The Role of Histone Lysine Methylation in the Response of Mammalian Cells to Ionizing Radiation

Eukaryotic genomes are wrapped around nucleosomes and organized into different levels of chromatin structure. Chromatin organization has a crucial role in regulating all cellular processes involving DNA-protein interactions, such as DNA transcription, replication, recombination and repair. Histone post-translational modifications (HPTMs) have a prominent role in chromatin regulation, acting as a sophisticated molecular code, which is interpreted by HPTM-specific effectors. Here, we review the role of histone lysine methylation changes in regulating the response to radiation-induced genotoxic damage in mammalian cells. We also discuss the role of histone methyltransferases (HMTs) and histone demethylases (HDMs) and the effects of the modulation of their expression and/or the pharmacological inhibition of their activity on the radio-sensitivity of different cell lines. Finally, we provide a bioinformatic analysis of published datasets showing how the mRNA levels of known HMTs and HDMs are modulated in different cell lines by exposure to different irradiation conditions.

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Histone Lysine Methylation in TGF-β1 Mediated p21 Gene Expression in Rat Mesangial Cells

BioMed Research International ◽

10.1155/2016/6927234 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Qiaoyan Guo ◽

Xiaoxia Li ◽

Hongbo Han ◽

Chaoyuan Li ◽

Shujun Liu ◽

...

Keyword(s):

Gene Expression ◽

Transforming Growth Factor ◽

Mesangial Cells ◽

Gene Promoter ◽

Renal Diseases ◽

Lysine Methylation ◽

Histone Lysine Methylation ◽

Histone Lysine ◽

Chronic Renal Diseases

Transforming growth factor beta1- (TGF-β1-) induced p21-dependent mesangial cell (MC) hypertrophy plays a key role in the pathogenesis of chronic renal diseases including diabetic nephropathy (DN). Increasing evidence demonstrated the role of posttranscriptional modifications (PTMs) in the event; however, the precise regulatory mechanism of histone lysine methylation remains largely unknown. Here, we examined the roles of both histone H3 lysine 4 and lysine 9 methylations (H3K4me/H3K9me) in TGF-β1 induced p21 gene expression in rat mesangial cells (RMCs). Our results indicated that TGF-β1 upregulated the expression of p21 gene in RMCs, which was positively correlated with the increased chromatin marks associated with active genes (H3K4me1/H3K4me2/H3K4me3) and negatively correlated with the decreased levels of repressive marks (H3K9me2/H3K9me3) at p21 gene promoter. TGF-β1 also elevated the recruitment of the H3K4 methyltransferase (HMT) SET7/9 to the p21 gene promoter. SET7/9 gene silencing with small interfering RNAs (siRNAs) significantly abolished the TGF-β1 induced p21 gene expression. Taken together, these results reveal the key role of histone H3Kme in TGF-β1 mediated p21 gene expression in RMC, partly through HMT SET7/9 occupancy, suggesting H3Kme and SET7/9 may be potential renoprotective agents in managing chronic renal diseases.

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Profile of Histone Lysine Methylation across Transcribed Mammalian Chromatin

Molecular and Cellular Biology ◽

10.1128/mcb.01529-06 ◽

2006 ◽

Vol 26 (24) ◽

pp. 9185-9195 ◽

Cited By ~ 256

Author(s):

Christopher R. Vakoc ◽

Mira M. Sachdeva ◽

Hongxin Wang ◽

Gerd A. Blobel

Keyword(s):

Mammalian Cells ◽

Gene Activation ◽

Gene Activity ◽

Lysine Methylation ◽

Transcription Start Sites ◽

Mammalian Gene ◽

Histone Lysine Methylation ◽

Histone Lysine ◽

Mammalian Genes ◽

Active Genes

ABSTRACT Complex patterns of histone lysine methylation encode distinct functions within chromatin. We previously reported that trimethylation of lysine 9 of histone H3 (H3K9) occurs at both silent heterochromatin and at the transcribed regions of active mammalian genes, suggesting that the extent of histone lysine methylation involved in mammalian gene activation is not completely defined. To identify additional sites of histone methylation that respond to mammalian gene activity, we describe here a comparative assessment of all six known positions of histone lysine methylation and relate them to gene transcription. Using several model loci, we observed high trimethylation of H3K4, H3K9, H3K36, and H3K79 in the transcribed region, consistent with previous findings. We identify H4K20 monomethylation, a modification previously linked with repression, as a mark of transcription elongation in mammalian cells. In contrast, H3K27 monomethylation, a modification enriched at pericentromeric heterochromatin, was observed broadly distributed throughout all euchromatic sites analyzed, with selective depletion in the vicinity of the transcription start sites at active genes. Together, these results underscore that similar to other described methyl-lysine modifications, H4K20 and H3K27 monomethylation are versatile and dynamic with respect to gene activity, suggesting the existence of novel site-specific methyltransferases and demethylases coupled to the transcription cycle.

