The many faces of histone H3K79 methylation

Farooq, Zeenat; Banday, Shahid; Pandita, Tej K.; Altaf, Mohammad

doi:10.1016/j.mrrev.2016.03.005

Cited by 146 publications

(107 citation statements)

References 88 publications

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“…Methylation of H3K79 is involved in the regulation of telomeric silencing, cellular development, cell-cycle checkpoint, DNA repair, and regulation of transcription [39, 40]. Several studies show that DOT1L is a critical regulator of the cell cycle [41, 42].…”

Section: Discussionmentioning

confidence: 99%

2D-DIGE proteomic analysis of vastus lateralis from COPD patients with low and normal fat free mass index and healthy controls

et al. 2017

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BackgroundChronic obstructive pulmonary disease (COPD) is associated with several extra-pulmonary effects of which skeletal muscle wasting is one of the most common and contributes to reduced quality of life, increased morbidity and mortality. The molecular mechanisms leading to muscle wasting are not fully understood. Proteomic analysis of human skeletal muscle is a useful approach for gaining insight into the molecular basis for normal and pathophysiological conditions.MethodsTo identify proteins involved in the process of muscle wasting in COPD, we searched differentially expressed proteins in the vastus lateralis of COPD patients with low fat free mass index (FFMI), as a surrogate of muscle mass (COPDL, n = 10) (FEV1 33 ± 4.3% predicted, FFMI 15 ± 0.2 Kg.m−2), in comparison to patients with COPD and normal FFMI (COPDN, n = 8) and a group of age, smoking history, and sex matched healthy controls (C, n = 9) using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) technology, combined with mass spectrometry (MS). The effect of silencing DOT1L protein expression on markers of cell arrest was analyzed in skeletal muscle satellite cells (HSkMSCs) in vitro and assessed by qPCR and Western blotting.ResultsA subset of 7 proteins was differentially expressed in COPDL compared to both COPDN and C. We found an increased expression of proteins associated with muscle homeostasis and protection against oxidative stress, and a decreased expression of structural muscle proteins and proteins involved in myofibrillogenesis, cell proliferation, cell cycle arrest and energy production. Among these was a decreased expression of the histone methyltransferase DOT1L. In addition, silencing of the DOT1L gene in human skeletal muscle satellite cells in vitro was significantly related to up regulation of p21 WAF1/Cip1/CDKN1A, a marker of cell arrest and ageing.Conclusions2D-DIGE coupled with MS identified differences in the expression of several proteins in the wasted vastus lateralis that are relevant to the disease process. Down regulation of DOT1L in the vastus lateralis of COPDL patients may mediate the muscle wasting process through up regulation of markers of cell arrest and senescence.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-017-0525-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

2D-DIGE proteomic analysis of vastus lateralis from COPD patients with low and normal fat free mass index and healthy controls

et al. 2017

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“…Interestingly, non-Pol-II TSS show absence of H3K36me3 and H3K79me2 signals (Supplementary Figure 4). H3K36 histone modification marks are enriched on the gene body region and play important roles in transcriptional activation [29] while H3K79me2 marks have been shown to be strongly correlated with gene activity [30]. Our data suggest that the enrichment observed for H3K36me3 and H3K79me2 are specific to Pol-II transcripts (Supplementary Figure 4).…”

Section: Classification Of Tss Into Pol II and Non-pol Ii Tssmentioning

confidence: 53%

ReCappable Seq: Comprehensive Determination of Transcription Start Sites derived from all RNA polymerases

Yan

Tzertzinis

Schildkraut

et al. 2019

Preprint

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Methodologies for determining eukaryotic Transcription Start Sites (TSS) rely on the selection of the 5’ canonical cap structure of Pol-II transcripts and are consequently ignoring entire classes of TSS derived from other RNA polymerases which play critical roles in various cell functions. To overcome this limitation, we developed ReCappable-seq and identified TSS from Pol-ll and non-Pol-II transcripts at nucleotide resolution. Applied to the human transcriptome, ReCappable-seq identifies Pol-II TSS with higher specificity than CAGE and reveals a rich landscape of TSS associated notably with Pol-III transcripts which have been previously not possible to study on a genome-wide scale. Novel TSS consistent with non-Pol-II transcripts can be found in the nuclear and mitochondrial genomes. By identifying TSS derived from all RNA-polymerases, ReCappable-seq reveals distinct epigenetic marks among Pol-lI and non-Pol-II TSS and provides a unique opportunity to concurrently interrogate the regulatory landscape of coding and non-coding RNA.

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“…The adenosine derivative ( 29 ) and its phenylurea analog ( 31 ) (EPZ004777) [101] showed very good inhibition and specificity for DOT1L, reduced leukemia-relevant gene expression and induced differentiation of MLL (mixed-lineage leukemia) leukemia cells. DOT1L is the only non-SET domain HKMT and it is the only enzyme responsible for mono-, di- and trimethylation of H3K79, leading to transcriptional activation of certain oncogenes [102,103,104,105,106,107]. It is mainly involved in myeloid lymphoid leukemia with MLL rearrangements by favoring transcription of HOX (subset of homeotic genes) and MEIS (Meis homeobox 1) genes involved in acute leukemia development [105,106,108].…”

Section: Inhibition Of Histone Methylationmentioning

confidence: 99%

“…DOT1L is the only non-SET domain HKMT and it is the only enzyme responsible for mono-, di- and trimethylation of H3K79, leading to transcriptional activation of certain oncogenes [102,103,104,105,106,107]. It is mainly involved in myeloid lymphoid leukemia with MLL rearrangements by favoring transcription of HOX (subset of homeotic genes) and MEIS (Meis homeobox 1) genes involved in acute leukemia development [105,106,108]. Therefore, medicinal chemistry efforts for DOT1L inhibition have led to the first HMTi in clinics, compound ( 29 ) that completed phase I clinical trials for leukemia treatment and myelodysplastic syndromes (NCT02141828, NCT01684150).…”

Section: Inhibition Of Histone Methylationmentioning

confidence: 99%

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

et al. 2017

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Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action.

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The many faces of histone H3K79 methylation

Cited by 146 publications

References 88 publications

2D-DIGE proteomic analysis of vastus lateralis from COPD patients with low and normal fat free mass index and healthy controls

2D-DIGE proteomic analysis of vastus lateralis from COPD patients with low and normal fat free mass index and healthy controls

ReCappable Seq: Comprehensive Determination of Transcription Start Sites derived from all RNA polymerases

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

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