Novel Risk Associations between microRNA Polymorphisms and Gastric Cancer in a Chilean Population

Gastric cancer (GC) is the fifth leading cause of cancer deaths in the world, with variations across geographical regions and ethnicities. Emerging evidence indicates that miRNA expression is dysregulated in GC and its polymorphisms may contribute to these variations, which has yet to be explored in Latin American populations. In a case-control study of 310 GC patients and 311 healthy donors from Chile, we assessed the association of 279 polymorphisms in 242 miRNA genes. Two novel polymorphisms were found to be associated with GC: rs4822739:C>G (miR-548j) and rs701213:T>C (miR-4427). Additionally, rs1553867776:T>TCCCCA (miR-4274) and rs12416605:C>T (miR-938) were associated with intestinal-type GC, and rs4822739:C>G (miR-548j) and rs1439619:T>G (miR-3175) with TNM I-II stage. The polymorphisms rs6149511:T> TGAAGGGCTCCA (miR-6891), rs404337:G>A (miR-8084), and rs1439619:T>G (miR-3175) were identified among H.pylori-infected GC patients and rs7500280:T>C (miR-4719) and rs1439619:T>G (miR-3175) were found among H. pylori cagPAI+ infected GC cases. Prediction analysis suggests that seven polymorphisms could alter the secondary structure of the miRNA, and the other one is located in the seed region of miR-938. Targets of miRNAs are enriched in GC pathways, suggesting a possible biological effect. In this study, we identified seven novel associations and replicated one previously described in Caucasian population. These findings contribute to the understanding of miRNA genetic polymorphisms in the GC pathogenesis.

Polymorphisms in MicroRNA Genes Associated with Schizophrenia Susceptibility but Not with Effectiveness of MECT

Schizophrenia (SCZ) is a common and complex psychiatric disease associated with hereditary and environmental risk factors. MicroRNAs (miRNAs or miRs) are small, noncoding RNA molecules that endogenously regulate gene expression. Single nucleotide polymorphisms (SNPs) in related miRNA genes are associated with susceptibility of the disorder. We wonder if the SNPs have influence on the effectiveness of modified electroconvulsive therapy (MECT) for SCZ. rs1625579 within miR-137, rs6577555 within miR-34, and rs2296616 within miR-107 were sequenced in 150 cases and 150 controls to check the potential association between the SNPs and SCZ. Our results showed that allele G in rs1625579 ( p = 0.005 , adjusted OR = 1.379 , 95 % CI = 1.108 − 1.634 ), allele A in rs6577555 ( p = 0.014 , adjusted OR = 1.246 , 95 % CI = 1.045 − 1.463 ), allele G in rs2296616 ( p < 0.001 , adjusted OR = 1.646 , 95 % CI = 1.374 − 1.879 ) are positively associated with the disorder risk. MECT courses did significantly decrease the level of the miRNAs, except for the variant of rs2296616 with the AA genotype. Schizophrenic phenotypes assessed by the positive and negative syndrome scale (PANSS) were improved after MECT, and there was no significant relevance observed between the effectiveness of MECT and the variants of these loci. Thus, our findings indicate that polymorphisms within the loci may be involved in the pathogenesis of SCZ, and MECT is effective and unbiased for patients harboring different genotypes of the loci.

Are Argonaute-Associated Tiny RNAs Junk, Inferior miRNAs, or a New Type of Functional RNAs?

The biosynthesis pathways of microRNAs (miRNAs) have been well characterized with the identification of the required components. miRNAs are synthesized from the transcripts of miRNA genes and other RNAs, such as introns, transfer RNAs, ribosomal RNAs, small nucleolar RNAs, and even viral miRNAs. These small RNAs are loaded into Argonaute (AGO) proteins and recruit the effector complexes to target mRNAs, repressing their gene expression post-transcriptionally. While mature miRNAs were defined as 19–23 nucleotides (nt), tiny RNAs (tyRNAs) shorter than 19 nt have been found to bind AGOs as equivalent or lesser miRNAs compared to their full-length mature miRNAs. In contrast, my recent study revealed that when human AGO3 loads 14 nt cleavage-inducing tyRNAs (cityRNAs), comprised of the first 14 nt of their corresponding mature miRNA, it can become a comparable slicer to AGO2. This observation raises the possibility that tyRNAs play distinct roles from their mature form. This minireview focuses on human AGO-associated tyRNAs shorter than 19 nt and discusses their possible biosynthesis pathways and physiological benefits, including how tyRNAs could avoid target-directed miRNA degradation accompanied by AGO polyubiquitination.

