The Role of Histone Post-Translational Modifications in Merkel Cell Carcinoma

Mazziotta, Chiara; Lanzillotti, Carmen; Gafà, Roberta; Touzé, Antoine; Durand, Marie-Alice; Martini, Fernanda; Rotondo, John Charles

doi:10.3389/fonc.2022.832047

Cited by 37 publications

(35 citation statements)

References 114 publications

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“…Modulation of these dynamics by histone post-translational modifications, histone variants, and interactions with chromatin proteins is an essential mechanism of epigenetic regulation of gene expression [ 3 ]. Dysregulation of nucleosome dynamics through mutations or aberrant histone post-translational modifications is associated with human disease, particularly cancer [ 4 , 5 ]. Such dynamical modes as DNA wrapping/unwrapping, nucleosome sliding, H2A-H2B dimer exchange are known to affect transcription factor binding [ 6 , 7 ], transcription by Pol II through nucleosomes [ 8 ], higher-order chromatin architecture [ 9 ], etc.…”

Section: Introductionmentioning

confidence: 99%

H2A-H2B Histone Dimer Plasticity and Its Functional Implications

Kniazeva

Армеев

Shaytan

2022

Cells

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The protein core of the nucleosome is composed of an H3-H4 histone tetramer and two H2A-H2B histone dimers. The tetramer organizes the central 60 DNA bp, while H2A-H2B dimers lock the flanking DNA segments. Being positioned at the sides of the nucleosome, H2A-H2B dimers stabilize the overall structure of the nucleosome and modulate its dynamics, such as DNA unwrapping, sliding, etc. Such modulation at the epigenetic level is achieved through post-translational modifications and the incorporation of histone variants. However, the detailed connection between the sequence of H2A-H2B histones and their structure, dynamics and implications for nucleosome functioning remains elusive. In this work, we present a detailed study of H2A-H2B dimer dynamics in the free form and in the context of nucleosomes via atomistic molecular dynamics simulations (based on X. laevis histones). We supplement simulation results by comparative analysis of information in the structural databases. Particularly, we describe a major dynamical mode corresponding to the bending movement of the longest H2A and H2B α-helices. This overall bending dynamics of the H2A-H2B dimer were found to be modulated by its interactions with DNA, H3-H4 tetramer, the presence of DNA twist-defects with nucleosomal DNA and the amino acid sequence of histones. Taken together, our results shed new light on the dynamical mechanisms of nucleosome functioning, such as nucleosome sliding, DNA-unwrapping and their epigenetic modulation.

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Section: Introductionmentioning

confidence: 99%

H2A-H2B Histone Dimer Plasticity and Its Functional Implications

Kniazeva

Армеев

Shaytan

2022

Cells

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“…Given the important role of HDAC in modulating antitumour immune response in various cancers [ 58 , 66 , 67 , 68 ], the combination of HDACi with other therapeutic agents gains its popularity. In the present study, we demonstrated that belinostat, dacinostat, givinostat, and panobinostat enhanced CTL sensitivity in SW1990 CTLr and BxPC3 CTLr cells ( Figure 4 A, p value < 0.01), suggesting that the antitumour effects of CTL can be enhanced by HDACi.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Restore Cancer Cell Sensitivity towards T Lymphocytes Mediated Cytotoxicity in Pancreatic Cancer

Looi

Gan

Sim

et al. 2022

Cancers

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Despite medical advancements, the prognosis of pancreatic ductal adenocarcinoma (PDAC) has not improved significantly over the past 50 years. By utilising the large-scale genomic datasets available from the Australia Pancreatic Cancer Project (PACA-AU) and The Cancer Genomic Atlas Project (TCGA-PAAD), we studied the immunophenotype of PDAC in silico and identified that tumours with high cytotoxic T lymphocytes (CTL) killing activity were associated with favourable clinical outcomes. Using the STRING protein–protein interaction network analysis, the identified differentially expressed genes with low CTL killing activity were associated with TWIST/IL-6R, HDAC5, and EOMES signalling. Following Connectivity Map analysis, we identified 44 small molecules that could restore CTL sensitivity in the PDAC cells. Further high-throughput chemical library screening identified 133 inhibitors that effectively target both parental and CTL-resistant PDAC cells in vitro. Since CTL-resistant PDAC had a higher expression of histone proteins and its acetylated proteins compared to its parental cells, we further investigated the impact of histone deacetylase inhibitors (HDACi) on CTL-mediated cytotoxicity in PDAC cells in vitro, namely SW1990 and BxPC3. Further analyses revealed that givinostat and dacinostat were the two most potent HDAC inhibitors that restored CTL sensitivity in SW1990 and BxPC3 CTL-resistant cells. Through our in silico and in vitro studies, we demonstrate the novel role of HDAC inhibition in restoring CTL resistance and that combinations of HDACi with CTL may represent a promising therapeutic strategy, warranting its further detailed molecular mechanistic studies and animal studies before embarking on the clinical evaluation of these novel combined PDAC treatments.

