SNHG16 promotes the progression of osteoarthritis through activating microRNA-93-5p/CCND1 axis.

OBJECTIVE: This study aims to investigate whether SNHG16 (small nucleolar RNA host gene 16) can promote the progression of osteoarthritis (OA) by regulating the microRNA-93-5p/Cyclin D1 (CCND1) axis, thereby finding new therapeutic targets for the treatment of OA. PATIENTS AND METHODS: A total of 23 OA patients and 23 patients undergoing lower extremity amputation were enrolled in this study. We collected their cartilage tissues from knee joint for isolating chondrocytes. The relative levels of SNHG16, CCND1 and microRNA-93-5p in cartilage tissues of OA patients and controls were determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The regulatory effect of SNHG16 on proliferative potential of chondrocytes was evaluated by Cell Counting Kit-8 (CCK-8) and colony formation assay, respectively. Cell cycle progression was examined using flow cytometry. Dual-Luciferase reporter gene assay was conducted to verify the binding between SNHG16 with microRNA-93-5p and microRNA-93-5p with CCND1. Rescue experiments were performed to elucidate whether SNHG16 regulated CCND1 expression by targeting microRNA-93-5p. RESULTS: The expressions of SNHG16 and CCND1 upregulated, while microRNA-93-5p downregulated in cartilage tissues of OA patients relative to controls. Correlation regression analyses showed a negative expression correlation between SNHG16 and microRNA-93-5p, as well as CCND1 and microRNA-93-5p in OA patients. On the contrary, SNHG16 expression was positively correlated to CCND1 expression in OA. The knockdown of SNHG16 suppressed viability, cloning ability and cell cycle progression, but induced apoptosis in chondrocytes. Dual-Luciferase reporter gene assay showed that SNHG16 could bind to microRNA-93-5p. SNHG16 knockdown markedly upregulated the expression of microRNA-93-5p. Moreover, the knockdown of microRNA-93-5p reversed the inhibited viability due to SNHG16 knockdown. Transfection of microRNA-93-5p mimics markedly inhibited CCND1 expression. Importantly, CCND1 overexpression reversed the inhibitory effect of SNHG16 knockdown on chondrocyte viability. CONCLUSIONS: SNHG16 promotes the development of OA by regulating microRNA-93-5p/CCND1 axis.

PETISCO is a novel protein complex required for 21U RNA biogenesis and embryonic viability.

Piwi proteins are important for germ cell development in most animals. These proteins are guided to specific targets by small guide RNAs, referred to as piRNAs or 21U RNAs in Caenorhabditis elegans In this organism, even though genetic screens have uncovered 21U RNA biogenesis factors, little is known about how these factors interact or what they do. Based on the previously identified 21U biogenesis factor PID-1 (piRNA-induced silencing-defective 1), we here define a novel protein complex, PETISCO (PID-3, ERH-2, TOFU-6, and IFE-3 small RNA complex), that is required for 21U RNA biogenesis. PETISCO contains both potential 5' cap and 5' phosphate RNA-binding domains and interacts with capped 21U precursor RNA. We resolved the architecture of PETISCO and revealed a second function for PETISCO in embryonic development. This essential function of PETISCO is mediated not by PID-1 but by the novel protein TOST-1 (twenty-one U pathway antagonist). In contrast, TOST-1 is not essential for 21U RNA biogenesis. Both PID-1 and TOST-1 interact directly with ERH-2 using a conserved sequence motif. Finally, our data suggest a role for TOST-1:PETISCO in SL1 homeostasis in the early embryo. Our work describes a key complex for 21U RNA processing in C. elegans and strengthens the view that 21U RNA biogenesis is built on an snRNA-related pathway.

Translocation breakpoint disrupting the host SNHG14 gene but not coding genes or snoRNAs in typical Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a well-known imprinting disorder arising from a loss of paternally imprinted gene(s) at 15q11.2-q13. We report a typical PWS patient with a balanced reciprocal translocation, 46, XY, t(15;19)(q11.2;q13.3). After Illumina whole-genome sequencing, we used BreakDancer-1.45 software to predict candidate breakpoints and manually investigated via the Integrated Genome Viewer. Breakpoint PCR followed by Sanger sequencing determined the t(15;19) breakpoints. We investigated the expression of upstream/centromeric and downstream/telomeric genes of the 15q11.2 breakpoint by reverse transcriptase PCR, using total RNA extracted from the patient's lymphoblasts. Of note, the expression of paternally expressed genes PWAR6, SNORD109A/B, SNORD116, IPW, and PWAR1, downstream of the breakpoint, was abolished. Interestingly, the breakpoint did not destroy protein coding genes or individual snoRNAs. These results indicate that these genes may play a major role in the PWS phenotype.