Metagenome-genome-wide association studies reveal human genetic impact on the oral microbiome

The oral microbiota contains billions of microbial cells, which could contribute to diseases in many body sites. Challenged by eating, drinking, and dental hygiene on a daily basis, the oral microbiota is regarded as highly dynamic. Here, we report significant human genomic associations with the oral metagenome from more than 1915 individuals, for both the tongue dorsum (n = 2017) and saliva (n = 1915). We identified five genetic loci associated with oral microbiota at study-wide significance (p < 3.16 × 10−11). Four of the five associations were well replicated in an independent cohort of 1439 individuals: rs1196764 at APPL2 with Prevotella jejuni, Oribacterium uSGB 3339 and Solobacterium uSGB 315; rs3775944 at the serum uric acid transporter SLC2A9 with Oribacterium uSGB 1215, Oribacterium uSGB 489 and Lachnoanaerobaculum umeaense; rs4911713 near OR11H1 with species F0422 uSGB 392; and rs36186689 at LOC105371703 with Eggerthia. Further analyses confirmed 84% (386/455 for tongue dorsum) and 85% (391/466 for saliva) of host genome-microbiome associations including six genome-wide significant associations mutually validated between the two niches. As many of the oral microbiome-associated genetic variants lie near miRNA genes, we tentatively validated the potential of host miRNAs to modulate the growth of specific oral bacteria. Human genetics accounted for at least 10% of oral microbiome compositions between individuals. Machine learning models showed that polygenetic risk scores dominated over oral microbiome in predicting risk of dental diseases such as dental calculus and gingival bleeding. These findings indicate that human genetic differences are one explanation for a stable or recurrent oral microbiome in each individual.

Investigations on Regulation of MicroRNAs in Rice Reveal [Ca2+]cyt Signal Transduction Regulated MicroRNAs

MicroRNAs (miRNAs) are critical components of the multidimensional regulatory networks in eukaryotic systems. Given their diverse spectrum of function, it is apparent that the transcription, processing, and activity of the miRNAs themselves, is very dynamically regulated. One of the most important and universally implicated signaling molecules is [Ca2+]cyt. It is known to regulate a plethora of developmental and metabolic processes in both plants and animals; however, its impact on the regulation of miRNA expression is relatively less explored. The current study employed a combination of internal and external calcium channel inhibitors to establishing that [Ca2+]cyt signatures actively regulate miRNA expression in rice. Involvement of [Ca2+]cyt in the regulation of miRNA expression was further confirmed by treatment with calcimycin, the calcium ionophore. Modulation of the cytosolic calcium levels was also found to regulate the drought-responsive expression as well as ABA-mediated response of miRNA genes in rice seedlings. The study further establishes the role of calmodulins and Calmodulin-binding Transcription Activators (CAMTAs) as important components of the signal transduction schema that regulates miRNA expression. Yeast one-hybrid assay established that OsCAMTA4 &amp; 6 are involved in the transcriptional regulation of miR156a and miR167h. Thus, the study was able to establish that [Ca2+]cyt is actively involved in regulating the expression of miRNA genes both under control and stress conditions.

What Is in the Field for Genetics and Epigenetics of Diabetic Neuropathy: The Role of MicroRNAs

Despite the high prevalence of diabetic neuropathy, its early start, and its impact on quality of life and mortality, unresolved clinical issues persist in the field regarding its screening implementation, the understanding of its mechanisms, and the search for valid biomarkers, as well as disease-modifying treatment. Genetics may address these needs by providing genetic biomarkers of susceptibility, giving insights into pathogenesis, and shedding light on how to select possible responders to treatment. After a brief summary of recent studies on the genetics of diabetic neuropathy, the current review focused mainly on microRNAs (miRNAs), including the authors’ results in this field. It summarized the findings of animal and human studies that associate miRNAs with diabetic neuropathy and explored the possible pathogenetic meanings of these associations, in particular regarding miR-128a, miR-155a, and miR-499a, as well as their application for diabetic neuropathy screening. Moreover, from a genetic perspective, it examined new findings of polymorphisms of miRNA genes in diabetic neuropathy. It considered in more depth the pathogenetic implications for diabetic neuropathy of the polymorphism of MIR499A and the related changes in the downstream action of miR-499a, showing how epigenetic and genetic studies may provide insight into pathogenetic mechanisms like mitochondrial dysfunction. Finally, the concept and the data of genotype-phenotype association for polymorphism of miRNA genes were described. In conclusion, although at a very preliminary stage, the findings linking the genetics and epigenetics of miRNAs might contribute to the identification of exploratory risk biomarkers, a comprehensive definition of susceptibility to specific pathogenetic mechanisms, and the development of mechanism-based treatment of diabetic neuropathy, thus addressing the goals of genetic studies.

