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.

Dopamine transport, serotonin transport, noradrenaline transport and GABA transport are all sodium dependent

The dopamine transporter is sodium dependent. The serotonin transporter is a member of the sodium:neurotransmitter symporter family. The norepinephrine transporter is sodium dependent. GABA transporters are sodium symporters.A symporter is a membrane protein that is involved in the transport of two different molecules across the cell membrane in the same direction.

All classes of psychotropic drugs are either directly or very closely connected to sodium symporters. Yet sodium levels in mental illness are very frequently in the normal range. How could neurotransmitter sodium symporters be dysregulated in mental illness while at the same time sodium levels are normal?

Sodium:neurotransmitter symporters are heavily regulated proteins. When epigenenetic . mechanisms go awry heavily regulated processes can go awry. When epigenetic mechanisms go awry then there is a high probability that sodium:neurotransmitter symporters will go awry.. However, the difficulty can not be fixed by increasing sodium levels. The epigenome must be reprogrammed. When reprogramming the epigenome the gut epigenome must not be overlooked TET and JmjC domain containing proteins demethylate DNA and histones respectively.

TET and JmjC domain containing proteins are vitamin C and iron dependent enzymes. . Carbonyl iron would also be required. Only trace minerals that are available in the gut can be supplemented.There are some extremely well formulated chelated minerals on the market all of which must be avoided.

Vitamin C and iron, however, cannot be taken at the same time. Vitamin C complexes with iron which would make iron unavailable in the gut even though iron absorption can be increased by vitamin C. The great overlooked fact about vitamin C supplementation is that vitamin C supplementation can reduce iron availability in the gut and iron must be available in the gut as well as systematically. Iron from iron carbonyl would be taken at bedtime five or so hours after the last vitamin C dosage of the day. Vitamin C can also interfere with copper absorption so copper from copper gluconate would also be taken at bedtime. Immediate release vitamin C, iron from carbonyl iron and copper from copper gluconate could lessen symptoms in a range of mental illnesses.

Looking into vitamin C one more time

Linus Pauling brought vitamin C to the world’s attention

Vitamin C has been repeatedly investigated since Linus Pauling focused on vitamin C. TET enzymes and JmjC domain-containing proteins are vitamin C and iron dependent enzymes which demethylate DNA and histones respectively. .Vitamin C is being investigated as a way to reprogram the epigenome..

There are various difficulties with supplementation with vitamin C. First of all vitamin C is poorly absorbed. Secondly vitamin C can affect mineral absorption. The adverse affects on mineral absorption of vitamin C has not been sufficiently stressed as an important limiting factor in vitamin C supplementation. As iron must be available in the gut forming vitamin C-iron complexes in the gut may not be desirable.

Getting vitamin C to work could be as easy as not taking trace minerals such as iron and copper at the same time as vitamin C. What one would be looking for is whether activity of TET enzymes and JmjC domain-containing proteins could be be increased by supplemental vitamin C and carbonyl iron taken at different times of the day. Activity of TET enzymes and JmjC domain-containing proteins in the gut would be investigated. A combination of immediate release vitamin C and liposomal vitamin C where the vitamin C is taken away from trace minerals could be optimal.