SRPK1 facilitates tumor cell growth via modulating the small nucleolar RNA expression in gastric cancer.

Serine-arginine protein kinase 1 (SRPK1) is the main regulator in alternative splicing by phosphorylating splicing factors rich in serine/arginine repeats. Its overexpression has been found in multiple cancer types and contributes to cancer development. Here we report the role of SRPK1 and underlying mechanism in gastric cancer (GC) cell growth. We found that SRPK1 was frequently upregulated in GC samples compared with their adjacent corresponding normal tissues by immunohistochemistry and western blot analysis. Knockdown of SRPK1 in GC cells suppressed cell growth in cell viability assays, colony formation assays and nude mice xenograft model, whereas overexpression of SRPK1 promotes opposite phenotypes in these assays. By a complementary DNA microarray analysis, we found that SRPK1 knockdown had significant inhibitory effects on a majority of small nucleolar RNAs expression. Among them, snoRA42, snoRA74A, and snoRD10 were selected for further functional experiments. Cell growth curves on a plate and in soft agar indicated that the three snoRNAs play potential oncogenic function in GC. In addition, SRPK1 could co-immunoprecipitated with NCL, a nucleolar phosphoprotein involved in the synthesis and maturation of ribosomes. These results suggested that SRPK1 contributes to GC development by a new possible mechanism involving snoRNAs mediated signaling.

Processing and roles of snoRNA-ended long noncoding RNAs.

Small nucleolar RNAs (snoRNAs) are a family of conserved nuclear RNAs that function in the modification of small nuclear RNAs (snRNAs) or ribosomal RNAs (rRNAs), or participate in the processing of rRNAs during ribosome subunit maturation. Eukaryotic DNA transcription and RNA processing produce many long noncoding RNA (lncRNA) species. Although most lncRNAs are processed like typical mRNAs to be 5' capped and 3' polyadenylated, other types of lncRNAs are stabilized from primary Pol II transcripts by alternative mechanisms. One way to generate stable lncRNAs is to co-operate with snoRNA processing to produce snoRNA-ended lncRNAs (sno-lncRNAs) and 5' snoRNA-ended and 3'-polyadenylated lncRNAs (SPAs). Rather than silently accumulating in the nucleus, some sno-lncRNAs and SPAs are involved in the regulation of pre-rRNA transcription and alternative splicing of pre-mRNAs. Here we provide a mini-review to discuss the biogenesis and functions of these unusually processed lncRNAs.

The SNORA21 expression is upregulated and acts as a novel independent indicator in human gastric cancer prognosis.

OBJECTIVE: Emerging evidence indicates that small nucleolar RNAs (snoRNAs) act crucial roles in oncogenesis. Herein, the aim of this study is to investigate the clinical value of SNORA21 expression in gastric cancer (GC). PATIENTS AND METHODS: The expression of SNORA21 was determined in 79 cases of GC tissues and adjacent normal tissues by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) analysis. The association between SNORA21 expression and clinicopathological features was analyzed by the chi-square test. The survival curves were calculated by the Kaplan-Meier method and log-rank test. Univariate and multivariate analyses were used to assess the prognostic value of SNORA21 expression. RESULTS: Our results first demonstrated that SNORA21 expression was significantly upregulated in human GC tissues and cells compared to their corresponding adjacent normal tissues and GES-1 cells, respectively (p<0.05). Furthermore, elevated SNORA21 expression was significantly associated with distant metastasis (p<0.05) and lymph node metastasis (p<0.05) in GC patients. Kaplan-Meier survival plots demonstrated that higher SNORA21 expression was associated with poor disease-free survival (DFS) and overall survival (OS) rate, respectively. Univariate analysis and multivariate regression analysis indicated that a higher SNORA21 was an independent risk factor for prognosis in GC patients. CONCLUSIONS: The current results indicate that SNORA21 expression may be served as a predictor of GC prognosis.

The Prognostic Value of Expression of the Long Noncoding RNA (lncRNA) Small Nucleolar RNA Host Gene 1 (SNHG1) in Patients with Solid Malignant Tumors: A Systematic Review and Meta-Analysis.