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“…The currently employed gold standard and most broadly used molecular method worldwide for the detection of active SARS-CoV-2 infection is RT-PCR [26,45,46]. The RT-PCR assay is a broadly employed molecular biology technique which allows for the analysis and quantification of nucleic acids for a large variety of applications [47][48][49]. The method is performed on nasopharyngeal and oropharyngeal swabs, which are the preferred sampling method of the World Health Organization (WHO) and the Centers for The detection of active SARS-CoV-2 infection is performed using molecular diagnostics, i.e., real-time reverse transcriptionpolymerase chain reaction (RT-PCR), droplet-digital PCR (ddPCR), clustered regularly interspaced short palindromic repeats (CRISPR) and next-generation sequencing (NGS), in order to detect the viral RNA during the first weeks after the emergence of symptoms.…”

Section: Real-time Reverse Transcription-polymerase Chain Reactionmentioning

confidence: 99%

“…The currently employed gold standard and most broadly used molecular method worldwide for the detection of active SARS-CoV-2 infection is RT-PCR [26,45,46]. The RT-PCR assay is a broadly employed molecular biology technique which allows for the analysis and quantification of nucleic acids for a large variety of applications [47][48][49]. The method is performed on nasopharyngeal and oropharyngeal swabs, which are the preferred sampling method of the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC), although it can be underlined that oral throat wash (OTW) is an additional and less invasive, safer as well as more efficient sample-collection approach.…”

Section: Real-time Reverse Transcription-polymerase Chain Reactionmentioning

confidence: 99%

Advanced Molecular and Immunological Diagnostic Methods to Detect SARS-CoV-2 Infection

et al. 2022

Self Cite

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COVID-19 emerged in late 2019 in China and quickly spread across the globe, causing over 521 million cases of infection and 6.26 million deaths to date. After 2 years, numerous advances have been made. First of all, the preventive vaccine, which has been implemented in record time, is effective in more than 95% of cases. Additionally, in the diagnostic field, there are numerous molecular and antigenic diagnostic kits that are equipped with high sensitivity and specificity. Real Time-PCR-based assays for the detection of viral RNA are currently considered the gold-standard method for SARS-CoV-2 diagnosis and can be used efficiently on pooled nasopharyngeal, or oropharyngeal samples for widespread screening. Moreover, additional, and more advanced molecular methods such as droplet-digital PCR (ddPCR), clustered regularly interspaced short palindromic repeats (CRISPR) and next-generation sequencing (NGS), are currently under development to detect the SARS-CoV-2 RNA. However, as the number of subjects infected with SARS-CoV-2 continuously increases globally, health care systems are being placed under increased stress. Thus, the clinical laboratory plays an important role, helping to select especially asymptomatic individuals who are actively carrying the live replicating virus, with fast and non-invasive molecular technologies. Recent diagnostic strategies, other than molecular methods, have been adopted to either detect viral antigens, i.e., antigen-based immunoassays, or human anti-SARS-CoV-2 antibodies, i.e., antibody-based immunoassays, in nasal or oropharyngeal swabs, as well as in blood or saliva samples. However, the role of mucosal sIgAs, which are essential in the control of viruses entering the body through mucosal surfaces, remains to be elucidated, and in particular the role of the immune response in counteracting SARS-CoV-2 infection, primarily at the site(s) of virus entry that appears to be promising.

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The Role of Histone Post-Translational Modifications in Merkel Cell Carcinoma

Cited by 37 publications

References 114 publications

H2A-H2B Histone Dimer Plasticity and Its Functional Implications

H2A-H2B Histone Dimer Plasticity and Its Functional Implications

Histone Deacetylase Inhibitors Restore Cancer Cell Sensitivity towards T Lymphocytes Mediated Cytotoxicity in Pancreatic Cancer

Advanced Molecular and Immunological Diagnostic Methods to Detect SARS-CoV-2 Infection

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