Loss of TET is associated with global DNA hypomethylation and regional DNA hypermethylation

Paradoxical association of TET loss of function with genome-wide DNA hypomethylation

Isaac F L√≥pez-Moyado  1   2   3 Ageliki Tsagaratou  1 Hiroshi Yuita  1 Hyungseok Seo  1 Benjamin Delatte  1 Sven Heinz  4 Christopher Benner  4 Anjana Rao  5   3   6   7 Affiliations

Significance

Cancer genomes are characterized by focal increases in DNA methylation, co-occurring with widespread hypomethylation. We show that TET deficiency in diverse cell types (ESCs, NPCs, HSCs, pro-B cells, and T cells) results in a similar methylation landscape, with the expected localized increases in DNA methylation in active euchromatic regions, concurrently with unexpected losses of DNA methylation, reactivation of repeat elements, and enrichment for single-nucleotide alterations primarily in heterochromatic compartments. Thus, TET loss of function may be a primary mechanism underlying the characteristic pattern of global hypomethylation coupled to regional hypermethylation observed in diverse cancer genomes. Our data potentially explain the synergy between DNMT3A and TET2 mutations in hematopoietic malignancies, as well as the recurrent association of TET loss of function with cancer.

Abstract

Cancer genomes are characterized by focal increases in DNA methylation, co-occurring with widespread hypomethylation. Here, we show that TET loss of function results in a similar genomic footprint. Both 5hmC in wild-type (WT) genomes and DNA hypermethylation in TET-deficient genomes are largely confined to the active euchromatic compartment, consistent with the known functions of TET proteins in DNA demethylation and the known distribution of 5hmC at transcribed genes and active enhancers. In contrast, an unexpected DNA hypomethylation noted in multiple TET-deficient genomes is primarily observed in the heterochromatin compartment. In a mouse model of T cell lymphoma driven by TET deficiency (Tet2/3 DKO T cells), genomic analysis of malignant T cells revealed DNA hypomethylation in the heterochromatic genomic compartment, as well as reactivation of repeat elements and enrichment for single-nucleotide alterations, primarily in heterochromatic regions of the genome. Moreover, hematopoietic stem/precursor cells (HSPCs) doubly deficient for Tet2 and Dnmt3a displayed greater losses of DNA methylation than HSPCs singly deficient for Tet2 or Dnmt3a alone, potentially explaining the unexpected synergy between DNMT3A and TET2 mutations in myeloid and lymphoid malignancies. Tet1-deficient cells showed decreased localization of DNMT3A in the heterochromatin compartment compared with WT cells, pointing to a functional interaction between TET and DNMT proteins and providing a potential explanation for the hypomethylation observed in TET-deficient genomes. Our data suggest that TET loss of function may at least partially underlie the characteristic pattern of global hypomethylation coupled to regional hypermethylation observed in diverse cancer genomes, and highlight the potential contribution of heterochromatin hypomethylation to oncogenesis.

DNA (cytosine-5) methyltransferase inhibitors: a therapeutic agent for schizophrenia?

I think increasing DNA demethylation by increasing activity of TET enzymes, which demethylate DNA, would be much safer. Cancers are associated with a global hypomethylation in what are called seas as opposed to CpG islands which are hypermethylated

DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes

Marija Kundakovic  1 Ying ChenErminio CostaDennis R Grayson Affiliations

Abstract

Reelin and glutamic acid decarboxylase 67 (GAD67) mRNAs and protein levels are substantially reduced in postmortem brains of patients with schizophrenia. Increasing evidence suggests that the observed down-regulation of reelin and GAD67 gene expression may be caused by dysfunction of the epigenetic regulatory mechanisms operative in cortical GABAergic interneurons. To explore whether human reelin and GAD67 mRNAs are coordinately regulated through DNA methylation-dependent mechanisms, we studied the effects of DNA methyltransferase inhibitors on reelin and GAD67 expression in NT-2 neuronal precursor cells. Competitive reverse transcription-polymerase chain reaction with internal standards was used to quantitate mRNA levels. The data showed that reelin and GAD67 mRNAs are induced in the same dose- and time-dependent manners. We further demonstrated that the activation of these two genes correlated with a reduction in DNA methyl-transferase activity and DNA methyltransferase 1 (DNMT1) protein levels. Time course Western blot analysis showed that DNMT1 protein down-regulation occurs temporally before the reelin and GAD67 mRNA increase. In addition, chromatin immunoprecipitation assays demonstrated that the activation of the reelin gene correlates with the dissociation of DNMT1 and methyl-CpG binding protein 2 (MeCP2) from the promoter, and an increased acetylation of histones H3 in the region. Together, our data strongly imply that human reelin and GAD67 genes are coordinately regulated through epigenetic mechanisms that include the action of DNMT1. Our study also suggests that negative regulation of the reelin gene involves methylation-dependent recruitment of DNMT1, MeCP2, and certain histone deacetylases, which most likely reduce the activity of the promoter by shifting the surrounding chromatin into a more compact state.

TET2 is a tumor suppressor

There are a lot of grounds for re-regulating TET enzymes. One could be enhancing anti-tumor immunity in the treatment of cancer. Stimulating TET activity by systematic injection of its co-factor, ascorbate/vitamin C, increased chemokine and TILs, leading to enhanced anti-tumor immunity and anti-PD-L1 efficacy and extended lifespan of tumor-bearing mice.

Astonishing facts

Black holes exist.

The universe was created from something smaller than a grain of sand in a Big Bang .

Most energy is dark energy of which almost nothing is understood. Most matter is dark matter of which almost nothing is understood.

Dinosaurs walked the Earth

A meteor killed the dinosaurs and most of life on Earth.

Via a process of symbiosis cells acquired mitochondria.

The continents are plates that float around the Earth.

There is something rather than nothing

Landing rockets on a launching pad after delivering second stages into space is very doable. .

Vaccines work, that is if individuals get vaccinated.

Kings ruled the Earth for long periods of history even though the chances of having good rulers when kings rule is very, very dicey. The masses by and large loved their absolute rulers even though their absolute rulers were very frequently incompetent.

All of human history is not even a blink of the eye in geological time.

Billions and billions of microorganisms live inside each of us.

The universe is 13.5 billion years old. The observable universe is 93 billion light years across. .

I am alive at this particular time and place. You are alive at a particular time and place.

A list of astonishing facts could go on and on.

A fact that is not astonishing is that trace minerals must be available in guts as well as systematically.

Manganese and mental illnesses

There is no doubt that high blood levels of manganese can be neurotoxic and can cause movement disorders. Backing out of manganese toxicity can’t really be done as neurons have been killed

Yet manganese is an essential trace element. For animals, such as humans, manganese is required. Manganese is required by a range of enzymes, for example, glutamine synthetase and arginase. Divalent metal transporter 1 (DMT1) transports both iron and manganese and is regulated by iron levels. Dysregulation of iron metabolism could also dysregulate manganese metabolism.

Tea can reduce manganese levels which would suggest that manganese reacts with polyphenols. A main point of this blog is that trace minerals must be available in the gut as well as systematically. The way to take trace minerals so trace minerals are available in the gut as well as systematically is take trace minerals at bedtime away from coffee, tea and other drinks except water, away from food and away from other supplements such as vitamin C.

Supplementation with a non-chelated form of manganese could be required to treat a range of mental illnesses. Tests on manganese bloods are required and not an option if manganese is supplemented. The goal is most definitely not high blood levels of manganese but rather normal blood levels of manganese where manganese is available in the gut and liver as well as systematically.

I think non-chelated forms of iron, manganese and copper have to be supplemented at bedtime in a range of mental illnesses.. I know that if iron, manganese and copper are supplemented that tests on mineral levels are required and not an option Individuals who are heavy coffee, tea and/or soda drinkers should suspect that manganese metabolism is dysregulated.