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Histone tales: lysine methylation, a protagonist in Arabidopsis development

Journal of Experimental Botany ◽

10.1093/jxb/erz435 ◽

2019 ◽

Cited By ~ 2

Author(s):

Kai Cheng ◽

Yingchao Xu ◽

Chao Yang ◽

Luc Ouellette ◽

Longjian Niu ◽

...

Keyword(s):

Developmental Programming ◽

Lysine Methylation ◽

Histone Lysine Methylation ◽

Histone Lysine ◽

Recent Advances

Recent advances in the regulation of histone lysine methylation in plants and the role of this modification in the developmental programming of Arabidopsis are discussed.

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NACC-1 regulates hepatocellular carcinoma cell malignancy and is targeted by miR-760

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmz167 ◽

2020 ◽

Vol 52 (3) ◽

pp. 302-309

Author(s):

Linan Yin ◽

Tingting Sun ◽

Ruibao Liu

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Lines ◽

Bioinformatic Analysis ◽

Cellular Growth ◽

Luciferase Assay ◽

Migration And Invasion ◽

Cellular Processes ◽

Therapeutic Benefits ◽

The Impact

Abstract Hepatocellular carcinoma (HCC) is the most prominent form of presentation in liver cancer. It is also the fourth most common cause of cancer-associated deaths globally. The role of nucleus accumbens associated protein-1 (NACC-1) has been evaluated in several cancers. This protein is a transcriptional regulator that regulates a number of significant cellular processes. In the current study, we aimed to understand the role of NACC-1 in HCC. Primarily, we measured the expression of NACC-1 using quantitative real time polymerase chain reaction and western blot analysis. We knocked down the expression of NACC-1 in HCC cell lines Huh7 and HepG2 by transferring a commercially synthesized small interfering RNA and explored the impact of NACC-1 knockdown on cellular growth, migration, invasion, and chemoresistance to doxorubicin. Through bioinformatic analysis, we identified NACC-1 as a potential target of miR-760. Using a dual reporter luciferase assay, we confirmed the predicted target and assessed miR-760-mediated regulation of NACC-1 and rescue of tumorigenic phenotypes. We observed increased expression of NACC-1 in HCC. Furthermore, knockdown of NACC-1 resulted in reduced cell proliferation and invasion and increased susceptibility to doxorubicin-mediated chemosensitivity. Overexpression of miR-760 in HCC cell lines rescued NACC-1-mediated migration and invasion. We revealed that miR-760 regulated NACC-1 expression in HCC. Our data indicated that both miR-760 and NACC-1 could be used as prognostic markers, and miR-760 may have therapeutic benefits for HCC and other cancers.

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Lysine Methyltransferases Signaling: Histones are Just the Tip of the Iceberg

Current Protein and Peptide Science ◽

10.2174/1871527319666200102101608 ◽

2020 ◽

Vol 21 (7) ◽

pp. 655-674

Author(s):

Valentina Lukinović ◽

Alexandre G. Casanova ◽

Gael S. Roth ◽

Florent Chuffart ◽

Nicolas Reynoird

Keyword(s):

