Редактирование: DOT1L

Histone-lysine N-methyltransferase, H3 lysine-79 specific (EC 2.1.1.360) (DOT1-like protein) (Histone H3-K79 methyltransferase) (H3-K79-HMTase) (Lysine N-methyltransferase 4) [KIAA1814] [KMT4]

==Publications==

{{medline-entry
|title=Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: Relevance in age-associated vascular dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29366775
|abstract=Endothelial senescence in conjunction with mitochondrial dysfunction orchestrates age-associated cardiovascular disorders. In this study we investigated the causal link between these two processes and studied the molecular mechanisms by which metformin acts to coordinate the delay of endothelial senescence via enhancing mitochondrial biogenesis/function. AMPK activators metformin and AICAR delayed endothelial senescence via [[SIRT1]]-mediated upregulation of [[DOT1L]], leading to increased trimethylation of H3K79 (H3K79me3). Treatment of cells with either siAMPK or si[[SIRT1]] repressed [[DOT1L]]-mediated enhancement of H3K79me3. Moreover, the increase in [[SIRT3]] expression and mitochondrial biogenesis/function by AMPK activators was H3K79me-dependent as H3K79N mutant or si[[DOT1L]] abrogated these effects. This was confirmed by the enrichment of H3K79me3 in the [[SIRT3]] promoter with AMPK activation. Intriguingly, enhanced [[PGC]]-1α expression by [[SIRT3]] via AMPK activation was responsible for increased hTERT expression and delayed endothelial senescence. In contrast, [[SIRT3]] knockdown caused increased oxidative stress and premature senescence, possibly by depleting hTERT expression. Furthermore, a chronic low dose administration of metformin significantly attenuated vascular aging and inhibited age-associated atherosclerotic plaque formation in ApoE  mice. Overall, the results of this study show a novel regulation of mitochondrial biogenesis/function, and cellular senescence by H3K79me acting through [[SIRT3]], thus providing a molecular basis for metformin-mediated age-delaying effects.
|mesh-terms=* AMP-Activated Protein Kinases
* Animals
* Atherosclerosis
* Cellular Senescence
* Endothelial Cells
* Histone-Lysine N-Methyltransferase
* Histones
* Humans
* Metformin
* Methylation
* Methyltransferases
* Mice
* Mice, Knockout
* Mitochondria
* Mitochondrial Dynamics
* Sirtuin 1
* Telomerase
|keywords=* Aging
* Atherosclerosis
* Cardiovascular diseases
* Endothelial dysfunction
* Metformin
* Mitochondrial function
|full-text-url=https://sci-hub.do/10.1016/j.bbadis.2018.01.018
}}
{{medline-entry
|title=NF-κB activation impairs somatic cell reprogramming in ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26214134
|abstract=Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-κB activation blocks the generation of iPSCs in ageing. We also show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor [[DOT1L]], which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo progeria syndrome and Hutchinson-Gilford progeria syndrome patients, as well as from normal aged donors. Finally, we demonstrate that [[DOT1L]] inhibition in vivo extends lifespan and ameliorates the accelerated ageing phenotype of progeroid mice, supporting the interest of studying age-associated molecular impairments to identify targets of rejuvenation strategies. 
|mesh-terms=* Age Factors
* Aged, 80 and over
* Aging
* Animals
* Case-Control Studies
* Cell Differentiation
* Cell Line
* Cell Proliferation
* Cellular Reprogramming
* Cellular Senescence
* Disease Models, Animal
* Female
* Fibroblasts
* Gene Expression Regulation, Developmental
* Genetic Predisposition to Disease
* Histone-Lysine N-Methyltransferase
* Humans
* Induced Pluripotent Stem Cells
* Male
* Membrane Proteins
* Metalloendopeptidases
* Methyltransferases
* Mice, Inbred C57BL
* Mice, Knockout
* NF-kappa B
* Phenotype
* Progeria
* RNA Interference
* Signal Transduction
* Time Factors
* Transfection

|full-text-url=https://sci-hub.do/10.1038/ncb3207
}}