Chelation therapy – one of the worst ideas ever

EDTA binds copper and iron and has been frequently used to chelate minerals.. Chelation trials for autism were halted in 2008. Walmart and Amazon still have a selection of EDTA products in the health sections. Compounds that bind to minerals are everywhere in the food supply and generating huge unrecognized medical difficulties. A fundamental fact about nutrition is that minerals have to be available in the gut as well as systematically. Trace minerals should be supplemented only at bedtime and away from food, drinks and other supplements, such as vitamin C, to maximize availability in the gut as well as systematically. Iron, copper and manganese can compete for the same transporter, DMT1, but this is to be much preferred to minerals being chelated or complexed by food, drinks and/or supplements.

There is a place for chelation in terms of proven metal toxicites. Chelation therapy would only be done in a hospital under close medical supervision Purchasing EDTA suppositories at Walmart and then waiting around to be cured is very ill advised. Chelated mineral supplements are a sort of DIY chelation therapy for the gut which is very much a negative.

L-ornithine alleviates fatigue but would L-ornithine alleviate chronic fatigue syndrome?

L-ornithine supplementation attenuates physical fatigue in healthy volunteers. And L-ornithine levels are low in blood of individuals with chronic fatigue syndrome. Another study of individuals with chronic fatigue syndrome showed high levels of L-ornithine in plasma. The two studies may differ due to one study testing blood while the other study tested plasma. Dysregulation of cell membrane L-ornithine transporters could explain both results.

Would supplementation with L-ornithine be of assistance to individuals with chronic fatigue syndrome? Maybe and maybe not. L-ornithine would always be taken with vitamin B6 and and creatine. L-proline is synthesized from L-ornithine via ornithine aminotransferase which is a vitamin B6 dependent enzyme. L-orrithine can inhibit creatine synthesis.

Chronic fatigue syndrome could be an epigenetic illness and treatments for epigenetic illnesses are ugly in terms of simplicity. In all likelihood L-ornithine, vitamin B6 and creatine taken alone will not work for chronic fatigue syndrome. .

Manganese levels would be tested in chronic fatigue syndrome. Arginase which synthesizes L-ornithine is a manganese containing enzyme. Manganese levels have not been studied is chronic fatigue syndrome. If manganese levels are low in chronic fatigue syndrome almost certainly additional supplements would be required.

There are these two articles to consider Retinal risks of high-dose ornithine supplements: a review and Effect of long-term treatment of L-ornithine on visual function and retinal histology in the rats. Gyrate atrophy, which is a disease of the retina, results from a mutation in ornithine aminotransferase which results in high L-ornithine levels.

L-ornithine, L-lysine and L-arginine share the same transporter. High dosages of L-ornithine could competitively inhibit transport of L-lysine and/or L-arginine. Moderate dosages of L-ornithine would be taken if taken.

MCT oil is a disaster for individuals with schizophrenia

Any palmitic acid/stearic acid combination purchased must be very high quality and food grade otherwise shorter chain fatty acids could be mixed in which would cause very large difficulties. No stearic acid manufactured in Malaysia should be purchased.

Shorter Chain Triglycerides Are Negatively Associated with Symptom Improvement in Schizophrenia

Anna Tkachev,1,*Elena Stekolshchikova,1Nickolay Anikanov,1Svetlana Zozulya,2Aleksandra Barkhatova,2Tatiana Klyushnik,2 and Daria Petrova1Cecilia M. P. Rodrigues,

Abstract

Schizophrenia is a serious mental disorder requiring lifelong treatment. While medications are available that are effective in treating some patients, individual treatment responses can vary, with some patients exhibiting resistance to one or multiple drugs. Currently, little is known about the causes of the difference in treatment response observed among individuals with schizophrenia, and satisfactory markers of poor response are not available for clinical practice. Here, we studied the changes in the levels of 322 blood plasma lipids between two time points assessed in 92 individuals diagnosed with schizophrenia during their inpatient treatment and their association with the extent of symptom improvement. We found 20 triglyceride species increased in individuals with the least improvement in Positive and Negative Syndrome Scale (PANSS) scores, but not in those with the largest reduction in PANSS scores. These triglyceride species were distinct from the rest of the triglyceride species present in blood plasma. They contained a relatively low number of carbons in their fatty acid residues and were relatively low in abundance compared to the principal triglyceride species of blood plasma.