BACKGROUND The long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) is expressed in solid malignant tumors. The aim of this systematic review and meta-analysis was to determine whether expression of the lncRNA SNHG1 was associated with prognosis in patients with malignancy. MATERIAL AND METHODS A literature review from Jan 1970 to July 2018 identified publications in the English language. Databases searched included: PubMed, OVID, Web of Science, the Cochrane Database, Embase, EBSCO, Google Scholar. Systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Newcastle-Ottawa Scale (NOS) assessment tool for risk of bias was used. RESULTS Eight publications (570 patients) and eight solid tumors were identified, including osteosarcoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, esophageal cancer, ovarian cancer, glioma, and gastric cancer. Meta-analysis showed that expression of the lncRNA SNHG1 was significantly correlated with reduced overall survival (OS) (HR=1.917; 95% CI, 1.58-2.31) (P<0.001). Subgroup analysis showed that lncRNA SNHG1 expression was significantly correlated with TNM stage (OR=3.99; 95% CI, 2.48-6.43) and lymph node metastasis (OR=3.12; 95% CI, 1.95-4.98). There were no significant correlations between lncRNA SNHG1 expression and patient gender, tumor subtype, or tumor size. CONCLUSIONS Systematic literature review and meta-analysis identified eight publications that included 570 patients with eight types of solid malignant tumor, and showed that the expression of the lncRNA SNHG1 was significantly associated with worse clinical outcome.

The Canonical Poly (A) Polymerase PAP1 Polyadenylates Non-Coding RNAs and Is Essential for snoRNA Biogenesis in Trypanosoma brucei.

The parasite Trypanosoma brucei is the causative agent of African sleeping sickness and is known for its unique RNA processing mechanisms that are common to all the kinetoplastidea including Leishmania and Trypanosoma cruzi. Trypanosomes possess two canonical RNA poly (A) polymerases (PAPs) termed PAP1 and PAP2. PAP1 is encoded by one of the only two genes harboring cis-spliced introns in this organism, and its function is currently unknown. In trypanosomes, all mRNAs, and non-coding RNAs such as small nucleolar RNAs (snoRNAs) and long non-coding RNAs (lncRNAs), undergo trans-splicing and polyadenylation. Here, we show that the function of PAP1, which is located in the nucleus, is to polyadenylate non-coding RNAs, which undergo trans-splicing and polyadenylation. Major substrates of PAP1 are the snoRNAs and lncRNAs. Under the silencing of either PAP1 or PAP2, the level of snoRNAs is reduced. The dual polyadenylation of snoRNA intermediates is carried out by both PAP2 and PAP1 and requires the factors essential for the polyadenylation of mRNAs. The dual polyadenylation of the precursor snoRNAs by PAPs may function to recruit the machinery essential for snoRNA processing.

SIRT7-dependent deacetylation of CDK9 activates RNA polymerase II transcription.

SIRT7 is an NAD+-dependent protein deacetylase that regulates cell growth and proliferation. Previous studies have shown that SIRT7 is required for RNA polymerase I (Pol I) transcription and pre-rRNA processing. Here, we took a proteomic approach to identify novel molecular targets and characterize the role of SIRT7 in non-nucleolar processes. We show that SIRT7 interacts with numerous proteins involved in transcriptional regulation and RNA metabolism, the majority of interactions requiring ongoing transcription. In addition to its role in Pol I transcription, we found that SIRT7 also regulates transcription of snoRNAs and mRNAs. Mechanistically, SIRT7 promotes the release of P-TEFb from the inactive 7SK snRNP complex and deacetylates CDK9, a subunit of the elongation factor P-TEFb, which activates transcription by phosphorylating serine 2 within the C-terminal domain (CTD) of Pol II. SIRT7 counteracts GCN5-directed acetylation of lysine 48 within the catalytic domain of CDK9, deacetylation promoting CTD phosphorylation and transcription elongation.

Progressive changes in non-coding RNA profile in leucocytes with age.

