Respiratory diseases hold several genome, epigenome, and transcriptional aberrations as a cause of the accumulated damage promoted by, among others, environmental risk factors. Such aberrations can also come about as an adaptive response when faced with therapeutic oncological drugs. In epigenetic terms, aberrations in DNA methylation patterns, histone code marks balance, and/or chromatin-remodeling complexes recruitment, among Polycomb Repressive Complex-2 (PRC2) versus Trithorax (TRX) Activator Complex, have been proposed to be affected by several previously characterized functional long non-coding RNAs (lncRNAs). Such molecules are involved in modulating and/or controlling lung cancer epigenome and genome expression, as well as in malignancy and clinical progression in lung cancer.Several recent reports have described diverse epigenetic modifications in lung cancer cells and solid tumors, among others genomic DNA methylation and post-translational modifications (PTMs) on histone tails, as well as lncRNAs patterns and levels of expression. However, few systematic approaches have attempted to demonstrate a biological function and clinical association, aiming to improve therapeutic decisions in basic research and lung clinical oncology. A widely used example is the lncRNA HOTAIR and its functional histone mark H3K27me3, which is directly associated to the PRC2; however, few systematic pieces of solid evidence have been experimentally performed, conducted and/or validated to predict lung oncological therapeutic efficacy.Recent evidence suggests that chromatin-remodeling complexes accompanied by lncRNAs profiles are involved in several comprehensive lung carcinoma clinical parameters, including histopathology progression, prognosis, and/or responsiveness to unique or combined oncological therapies. The present manuscript offers a systematic revision of the current knowledge about the major epigenetic aberrations represented by changes in histone PTMs and lncRNAs expression levels and patterns in human lung carcinomas in cancer drug-based treatments, as an important comprehensive knowledge focusing on better oncological therapies. In addition, a new future direction must be refocusing on several gene target therapies, mainly on pharmaceutical EGFR-TKIs compounds, widely applied in lung cancer, currently the leading cause of death by malignant diseases.
Molecular model represents pieces of evidence, suggesting that LncRNA SOX2‐OT promotes AKT/ERK phosphorylation, as well as histone mark modifications (Activation H3K4me3/H3K27Ac versus Repression H3K9me3/H3K27me3) at GLI‐1 and SOX2‐OT gene promoter sequences (Likely SOX2) in a probable indirect manner (Dotted lines). Supporting that LncRNA SOX2‐OT is post‐translational and epigenetically involved in therapy resistance mechanisms, lung cancer malignancy, therapy resistance mechanisms, and clinical prognosis.
BackgroundIn human hosts, Entamoeba histolytica cysts can develop into trophozoites, suggesting that the life cycle of this parasite are regulated by changes in gene expression. To date, some evidence has suggested that epigenetic mechanisms such as DNA methylation and histone modification are involved in the regulation of gene expression in Entamoeba. Some post–translational modifications (PTMs) at the N-terminus of E. histolytica’s histones have been reported experimentally, including tri-methylation in the lysine 4 of histone H3 (H3K4me3) and dimethylation in the lysine 27 of histone H3 (H3K27me2), dimethylation of arginine 3 (H4R3me2) and the indirect acetylation of histone H4 in the N-terminal region. However, it is not known which residues of histone H4 are subject to acetylation and/or methylation or where in the nucleus these epigenetic marks are located.MethodsHistones from trophozoites of E. histolytica were obtained and analyzed by LC-MS/MS. WB assays were performed using antibodies against epigenetic marks (acetylated lysines and methylated arginines). Immunofluorescence assays (IFA) were carried out to determine the distribution of PTMs and the localization of DNA methylation as a heterochromatin marker. Nuclear bodies such as the nucleolus were identified by using antibodies against fibrillarin and nucleolin and speckles by using anti-PRP6 antibody.ResultsSome new PTMs in histone H4 of E. histolytica, such as the acetylation of lysines 5, 8, 12 and 16 and the monomethylation of arginine 3, were identified by WB. IFA demonstrated that some marks are associated with transcriptional activity (such as acetylation and/or methylation) and that these marks are distributed throughout the E. histolytica nucleus. Staining with antibodies against anti-pan-acetylated lysine H4 histone and 5-methyl cytosine showed that the activation and transcriptional repression marks converge. Additionally, two nuclear bodies, the nucleolus and speckles, were identified in this parasite.ConclusionsThis study provides the first evidence that the nucleus of E. histolytica is not compartmentalized and contains two nuclear bodies, the nucleolus and speckles, the latter of which was not identified previously. The challenge is now to understand how these epigenetic marks and nuclear bodies work together to regulate gene expression in E. histolytica.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1298-7) contains supplementary material, which is available to authorized users.
