Retrotransposons Down- and Up-Regulation in Aging Somatic Tissues.
Ontology highlight
ABSTRACT:
SUBMITTER: Giordani G
PROVIDER: S-EPMC8750722 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Long terminal repeat (LTR) retrotransposons are widely distributed across the human genome. They have accumulated through retroviral integration into germline DNA and are latent genetic modules. Active LTR promoters are observed in germline cells; however, little is known about the mechanisms underlying their active transcription in somatic tissues. Here, by integrating our previous transcriptome data set with publicly available data sets, we show that the LTR families MLT2A1 and MLT2A2 are primarily expressed in human four-cell and eight-cell embryos and are also activated in some adult somatic tissues, particularly pineal gland. Three MLT2A elements function as the promoters and first exons of the protein-coding genes ABCE1, COL5A1, and GALNT13 specifically in the pineal gland of humans but not in that of macaques, suggesting that the exaptation of these LTRs as promoters occurred during recent primate evolution. This analysis provides insight into the possible transition from germline insertion to somatic expression of LTR retrotransposons.
| S-EPMC8559712 | biostudies-literature
Project description:Proteasome is central to proteostasis maintenance, as it degrades both normal and damaged proteins. Herein, we undertook a detailed analysis of proteasome regulation in the in vivo setting of Drosophila melanogaster. We report that a major hallmark of somatic tissues of aging flies is the gradual accumulation of ubiquitinated and carbonylated proteins; these effects correlated with a ~50% reduction of proteasome expression and catalytic activities. In contrast, gonads of aging flies were relatively free of proteome oxidative damage and maintained substantial proteasome expression levels and highly active proteasomes. Moreover, gonads of young flies were found to possess more abundant and more active proteasomes than somatic tissues. Exposure of flies to oxidants induced higher proteasome activities specifically in the gonads, which were, independently of age, more resistant than soma to oxidative challenge and, as analyses in reporter transgenic flies showed, retained functional antioxidant responses. Finally, inducible Nrf2 activation in transgenic flies promoted youthful proteasome expression levels in the aged soma, suggesting that age-dependent Nrf2 dysfunction is causative of decreasing somatic proteasome expression during aging. The higher investment in proteostasis maintenance in the gonads plausibly facilitates proteome stability across generations; it also provides evidence in support of the trade-off theories of aging.
| S-EPMC4050428 | biostudies-literature
Project description:Insulin-like growth factor 2 (IGF2) is an important fetal growth factor. Its expression is dramatically down-regulated in multiple organs after birth but is frequently up-regulated in cancers. The mechanisms that drive down-regulation of IGF2 in postnatal tissues or the up-regulation in malignancy are unclear. We found evidence that E2F transcription factor 3 (E2F3) drives these changes in expression. E2f3 mRNA expression, protein expression, and binding to the Igf2 promoter all decreased with age postnatally in multiple mouse organs. In late juvenile hepatocytes, restoration of high E2f3 expression restored high Igf2 expression, indicating a causal relationship, but this induction did not occur in fetal hepatocytes, which already have high E2f3 and Igf2 expression. Transient expression of E2f3 in both HEK293 cells and in late juvenile hepatocytes were able to activate reporter constructs containing the mouse Igf2 promoter P2, which includes consensus E2F-binding sites. In humans, microarray data revealed declines in E2F3 and IGF2 expression with age similar to the mouse. In addition, E2F3-overexpressing human prostate and bladder cancers showed increased IGF2 expression, and levels of E2F3 and IGF2 mRNA in these cancers were positively correlated. Taken together, the findings suggest that down-regulation of E2f3 with age helps drive the dramatic decline in Igf2 expression in postnatal organs, and E2F3 overexpression in human cancers induces IGF2 overexpression.
