The cis-regulatory function of long mononucleotide A-T repeats in maintaining high transcription activity in cancer
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ABSTRACT:
PROVIDER: PRJNA477540 | ENA |
REPOSITORIES: ENA
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2022-02-25 | PXD022547 | Pride
Project description:A-repeats are the simplest form of tandem repeats and are found ubiquitously throughout genomes. These mononucleotide repeats have been widely believed to be non-functional 'junk' DNA. However, studies in yeasts suggest that A-repeats play crucial biological functions, and their role in humans remains largely unknown. Here, we showed a non-random pattern of distribution of sense A- and T-repeats within 20 kb around transcription start sites (TSSs) in the human genome. Different distributions of these repeats are observed upstream and downstream of TSSs. Sense A-repeats are enriched upstream, whereas sense T-repeats are enriched downstream of TSSs. This enrichment directly correlates with repeat size. Genes with different functions contain different lengths of repeats. In humans, tissue-specific genes are enriched for short repeats of <10 bp, whereas housekeeping genes are enriched for long repeats of ≥10 bp. We demonstrated that DICER1 and Argonaute proteins are required for the cis-regulatory role of A-repeats. Moreover, in the presence of a synthetic polymer that mimics an A-repeat, protein binding to A-repeats was blocked, resulting in a dramatic change in the expression of genes containing upstream A-repeats. Our findings suggest a length-dependent cis-regulatory function of A-repeats and that Argonaute proteins serve as trans-acting factors, binding to A-repeats.
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Project description:BackgroundIntratumour heterogeneous gene expression among cancer and cancer stem cells (CSCs) can cause failure of current targeted therapies because each drug aims to target the function of a single gene. Long mononucleotide A-T repeats are cis-regulatory transcriptional elements that control many genes, increasing the expression of numerous genes in various cancers, including lung cancer. Therefore, targeting A-T repeats may dysregulate many genes driving cancer development. Here, we tested a peptide nucleic acid (PNA) oligo containing a long A-repeat sequence [A(15)] to disrupt the transcriptional control of the A-T repeat in lung cancer and CSCs.MethodsFirst, we separated CSCs from parental lung cancer cell lines. Then, we evaluated the role of A-T repeat gene regulation by counting the number of repeats in differentially regulated genes between CSCs and the parental cells of the CSCs. After testing the dosage and effect of PNA-A15 on normal and cancer cell toxicity and CSC phenotypes, we analysed genome-wide expression to identify dysregulated genes in CSCs.ResultsThe number of A-T repeats in genes differentially regulated between CSCs and parental cells differed. PNA-A15 was toxic to lung cancer cells and CSCs but not to noncancer cells. Finally, PNA-A15 dysregulated a number of genes in lung CSCs.ConclusionPNA-A15 is a promising novel targeted therapy agent that targets the transcriptional control activity of multiple genes in lung CSCs.
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Project description:In this study we investigated whether nicotinamide mononucleotide (NMN) could protect against Doxorubicin-induced cardiotoxicity and physical dysfunction in vivo. To assess the short- and long-term toxicity, two Doxo regimens were tested, acute and chronic. In the acute study, C57BL6/J (B6) mice were injected intraperitoneally (i.p.) once with Doxo (20 mg/kg) and NMN (180 mg/kg/day, i.p.) was administered daily for five days before and after the Doxo injection. In the chronic study, B6 mice received a cumulative dose of 20 mg/kg Doxo administered in fractionated doses for five days. NMN (500 mg/kg/day) was supplied in the mice’s drinking water beginning five days before the first injection of Doxo and continuing for 60 days after.
2023-01-11 | GSE221003 | GEO
Project description:BackgroundSystematic analyses of sequence features have resulted in a better characterisation of the organisation of the genome. A previous study in prokaryotes on the distribution of sequence repeats, which are notoriously variable and can disrupt the reading frame in genes, showed that these motifs are skewed towards gene termini, specifically the 5' end of genes. For eukaryotes no such intragenic analysis has been performed, though this could indicate the pervasiveness of this distribution bias, thereby helping to expose the selective pressures causing it.ResultsIn fungal gene repertoires we find a similar 5' bias of intragenic mononucleotide repeats, most notably for Candida spp., whereas e.g. Coccidioides spp. display no such bias. With increasing repeat length, ever larger discrepancies are observed in genome repertoire fractions containing such repeats, with up to an 80-fold difference in gene fractions at repeat lengths of 10 bp and longer. This species-specific difference in gene fractions containing large repeats could be attributed to variations in intragenic repeat tolerance. Furthermore, long transcripts experience an even more prominent bias towards the gene termini, with possibly a more adaptive role for repeat-containing short transcripts.ConclusionMononucleotide repeats are intragenically biased in numerous fungal genomes, similar to earlier studies on prokaryotes, indicative of a similar selective pressure in gene organization.
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Project description:NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12 month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.
2016-12-01 | GSE85718 | GEO
Project description:Microsatellite instability (MSI) status is a prognostic biomarker for immunotherapy in certain types of cancers, such as colorectal cancers (CRCs) and endometrial cancers (ECs). Tumors that are categorized as having high MSI (MSI-H) express high levels of neoantigens for immune recognition. The typical MSI test measures the length of short mononucleotide repeats (SMR) poly(A) 21-27; however, a limitation of this test is the difficulty in determining the shift size, particularly in endometrial cancer. To investigate an MSI detection assay with improved performance, the present study analyzed the use of poly(A) 40-44 mononucleotide repeats to detect the MSI status of 100 patients with either CRC (n=50) or EC (n=50). Capillary electrophoresis was used to evaluate five long mononucleotide repeat (LMR) markers, including poly(A) 40-A, 40-B, 40-C, 40-D and 44. The concordance rate of the LMR-MSI assay compared with an immunohistochemistry MSI detection assay was 96.0 and 95.1% for CRCs and ECs respectively, with the detection limit of the LMR-MSI assay demonstrated to be 2.5% MSI-H in HCT116 colorectal carcinoma cell lines. The LMR-MSI assay yielded a 95.1% concordance rate in ECs compared with that in the SMR-MSI test (87.8%). The LMR-MSI test identified a significantly higher mean shift size (13 bp) in MSI-H tumors compared with the SMR-MSI test (10 bp), in both EC and CRC tissue samples. Together, the present study suggested that the LMR-MSI test could potentially be a sensitive and practical technology for molecular laboratory testing, particularly in the use of immunotherapy for patients with CRCs and ECs.
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