It has been observed that immune cell deterioration occurs in the elderly, as well as a chronic low-grade inflammation called inflammaging. These cellular changes must be driven by numerous changes in gene expression and in fact, both protein-coding and non-coding RNA expression alterations have been observed in peripheral blood mononuclear cells from elder people. In the present work we have studied the expression of small non-coding RNA (microRNA and small nucleolar RNA -snoRNA-) from healthy individuals from 24 to 79 years old. We have observed that the expression of 69 non-coding RNAs (56 microRNAs and 13 snoRNAs) changes progressively with chronological age. According to our results, the age range from 47 to 54 is critical given that it is the period when the expression trend (increasing or decreasing) of age-related small non-coding RNAs is more pronounced. Furthermore, age-related miRNAs regulate genes that are involved in immune, cell cycle and cancer-related processes, which had already been associated to human aging. Therefore, human aging could be studied as a result of progressive molecular changes, and different age ranges should be analysed to cover the whole aging process.

The ribosome biogenesis factor yUtp23/hUTP23 coordinates key interactions in the yeast and human pre-40S particle and hUTP23 contains an essential PIN domain.

Two proteins with PIN endonuclease domains, yUtp24(Fcf1)/hUTP24 and yUtp23/hUTP23 are essential for early pre-ribosomal (r)RNA cleavages at sites A0, A1/1 and A2/2a in yeast and humans. The yUtp24/hUTP24 PIN endonuclease is proposed to cleave at sites A1/1 and A2/2a, but the enzyme cleaving at site A0 is not known. Yeast yUtp23 contains a degenerate, non-essential PIN domain and functions together with the snR30 snoRNA, while human hUTP23 is associated with U17, the human snR30 counterpart. Using in vivo RNA-protein crosslinking and gel shift experiments, we reveal that yUtp23/hUTP23 makes direct contacts with expansion sequence 6 (ES6) in the 18S rRNA sequence and that yUtp23 interacts with the 3΄ half of the snR30 snoRNA. Protein-protein interaction studies further demonstrated that yeast yUtp23 and human hUTP23 directly interact with the H/ACA snoRNP protein yNhp2/hNHP2, the RNA helicase yRok1/hROK1(DDX52), the ribosome biogenesis factor yRrp7/hRRP7 and yUtp24/hUTP24. yUtp23/hUTP23 could therefore be central to the coordinated integration and release of ES6 binding factors and likely plays a pivotal role in remodeling this pre-rRNA region in both yeast and humans. Finally, studies using RNAi-rescue systems in human cells revealed that intact PIN domain and Zinc finger motifs in human hUTP23 are essential for 18S rRNA maturation.

Characterization of Small RNAs Derived from tRNAs, rRNAs and snoRNAs and Their Response to Heat Stress in Wheat Seedlings.

Small RNAs (sRNAs) derived from non-coding RNAs (ncRNAs), such as tRNAs, rRNAs and snoRNAs, have been identified in various organisms. Several observations have indicated that cleavage of tRNAs and rRNAs is induced by various stresses. To clarify whether sRNAs in wheat derived from tRNAs (stRNAs), rRNAs (srRNAs) and snoRNAs (sdRNAs) are produced specifically in association with heat stress responses, we carried out a bioinformatic analysis of sRNA libraries from wheat seedlings and performed comparisons between control and high-temperature-treated samples to measure the differential abundance of stRNAs, srRNAs and sdRNAs. We found that the production of sRNAs from tRNAs, 5.8S rRNAs, and 28S rRNAs was more specific than that from 5S rRNAs and 18S rRNAs, and more than 95% of the stRNAs were processed asymmetrically from the 3' or 5' ends of mature tRNAs. We identified 333 stRNAs and 8,822 srRNAs that were responsive to heat stress. Moreover, the expression of stRNAs derived from tRNA-Val-CAC, tRNA-Thr-UGU, tRNA-Tyr-GUA and tRNA-Ser-UGA was not only up-regulated under heat stress but also induced by osmotic stress, suggesting that the increased cleavage of tRNAs might be a mechanism that developed in wheat seedlings to help them cope with adverse environmental conditions.

SncRNA (microRNA &snoRNA) opposite expression pattern found in multiple sclerosis relapse and remission is sex dependent.

Multiple sclerosis (MS) is a common inflammatory and degenerative disease that causes neurological disability. It affects young adults and its prevalence is higher in women. The most common form is manifested as a series of acute episodes of neurological disability (relapses) followed by a recovery phase (remission). Recently, non-coding RNAs have emerged as new players in transcriptome regulation, and in turn, they could have a significant role in MS pathogenesis. In this context, our aim was to investigate the involvement of microRNAs and snoRNAs in the relapse-remission dynamics of MS in peripheral blood leucocytes, to shed light on the molecular and regulatory mechanisms that underlie this complex process. With this approach, we found that a subset of small non-coding RNAs (sncRNA) is altered in relapse and remission, revealing unexpected opposite changes that are sex dependent. Furthermore, we found that a relapse-related miRNA signature regulated general metabolism processes in leucocytes, and miRNA altered in remission are involved in the regulation of innate immunity. We observed that sncRNA dysregulation is different in relapse and remission leading to differences in transcriptome regulation, and that this process is sex dependent. In conclusion, relapse and remission have a different molecular background in men and women.