| S-EPMC3625270 | biostudies-literature
Project description:Somatic cells are equipped with different silencing mechanisms that protect the genome against retrotransposons. In Drosophila melanogaster, a silencing pathway implicating the argonaute protein PIWI represses retrotransposons in cells surrounding the oocyte, whereas a PIWI-independent pathway is involved in other somatic tissues. Here, we show that these two silencing mechanisms result in distinct chromatin structures. Using sensor transgenes, we found that, in somatic tissues outside of the ovaries, these transgenes adopt a heterochromatic configuration implicating hypermethylation of H3K9 and K27. We identified the Polycomb repressive complexes (PRC1 and 2), but not heterochromatin protein 1 to be necessary factors for silencing. Once established, the compact structure is stably maintained through cell divisions. By contrast, in cells where the silencing is PIWI-dependent, the transgenes display an open and labile chromatin structure. Our data suggest that a post-transcriptional gene silencing (PTGS) mechanism is responsible for the repression in the ovarian somatic cells, whereas a mechanism that couples PTGS to transcriptional gene silencing operates to silence retrotransposons in the other somatic tissues.
| S-EPMC3223077 | biostudies-literature
Project description:Transposable elements (TEs) were discovered by Barbara McClintock in maize and have since been found to be ubiquitous in all living organisms. Transposition is mutagenic and organisms have evolved mechanisms to repress the activity of their endogenous TEs. Transposition in somatic cells is very low, but recent evidence suggests that it may be derepressed in some cases, such as cancer development. We have found that during normal aging several families of retrotransposable elements (RTEs) start being transcribed in mouse tissues. In advanced age the expression culminates in active transposition. These processes are counteracted by calorie restriction (CR), an intervention that slows down aging. Retrotransposition is also activated in age-associated, naturally occurring cancers in the mouse. We suggest that somatic retrotransposition is a hitherto unappreciated aging process. Mobilization of RTEs is likely to be an important contributor to the progressive dysfunction of aging cells.
| S-EPMC3883704 | biostudies-literature
Project description:Long non-coding RNAs (LncRNAs) in hypertensives and their mechanisms in regulating blood pressure still remain unexplored. The aim of present study is to construct the profiles of LncRNAs in blood of patients with essential hypertension and healthy controls. Methods and results, LncRNA microarray identified up-regulated, anddown-regulated LncRNAs, in hypertensives compared to their healthy controls. Among them, one vascular smooth muscle (VSM)-specific LncRNA AK096656 (LncVSM) was quantitated in plasma of patients with hypertension and their healthy controls using the real-time qRT-PCR. LncVSM shows specific expression in human arterial vascular smooth muscle cells (HASMCs) and promote its proliferation and migration. Expression profiles and Ingenuity Pathway Analysis (IPA) revealed that LncVSM activated Renin-Angiotensin Signaling (RAS). the overexpression of LncVSM would result hypertension related complications.
2015-12-12 | GSE75940 | GEO
Project description:BackgroundRASSF1A gene silencing by DNA methylation has been suggested as a major event in pancreatic endocrine tumor (PET) but RASSF1A expression has never been studied. The RASSF1 locus contains two CpG islands (A and C) and generates seven transcripts (RASSF1A-RASSF1G) by differential promoter usage and alternative splicing.MethodsWe studied 20 primary PETs, their matched normal pancreas and three PET cell lines for the (i) methylation status of the RASSF1 CpG islands using methylation-specific PCR and pyrosequencing and (ii) expression of RASSF1 isoforms by quantitative RT-PCR in 13 cases. CpG island A methylation was evaluated by methylation-specific PCR (MSP) and by quantitative methylation-specific PCR (qMSP); pyrosequencing was applied to quantify the methylation of 51 CpGs also encompassing those explored by MSP and qMSP approaches.ResultsMSP detected methylation in 16/20 (80%) PETs and 13/20 (65%) normal pancreas. At qMSP, 11/20 PETs (55%) and 9/20 (45%) normals were methylated in at least 20% of RASSF1A alleles.Pyrosequencing showed variable distribution and levels of methylation within and among samples, with PETs having average methylation higher than normals in 15/20 (75%) cases (P = 0.01). The evaluation of mRNA expression of RASSF1 variants showed that: i) RASSF1A was always expressed in PET and normal tissues, but it was, on average, expressed 6.8 times less in PET (P = 0.003); ii) RASSF1A methylation inversely correlated with its expression; iii) RASSF1 isoforms were rarely found, except for RASSF1B that was always expressed and RASSF1C whose expression was 11.4 times higher in PET than in normal tissue (P = 0.001). A correlation between RASSF1A expression and gene methylation was found in two of the three PET cell lines, which also showed a significant increase in RASSF1A expression upon demethylating treatment.ConclusionsRASSF1A gene methylation in PET is higher than normal pancreas in no more than 75% of cases and as such it cannot be considered a marker for this neoplasm. RASSF1A is always expressed in PET and normal pancreas and its levels are inversely correlated with gene methylation. Isoform RASSF1C is overexpressed in PET and the recent demonstration of its involvement in the regulation of the Wnt pathway points to a potential pathogenetic role in tumor development.