Post‐translational modifications of histone H3 N‐terminal tails are key epigenetic regulators of virulence gene expression and sexual commitment in the human malaria parasite Plasmodium falciparum . Here, we identify proteolytic clipping of the N‐terminal tail of nucleosome‐associated histone H3 at amino acid position 21 as a new chromatin modification. A cathepsin C‐like proteolytic clipping activity is observed in nuclear parasite extracts. Notably, an ectopically expressed version of clipped histone H3, PfH3p‐ HA , is targeted to the nucleus and integrates into mononucleosomes. Furthermore, chromatin immunoprecipitation and next‐generation sequencing analysis identified PfH3p‐ HA as being highly enriched in the upstream region of six genes that play a key role in DNA replication and repair: In these genes, PfH3p‐ HA demarcates a specific 1.5 kb chromatin island adjacent to the open reading frame. Our results indicate that, in P. falciparum , the process of histone clipping may precede chromatin integration hinting at preferential targeting of pre‐assembled PfH3p‐containing nucleosomes to specific genomic regions. The discovery of a protease‐directed mode of chromatin organization in P. falciparum opens up new avenues to develop new anti‐malarials.
Lung cancer remains the most progressive malignant disease strongly resistant to oncological therapies including platinum-derived cancer drugs and Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinases Inhibitors (TKIs). Homeobox-related gene (HOX) transcription factors as Mesenchyme HOX-2 (MEOX2) have previously been associated with cancer-drug resistance, progression and/or clinical prognosis in lung cancer patients. However, transcriptional mechanisms epigenetically modulated have not totally been elucidated in lung cancer therapy resistance. Here an epigenomic strategy was conducted to identify a novel MEOX2 gene sequence-promoter targets profile, associated or involved in therapy resistance mechanisms in human lung cancer. For that chromatin from human non-small cell lung carcinomas (NSCLC), MEOX2 versus RNA Pol II immunoprecipitation and hybridization assays using gene promoter tiling-arrays and bioinformatics analyses were performed, while a set of quantitative and functional assays with clinical-outcome prognosis validation predictions analyses, were assessed. Stringent bioinformatics results identified a common profile of 13 gene promoter sequences, which included in others Sonic Hedgehog-GLI-1, ALDH1A2, MMP24, RUFY3 and ZEB1 (FDR≤0.1) in NSCLC patients with different clinical outcome data. GLI-1 gene promoter-sequences upstream -2,192 to -109 quantitatively validated, were occupied by MEOX2 and RNA Pol II in both NSCLC cell lines and NSCLC patients, as well as consistently enriched with the histone activation marks H3K27Ac and H3K4me3, in addition, confirmed by the ENCODE database bioinformatics analyses. Furthermore, a set of genetic silencing functional assays validated a novel transcriptional MEOX2-GLI1 axis in a cisplatinum dose-dependent manner, involved in cellular migration, invasion, and proliferation capacity. Finally, MEOX2-GLI1 axis expression was clinically validated and analyzed using Kaplan-Maier survival analyses on an independent cohort of 90 NSCLC patients, identifying a significant MEOX2-dependent GLI-1 overexpression statistically associated with clinical poorer overall survival prognosis and treatment response into cisplatinum-based first-line therapy and/or second-line EGFR-TKIs target therapy protocols. In conclusion, a chromatin-immunoprecipitation and epigenome-wide analysis based on the MEOX2-transcriptional occupation study, identified novel MEOX2-transcriptional gene promoter axes involved in embryonic development, oxidoreductase activity, matrix metalloprotease, cellular polarity, epithelial-mesenchyme phenotype, cancer cell migration and invasion pathways. Promoting cisplatinum-based resistance mechanisms and EGFR-TKIs based therapy response prognosis in human lung cancer. Note: This abstract was not presented at the meeting. Citation Format: Federico Avila Moreno, Leonel Armas lopez, Patricia Piña-Sánchez, Oscar Arrieta, Enrique Gúzman de Alba, Abril Marcela Herrera-Solorio, Blanca Ortiz-Quintero, Patricio Santillán-Doherty, David C Christiani, Joaquín Zúñiga. Novel Mesenchyme Homeobox2-target transcription axes are involved in cancer-drug resistance, overall survival and therapy prognosis in lung cancer patients: a functional epigenome wide study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 682. doi:10.1158/1538-7445.AM2017-682
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