Long non-coding RNA growth arrest-specific transcript 5 is involved in ovarian cancer cell apoptosis through the mitochondria-mediated apoptosis pathway.

The present study investigated the underlying role of growth arrest-specific transcript 5 (GAS5) in epithelial ovarian cancer (EOC), which is the main cause of death in women with malignant tumor of the genital system. In vivo GAS5 expression in 60 EOC specimens was evaluated by quantitative reverse transcription (qRT)-PCR, which was used to study the differences of GAS5 expression between EOC tissues and normal ovarian epithelium. In vitro GAS5 overexpression was applied to discover the biological functions in EOC cell lines. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide and colony formation assays were employed to investigate the effect on proliferation. The function of apoptosis was assessed by flow cytometry, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and JC-1 probe staining, and migration and invasion were detected by Transwell assay. The data show that no significant differences of GAS5 expression were observed between normal ovarian epithelium and benign epithelial lesions; however, GAS5 expression was lower in EOC tissues compared with normal ovarian epithelial tissues (6.44-fold), which was closely related to lymph node metastasis (P=0.025) and tumor node metastasis stage (P=0.035). Moreover, exogenous GAS5-inhibited proliferation promoted apoptosis and decreased migration and invasion in ovarian cancer cells. Finally, through mitochondrial potential and western blot analyses, GAS5 could disrupt mitochondrial membrane potential and promote BAX, BAK, cleaved-caspase 3 and cleaved-caspase 9 expression. Taken together, the findings of the present study revealed that GAS5 is downregulated in EOC specimens, and GAS5 inhibits EOC cell proliferation, migration and invasion, and promotes cell apoptosis. GAS5 can serve as a novel therapeutic target in patients with EOC.

MicroRNA Expression Profile Reveals miR-17-92 and miR-143-145 Cluster in Synchronous Colorectal Cancer.

The expression of abnormal microRNA (miRNA, miR) is a ubiquitous feature of colorectal cancer (CRC). The pathological features and clinical behaviors of synchronous CRC have been comprehensively described; however, the expression profile of miRNA and small nucleolar RNA (snoRNA) in synchronous CRC has not been elucidated. In the present study, the expression profile of miRNA and snoRNA in 5 synchronous CRCs, along with the matched normal colorectal tissue was evaluated by microarray. Function and pathway analyses of putative targets, predicted from miRNA-mRNA interaction, were performed. Moreover, we analyzed clinicopathological and molecular characteristics of 22 patients with synchronous CRC and 579 solitary CRCs in a retrospective cohort study. We found a global dysregulation of miRNAs, including an oncogenic miR-17-92 cluster and oncosuppressive miR-143-145 cluster, and snoRNAs in synchronous CRC. Differential miRNA rather than snoRNA expression was robust enough to distinguish synchronous cancer from normal mucosa. Function analysis of putative targets suggested that miRNA clusters may modulate multiple effectors of oncogenic pathways involved in the pathogenesis of synchronous CRC. A comparison of normal mucosa between synchronous and solitary CRC suggested a differential genetic background of synchronous CRC from solitary CRC during carcinogenesis. Compared with solitary cancer patients, synchronous cases exhibited multiple extra-colonic cancers (P = 0.012), coexistence of adenoma (P = 0.012), microsatellite instability (P = 0.024), and less glucose transporter 1 (P = 0.037). Aberrant miRNA expression profiles could potentially be used as a diagnostic tool for synchronous CRC. Our findings represent the first comprehensive miRNA and snoRNA expression signatures for synchronous CRC, implicating that the miRNAs and snoRNAs may present therapeutic targets for synchronous CRC.

The SMC Loader Scc2 Promotes ncRNA Biogenesis and Translational Fidelity.