Characterization of Heat Responsive microRNAs and Phased Small Interfering RNAs in Reproductive Development of Flax

Plants will face increased heat stress due to rising global temperatures. Heat stress affects plant reproductive development and decreases productivity; however, the underlying molecular mechanisms of these processes are poorly characterized. Plant small RNAs (sRNAs) have important regulatory roles in plant reproductive development following abiotic stress responses. We generated sRNA transcriptomes of three reproductive bud stages at three different time points to identify sRNA-mediated pathways responsive to heat stress in flax. With added sRNA transcriptomes of vegetative tissues, we comprehensively annotated miRNA and phasiRNA-encoding genes (PHAS) in flax. We identified 173 miRNA genes, of which 42 are novel. Our analysis revealed that 141 miRNA genes were differentially expressed between tissue types while 18 miRNA genes were differentially expressed in reproductive tissues following heat stress, including members of miR2118/482 and miR2275 families, known triggers of reproductive phasiRNAs. Furthermore, we identified 68 21-PHAS flax loci from protein coding and non-coding regions, four 24-PHAS loci triggered by miR2275, and 658 24-PHAS-like loci with unknown triggers, derived mostly from non-coding regions. The reproductive phasiRNAs are mostly downregulated in response to heat stress. Overall, we found that several previously unreported miRNAs and phasiRNAs are responsive to heat stress in flax reproductive tissues.

Changes in the methylation level of microRNA genes as a factor of breast cancer development and progression

Введение. Метилирование как процесс эпигенетической регуляции экспрессии генов является важнейшим в поддержании геномной стабильности. В норме этот процесс определяет подавление активности онкогенов и поддержание работы супрессоров опухолевого роста. Другим важнейшим эпигенетическим регулятором являются микроРНК. Нарушения метилирования CpG-островков в промоторных районах генов, кодирующих микроРНК, являются важнейшим фактором онкогенеза. Цель - расширение спектра генов микроРНК гиперметилируемых при раке молочной железы и изучение их связи с метастазированием и иммуногистохимическим статусом опухоли. Методика. В настоящей работе был проведен отбор ряда генов микроРНК, изменяющих уровень метилирования при раке молочной железы. Методом количественной метилспецифичной ПЦР на представительной выборке из 70 парных образцов рака молочной железы изучен уровень метилирования 8 генов микроРНК, ассоциированных с раком молочной железы: MIR107, MIR124-2, MIR1258, MIR130B, MIR137, MIR191, MIR203А, MIR339. Результаты. Показано статистически значимое увеличение уровня метилирования в опухолевой ткани РМЖ по сравнению с гистологически нормальной тканью молочной железы для генов MIR107, MIR124-2, MIR1258, MIR130В, MIR137, MIR339 и снижение уровня метилирования для гена MIR191. Кроме того, показано статистически значимое увеличение уровня метилирования на III-IV (поздних) стадиях РМЖ для генов MIR107, MIR1258, MIR130В, MIR137, MIR339, в опухолях с большим размером - MIR107, MIR1258, MIR130В, MIR137, MIR339, с низким уровнем дифференцировки - MIR124-2, с наличием метастазов в лимфатические узлы - MIR107, MIR1258, MIR137, MIR339. Опухоли, не экспрессирующие рецептор прогестерона (PR), имеют статистически значимо более высокий уровень метилирования генов MIR137, MIR339. Заключение. Таким образом, определены новые молекулярные показатели прогрессии РМЖ и биомаркеры, которые могут быть использованы при дифференциальной диагностике молекулярного подтипа РМЖ. Background. Methylation, as an epigenetic mechanism for regulation of gene expression, is crucial for the genome stability. Normally, this process is characterized by the ability to silence the oncogene activity and to support the action of suppressor genes. MicroRNAs (miRNAs) are another key epigenetic regulator of gene expression. Aberrant methylation of CpG islands in promoter regions of the genes that code miRNAs is the most important oncogenic factor. Aim. To expand the spectrum of miRNA genes hypermethylated in breast cancer and to study their relationship with metastasis and immunohistochemical status of the tumor. Methods. MiRNA tumor suppressor genes were selected that changed their methylation level in breast cancer patients. Using the method of quantitative methylation-specific PCR, the methylation level of eight miRNA genes associated with breast cancer was studied on a representative set of 70 paired breast cancer samples: MIR107, MIR124-2, MIR1258, MIR130B, MIR137, MIR191, MIR203A, and MIR339. Results. The methylation level of the genes MIR-107, MIR124-2, MIR1258, MIR130B, MIR137, MIR339 was significantly higher in breast cancer tissue compared to normal breast tissue whereas for the gene MIR191, it was significantly lower. Also, the methylation levels of genes MIR107, MIR1258, MIR130B, MIR137, and MIR339 were significantly increased at stages III-IV (advanced) breast cancer; in large tumors, the methylation levels were increased for MIR107, MIR1258, MIR130B, MIR137, and MIR339; in poorly differentiated tumors, the methylation level was increased for MIR124-2; and in the presence of lymph node metastases, for MIR107, MIR1258, MIR-137, and MIR-339. Tumors not expressing the progesterone receptor (PR) had a higher methylation level of MIR137 and MIR339. Conclusion. The study determined new molecular indicators for breast cancer progression and identified biomarkers that may be used in the differential diagnosis of breast cancer molecular subtype.