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1.
Int J Mol Sci ; 18(12)2017 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-29186852

RESUMO

MicroRNAs (miRNAs) are small non-coding RNA molecules that post-transcriptionally regulate the translation of messenger RNAs. Given the crucial role of miRNAs in gene expression, genetic variants within miRNA-related sequences may affect miRNA function and contribute to disease risk. Osteoporosis is characterized by reduced bone mass, and bone mineral density (BMD) is a major diagnostic proxy to assess osteoporosis risk. Here, we aimed to identify miRNAs that are involved in BMD using data from recent genome-wide association studies (GWAS) on femoral neck, lumbar spine and forearm BMD. Of 242 miRNA-variants available in the GWAS data, we found rs11614913:C > T in the precursor miR-196a-2 to be significantly associated with femoral neck-BMD (p-value = 9.9 × 10-7, ß = -0.038) and lumbar spine-BMD (p-value = 3.2 × 10-11, ß = -0.061). Furthermore, our sensitivity analyses using the Rotterdam study data showed a sex-specific association of rs11614913 with BMD only in women. Subsequently, we highlighted a number of miR-196a-2 target genes, expressed in bone and associated with BMD, that may mediate the miRNA function in BMD. Collectively, our results suggest that miR-196a-2 may contribute to variations in BMD level. Further biological investigations will give more insights into the mechanisms by which miR-196a-2 control expression of BMD-related genes.


Assuntos
Densidade Óssea/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Colo do Fêmur/patologia , Humanos , Vértebras Lombares/metabolismo
2.
Cells ; 11(15)2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35954222

RESUMO

Histone deacetylases (HDACs) target acetylated lysine residues in histone and non-histone proteins. HDACs are implicated in the regulation of genomic stability, cell cycle, cell death and differentiation and thus critically involved in tumorigenesis. Further, HDACs regulate T-cell development and HDAC inhibitors (HDACis) have been approved for clinical use in some T-cell malignancies. Still, the exact targets and mechanisms of HDAC inhibition in cancer are understudied. We isolated tumor cell lines from a transgenic mouse model of anaplastic large cell lymphoma (ALCL), a rare T-cell lymphoma, and abrogated HDAC activity by treatment with the HDACis Vorinostat and Entinostat or Cre-mediated deletion of Hdac1. Changes in overall protein expression as well as histone and protein acetylation were measured following Hdac1 deletion or pharmacological inhibition using label-free liquid chromatography mass spectrometry (LC-MS/MS). We found changes in overall protein abundance and increased acetylation of histones and non-histone proteins, many of which were newly discovered and associated with major metabolic and DNA damage pathways. For non-histone acetylation, we mapped a total of 1204 acetylated peptides corresponding to 603 proteins, including chromatin modifying proteins and transcription factors. Hyperacetylated proteins were involved in processes such as transcription, RNA metabolism and DNA damage repair (DDR). The DDR pathway was majorly affected by hyperacetylation following HDAC inhibition. This included acetylation of H2AX, PARP1 and previously unrecognized acetylation sites in TP53BP1. Our data provide a comprehensive view of the targets of HDAC inhibition in malignant T cells with general applicability and could have translational impact for the treatment of ALCL with HDACis alone or in combination therapies.


Assuntos
Histona Desacetilases , Linfoma Anaplásico de Células Grandes , Acetilação , Animais , Cromatografia Líquida , Histona Desacetilases/metabolismo , Histonas/metabolismo , Ácidos Hidroxâmicos/farmacologia , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Camundongos , Espectrometria de Massas em Tandem
3.
Life Sci Alliance ; 4(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33310759

RESUMO

Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T-cell-specific lymphoma model based on the human oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK-positive tumors show a loss of associated methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Epigênese Genética , Linfoma/etiologia , Linfoma/metabolismo , Proteínas Tirosina Quinases/genética , Animais , Biomarcadores Tumorais , Biologia Computacional/métodos , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA , Modelos Animais de Doenças , Suscetibilidade a Doenças , Epigenômica , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imuno-Histoquímica , Imunofenotipagem , Linfoma/tratamento farmacológico , Linfoma/patologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Tirosina Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
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