalamic-pituitary-adrenocortical axis and the consequent release of corticosteroid hormones, is indeed aimed at promoting metabolic, functional, and behavioral adaptations. However, behavioral stress is also associated with fast and long-lasting neurochemical, structural, and behavioral changes, leading to long-term remodeling of glutamate transmission, and increased susceptibility to neuropsychiatric disorders. Of note, early-life events, both in utero and during the early postnatal life, trigger reprogramming of the stress response, which is often associated with loss of stress resilience and ensuing neurobehavioral (mal)adaptations.”


The reviewers’ intentional dismissal of the role of GABA in favor of the role of glutamate was a key point:

“The changes in neuronal excitability and synaptic plasticity induced by stress are the result of an imbalance of excitatory (glutamatergic) and inhibitory (GABAergic) transmission, leading to long-lasting (mal)adaptive functional modifications. Although both glutamate and GABA transmission are critically associated with stress-induced alteration of neuronal excitability, the present review will focus on the modulation of glutamate release and transmission induced by stress and glucocorticoids.”

No particular reason was given for this bias. I inferred from the review’s final sentence that the review’s sponsors and funding prompted this decision:

“In-depth studies of changes in glutamate transmission and dendrite remodeling induced by stress in early and late life will help to elucidate the biological underpinnings of the (mal)adaptive strategies the brain adopts to cope with environmental challenges in one’s life.”

The bias led to ignoring evidence for areas the reviewers posed as needing further research. An example of relevant research the reviewers failed to consider was the 2015 Northwestern University study I curated in A study that provided evidence for basic principles of Primal Therapy that found:

“In response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812483/ “Stress Response and Perinatal Reprogramming: Unraveling (Mal)adaptive Strategies”