| S-EPMC3170651 | biostudies-literature
Project description:ObjectivesBeryllium salts (here, beryllium sulphate) can produce a cytostatic effect in some cell types. The basis for this effect may include increased expression of proliferation inhibitors, reduced expression of proliferation promoters, or both. This study sought to determine the role of p53, the tumour-suppressing transcription factor, in mediating beryllium-induced cytostasis.Materials and methodsHuman A172 glioma cells express wild-type TP53 gene. Activity of p53 was experimentally manipulated using siRNA and related approaches. Key elements of the beryllium-response were compared in normal and p53-knockdown A172 cells using RT-PCR and Western blotting.ResultsIn A172 cells, 10 μm BeSO4 caused 300% increase in CDKN1A (cyclin-dependent kinase inhibitor p21) mRNA and 90% reduction of CCNE2 (cyclin E2) mRNA. The increased p21 mRNA and reduced cyclin E2 mRNA were each dependent on presence of functional p53. For p21, increased mRNA led to commensurately increased protein levels. In contrast, reduction in cyclin E2 mRNA levels did not lead to corresponding reductions in cyclin E2 protein. The proteasomal inhibitor MG-132 caused p53 protein to increase, but it had no effect on cyclin E2 protein levels. Cycloheximide time course studies indicated that the cyclin E2 protein half-life was more than 12 hours in these cells.ConclusionsBeryllium elicited p53-dependent changes in mRNA levels of key determinants of cell proliferation such as p21 and cyclin E2. However, cyclin E2 protein appeared to be aberrantly regulated in this cell type, as its turnover was unexpectedly slow.
| S-EPMC5096984 | biostudies-literature
Project description:Progranulin (PGRN) haploinsufficiency associated with loss-of-function mutations in the granulin gene causes frontotemporal dementia (FTD). This suggests that increasing PGRN levels could have promising therapeutic implications for patients carrying GRN mutations. In this study, we explored the therapeutic potential of sortilin1 (SORT1), a clearance receptor of PGRN, by generating and characterizing monoclonal antibodies against SORT1. Anti-SORT1 monoclonal antibodies were generated by immunizing Sort1 knockout mice with SORT1 protein. The antibodies were classified into 7 epitope bins based on their competitive binding to the SORT1 protein and further defined by epitope bin-dependent characteristics, including SORT1-PGRN blocking, SORT1 down-regulation, and binding to human and mouse SORT1. We identified a positive correlation between PGRN up-regulation and SORT1 down-regulation. Furthermore, we also characterized K1-67 antibody via SORT1 down-regulation and binding to mouse SORT1 in vivo and confirmed that K1-67 significantly up-regulated PGRN levels in plasma and brain interstitial fluid of mice. These data indicate that SORT1 down-regulation is a key mechanism in increasing PGRN levels via anti-SORT1 antibodies and suggest that SORT1 is a potential target to correct PGRN reduction, such as that in patients with FTD caused by GRN mutation.
| S-EPMC7770147 | biostudies-literature
Project description:Long non-coding RNAs (LncRNAs) in hypertensives and their mechanisms in regulating blood pressure still remain unexplored. The aim of present study is to construct the profiles of LncRNAs in blood of patients with essential hypertension and healthy controls. Methods and results, LncRNA microarray identified up-regulated, anddown-regulated LncRNAs, in hypertensives compared to their healthy controls. Among them, one vascular smooth muscle (VSM)-specific LncRNA AK096656 (LncVSM) was quantitated in plasma of patients with hypertension and their healthy controls using the real-time qRT-PCR. LncVSM shows specific expression in human arterial vascular smooth muscle cells (HASMCs) and promote its proliferation and migration. Expression profiles and Ingenuity Pathway Analysis (IPA) revealed that LncVSM activated Renin-Angiotensin Signaling (RAS). the overexpression of LncVSM would result hypertension related complications. LncVSM (AK098656) transfection
2015-12-12 | E-GEOD-75940 | biostudies-arrayexpress