The Scc2-Scc4 complex is essential for loading the cohesin complex onto DNA. Cohesin has important roles in chromosome segregation, DSB repair, and chromosome condensation. Here we report that Scc2 is important for gene expression in budding yeast. Scc2 and the transcriptional regulator Paf1 collaborate to promote the production of Box H/ACA snoRNAs which guide pseudouridylation of RNAs including ribosomal RNA. Mutation of SCC2 was associated with defects in the production of ribosomal RNA, ribosome assembly, and splicing. While the scc2 mutant does not have a general defect in protein synthesis, it shows increased frameshifting and reduced cap-independent translation. These findings suggest Scc2 normally promotes a gene expression program that supports translational fidelity. We hypothesize that translational dysfunction may contribute to the human disorder Cornelia de Lange syndrome, which is caused by mutations in NIPBL, the human ortholog of SCC2.

Nonsense-mediated RNA decay: at the 'cutting edge' of regulated snoRNA production.

Production of multiple functional RNAs from a single primary transcript is an extremely efficient use of genetic information, although it complicates the ability of the cell to independently regulate the production of each RNA. For the case of small nucleolar RNAs (snoRNAs) encoded within introns of mRNA genes, Lykke-Andersen and colleagues (pp. 2498-2517) demonstrated that alternative splicing and the SMG6 endonuclease of the nonsense-mediated RNA decay pathway are key regulators that control which RNAs accumulate.

Elevated snoRNA biogenesis is essential in breast cancer.

Hyperactive ribosomal biogenesis is widely observed in cancer, which has been partly attributed to the increased rDNA transcription by Pol I in cancer. However, whether small nucleolar RNAs (snoRNAs), a class of non-coding RNAs crucial in ribosomal RNA (rRNA) maturation and functionality, are involved in cancer remains elusive. We report that snoRNAs and fibrillarin (FBL, an enzymatic small nucleolar ribonucleoprotein, snoRNP) are frequently overexpressed in both murine and human breast cancer as well as in prostate cancers, and significantly, that this overexpression is essential for tumorigenicity in vitro and in vivo. We demonstrate that when the elevated snoRNA pathway is suppressed, the tumor suppressor p53 can act as a sentinel of snoRNP perturbation, the activation of which mediates the growth inhibitory effect. On the other hand, high level of FBL interferes with the activation of p53 by stress. We further show that p53 activation by FBL knockdown is not only regulated by the ribosomal protein-MDM2-mediated protein stabilization pathway, but also by enhanced PTB-dependent, cap-independent translation. Together, our data uncover an essential role of deregulated snoRNA biogenesis in tumors and a new mechanism of nucleolar modulation of p53.

A bacterial-like mechanism for transcription termination by the Sen1p helicase in budding yeast.

Transcription termination is essential to generate functional RNAs and to prevent disruptive polymerase collisions resulting from concurrent transcription. The yeast Sen1p helicase is involved in termination of most noncoding RNAs transcribed by RNA polymerase II (RNAPII). However, the mechanism of termination and the role of this protein have remained enigmatic. Here we address the mechanism of Sen1p-dependent termination by using a highly purified in vitro system. We show that Sen1p is the key enzyme of the termination reaction and reveal features of the termination mechanism. Like the bacterial termination factor Rho, Sen1p recognizes the nascent RNA and hydrolyzes ATP to dissociate the elongation complex. Sen1p-dependent termination is highly specific and, notably, does not require the C-terminal domain of RNAPII. We also show that termination is inhibited by RNA-DNA hybrids. Our results elucidate the role of Sen1p in controlling pervasive transcription.

Centenarians, but not octogenarians, up-regulate the expression of microRNAs.

Centenarians exhibit extreme longevity and a remarkable compression of morbidity. They have a unique capacity to maintain homeostatic mechanisms. Since small non-coding RNAs (including microRNAs) are implicated in the regulation of gene expression, we hypothesised that longevity of centenarians may reflect alterations in small non-coding RNA expression. We report the first comparison of microRNAs expression profiles in mononuclear cells from centenarians, octogenarians and young individuals resident near Valencia, Spain. Principal Component Analysis of the expression of 15,644 mature microRNAs and, 2,334 snoRNAs and scaRNAs in centenarians revealed a significant overlap with profiles in young individuals but not with octogenarians and a significant up-regulation of 7 small non-coding RNAs in centenarians compared to young persons and notably 102 small non-coding RNAs when compared with octogenarians. We suggest that the small non-coding RNAs signature in centenarians may provide insights into the underlying molecular mechanisms endowing centenarians with extreme longevity.