RESUMO
How individual genes are regulated from a mitochondrial polycistronic transcript to have variable expression remains an enigma. Here, through bisulfite sequencing and strand-specific mapping, we show mitochondrial genomes in humans and other animals are strongly biased to light (L)-strand non-CpG methylation with conserved peak loci preferentially located at gene-gene boundaries, which was also independently validated by MeDIP and FspEI digestion. Such mtDNA methylation patterns are conserved across different species and developmental stages but display dynamic local or global changes during development and aging. Knockout of DNMT3A alone perturbed mtDNA regional methylation patterns, but not global levels, and altered mitochondrial gene expression, copy number, and oxygen respiration. Overexpression of DNMT3A strongly increased mtDNA methylation and strand bias. Overall, methylation at gene bodies and boundaries was negatively associated with mitochondrial transcript abundance and also polycistronic transcript processing. Furthermore, HPLC-MS confirmed the methylation signals on mitochondria DNA. Together, these data provide high-resolution mtDNA methylation maps that revealed a strand-specific non-CpG methylation, its dynamic regulation, and its impact on the polycistronic mitochondrial transcript processing.
Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/genética , DNA Mitocondrial/genética , Epigenoma/genética , Animais , Ilhas de CpG/genética , DNA Metiltransferase 3A , Regulação da Expressão Gênica/genética , Humanos , Mitocôndrias/genéticaRESUMO
Lymphoid-specific helicase (LSH) is overexpressed in tumor tissues and its overexpression is associated with poor prognosis in several cancers. However, the role and molecular mechanism of LSH in hepatocellular carcinoma (HCC) remains largely unknown. Herein, we report that LSH was overexpressed in tumor tissues of HCC, and overexpression of LSH was associated with poor prognosis from a public HCC database, and validated by clinical samples from our department. Ectopic LSH expression promoted the growth of HCC cells in vivo and in vitro. Mechanistically, LSH overexpression promoted tumor growth by activating transcription of centromere protein F (CENPF). Clinically, overexpression of LSH and/or CENPF correlated with shorter overall survival and higher cumulative recurrence rates of HCC. In conclusion, LSH promotes tumor growth of HCC through transcriptional regulation of CENPF expression. Therefore, LSH may be a novel predictor for prognosis and a potential therapeutic target for HCC.
Assuntos
Carcinoma Hepatocelular/patologia , Proteínas Cromossômicas não Histona/genética , DNA Helicases/metabolismo , Neoplasias Hepáticas/patologia , Proteínas dos Microfilamentos/genética , Regulação para Cima , Idoso , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Transplante de Neoplasias , Prognóstico , Análise de Sequência de RNA , Análise de Sobrevida , Análise Serial de Tecidos , Ativação TranscricionalRESUMO
eIF3a is the largest subunit of eIF3 complex and is a key player in translational control. Recently eIF3a is recognized as a proto-oncogene, which is overexpressed and connected to tumorigenesis of many cancers. However, the mechanistic roles of eIF3a during the tumorigenesis remain largely elusive. Here, we report that depletion of eIF3a significantly reduced HIF1α protein level and cellular glycolysis ability. Mechanistically, we found that eIF3a regulates HIF1α protein synthesis through internal ribosomal entry site (IRES)-dependent translation. Importantly, through analyses of our own sample collection, we found that eIF3a is overexpressed in hepatocellular carcinoma (HCC) tissues, and a high level of eIF3a predicts poor prognosis of HCC patients. TCGA analyses further confirmed that eIF3a is coincident with an elevated activity of HIF1α pathway genes. Collectively, we identify eIF3a as a regulator for glycolysis through HIF1α IRES-dependent translational regulation, which may be a potential therapeutic target for HCC.