DOT1L stimulates MYC/Mondo transcription factor activity by promoting its degradation cycle on chromatin.

The proto-oncogene c-MYC is a key representative of the MYC transcription factor network regulating growth and metabolism. MML-1 (Myc- and Mondo-like) is its homolog in . The functional and molecular cooperation between c-MYC and H3 lysine 79 methyltransferase DOT1L was demonstrated in several human cancer types, and we have earlier discovered the connection between MML-1 and DOT-1.

The proline-rich domain of MML-1 is biologically important but not required for localization to target promoters.

The only representative of the MYC superfamily transcription factors in , MML-1 (Myc and Mondo-like 1), was shown to promote extended lifespan in a variety of models and to regulate some aspects of development. This previous research did not involve molecular characterization of MML-1. Here we use available mutant alleles and other reagents to demonstrate that MML-1 is modified by -GlcNAc, binds to promoters of some genes directly regulated by the DOT-1.

Deficient in DOT-1.1 Exhibit Increases in H3K9me2 at Enhancer and Certain RNAi-Regulated Regions.

The methylation of histone H3 at lysine 79 is a feature of open chromatin. It is deposited by the conserved histone methyltransferase DOT1. Recently, DOT1 localization and H3K79 methylation (H3K79me) have been correlated with enhancers in and mammalian cells.

DOT1L complex suppresses transcription from enhancer elements and ectopic RNAi in .

Methylation of histone H3 on lysine 79 (H3K79) by DOT1L is associated with actively transcribed genes. Earlier, we described that DOT-1.1, the homolog of mammalian DOT1L, cooperates with the chromatin-binding protein ZFP-1 (AF10 homolog) to negatively modulate transcription of highly and widely expressed target genes.

Interplay between small RNA pathways shapes chromatin landscapes in C. elegans.

The nematode Caenorhabditis elegans contains several types of endogenous small interfering RNAs (endo-siRNAs) produced by RNA-dependent RNA polymerase (RdRP) complexes. Both 'silencing' siRNAs bound by Worm-specific Argonautes (WAGO) and 'activating' siRNAs bound by the CSR-1 Argonaute require the DRH-3 helicase, an RdRP component. Here, we show that, in the drh-3(ne4253) mutant deficient in RdRP-produced secondary endo-siRNAs, the silencing histone mark H3K9me3 is largely depleted, whereas in the csr-1 partially rescued null mutant strain (WM193), this mark is ectopically deposited on CSR-1 target genes.

The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art.

Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid formed during the metabolism of the essential amino acid methionine. Hcy is considered a risk factor for atherosclerosis and cardiovascular disease (CVD), but the molecular basis of these associations remains elusive. The impairment of endothelial function, a key initial event in the setting of atherosclerosis and CVD, is recurrently observed in hyperhomocysteinemia (HHcy).

Folinic Acid Increases Protein Arginine Methylation in Human Endothelial Cells.

Elevated plasma total homocysteine (tHcy) is associated with increased risk of cardiovascular disease, but the mechanisms underlying this association are not completely understood. Cellular hypomethylation has been suggested to be a key pathophysiologic mechanism, since -adenosylhomocysteine (AdoHcy), the Hcy metabolic precursor and a potent inhibitor of methyltransferase activity, accumulates in the setting of hyperhomocysteinemia. In this study, the impact of folate and methionine on intracellular AdoHcy levels and protein arginine methylation status was studied.

High homocysteine induces betaine depletion.

Betaine is the substrate of the liver- and kidney-specific betaine-homocysteine (Hcy) methyltransferase (BHMT), an alternate pathway for Hcy remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinaemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause.

Protein arginine hypomethylation in a mouse model of cystathionine β-synthase deficiency.

Accumulation of the homocysteine (Hcy) precursor S-adenosylhomocysteine (AdoHcy) may cause cellular hypomethylation in the setting of hyperhomocysteinemia because of cystathionine β-synthase (CBS) deficiency, an inborn error of metabolism. To test this hypothesis, DNA and protein arginine methylation status were assessed in liver, brain, heart, and kidney obtained from a previously described mouse model of CBS deficiency. Metabolite levels in tissues and serum were determined by high-performance liquid chromatography or liquid chromatography-electrospray ionization-tandem mass spectrometry.

Protein arginine methylation is more prone to inhibition by S-adenosylhomocysteine than DNA methylation in vascular endothelial cells.

Methyltransferases use S-adenosylmethionine (AdoMet) as methyl group donor, forming S-adenosylhomocysteine (AdoHcy) and methylated substrates, including DNA and proteins. AdoHcy inhibits most methyltransferases. Accumulation of intracellular AdoHcy secondary to Hcy elevation elicits global DNA hypomethylation.

The TCN2 776CNG polymorphism correlates with vitamin B(12) cellular delivery in healthy adult populations.

Objectives: Vitamin B(12), or B(12), is an essential nutrient for humans, and its deficiency is a public health problem, especially in elderly population. Around 30% of circulating total B(12) levels are attached to transcobalamin II (TCN2), being referred as holotranscobalamin (holo-TC), and representing the biologically active fraction. After cellular uptake, B(12) participates in the homocysteine (Hcy) metabolism.