Cancer Progression ◽

Lysine Methylation ◽

Post Translational Modification ◽

Cancer Treatments ◽

Downstream Signaling ◽

Histone Lysine Methylation ◽

Cellular Processes ◽

Histone Lysine ◽

Lysine Methyltransferases ◽

Functionally Diverse

: Protein lysine methylation is a functionally diverse post-translational modification involved in various major cellular processes. Lysine methylation can modulate proteins activity, stability, localization, and/or interaction, resulting in specific downstream signaling and biological outcomes. Lysine methylation is a dynamic and fine-tuned process, deregulation of which often leads to human pathologies. In particular, the lysine methylome and its associated signaling network can be linked to carcinogenesis and cancer progression. : Histone modifications and chromatin regulation is a major aspect of lysine methylation importance, but increasing evidence suggests that a high relevance and impact of non-histone lysine methylation signaling has emerged in recent years. In this review, we draw an updated picture of the current scientific knowledge regarding non-histone lysine methylation signaling and its implication in physiological and pathological processes. We aim to demonstrate the significance of lysine methylation as a major and yet underestimated posttranslational modification, and to raise the importance of this modification in both epigenetic and cellular signaling by focusing on the observed activities of SET- and 7β-strandcontaining human lysine methyltransferases. : Recent evidence suggests that what has been observed so far regarding lysine methylation’s implication in human pathologies is only the tip of the iceberg. Therefore, the exploration of the “methylome network” raises the possibility to use these enzymes and their substrates as promising new therapeutic targets for the development of future epigenetic and methyllysine signaling cancer treatments.

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Writers and Erasers of Histone Lysine methylation with Clinically Applied Modulators: Promising Target for Cancer Therapy

Current Pharmaceutical Design ◽

10.2174/1381612822666160715125417 ◽

2016 ◽

Vol 22 (39) ◽

pp. 5943-5947 ◽

Cited By ~ 5

Author(s):

Yi-Chao Zheng ◽

Jin-Lian Ma ◽

Ying Liu ◽

Hong Liu

Keyword(s):

Cancer Therapy ◽

Lysine Methylation ◽

Histone Lysine Methylation ◽

Histone Lysine ◽

Promising Target

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Unlike its Paralog LEDGF/p75, HRP-2 Is Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell Survival

Cells ◽

10.3390/cells10010192 ◽

2021 ◽

Vol 10 (1) ◽

pp. 192

Author(s):

Siska Van Belle ◽

Sara El Ashkar ◽

Kateřina Čermáková ◽

Filip Matthijssens ◽

Steven Goossens ◽

...

Keyword(s):

Growth Factor ◽

Cell Survival ◽

Cell Lines ◽

Protein Interactions ◽

Leukemic Cell ◽

Related Protein ◽

Histone Tails ◽

Knockout Mouse Model ◽

Leukemic Cell Lines

HDGF-related protein 2 (HRP-2) is a member of the Hepatoma-Derived Growth Factor-related protein family that harbors the structured PWWP and Integrase Binding Domain, known to associate with methylated histone tails or cellular and viral proteins, respectively. Interestingly, HRP-2 is a paralog of Lens Epithelium Derived Growth Factor p75 (LEDGF/p75), which is essential for MLL-rearranged (MLL-r) leukemia but dispensable for hematopoiesis. Sequel to these findings, we investigated the role of HRP-2 in hematopoiesis and MLL-r leukemia. Protein interactions were investigated by co-immunoprecipitation and validated using recombinant proteins in NMR. A systemic knockout mouse model was used to study normal hematopoiesis and MLL-ENL transformation upon the different HRP-2 genotypes. The role of HRP-2 in MLL-r and other leukemic, human cell lines was evaluated by lentiviral-mediated miRNA targeting HRP-2. We demonstrate that MLL and HRP-2 interact through a conserved interface, although this interaction proved less dependent on menin than the MLL-LEDGF/p75 interaction. The systemic HRP-2 knockout mice only revealed an increase in neutrophils in the peripheral blood, whereas the depletion of HRP-2 in leukemic cell lines and transformed primary murine cells resulted in reduced colony formation independently of MLL-rearrangements. In contrast, primary murine HRP-2 knockout cells were efficiently transformed by the MLL-ENL fusion, indicating that HRP-2, unlike LEDGF/p75, is dispensable for the transformation of MLL-ENL leukemogenesis but important for leukemic cell survival.

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Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

Current Medicinal Chemistry ◽

10.2174/0929867324666170426095015 ◽

2018 ◽

Vol 25 (1) ◽

pp. 5-21 ◽

Cited By ~ 25

Author(s):

Ylenia Cau ◽

Daniela Valensin ◽

Mattia Mori ◽

Sara Draghi ◽

Maurizio Botta

Keyword(s):

Protein Interactions ◽

Molecular Mechanisms ◽

Physiological Role ◽

Specific Protein ◽

Protein Protein Interactions ◽

Cellular Processes ◽

Protein Partners ◽

High Sequence Homology ◽

Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

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