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PubMed2006

Aberrant regulation of imprinted gene expression in Gtl2lacZ mice.

The imprinted region on mouse distal chromosome 12 covers about 1 Mb and contains at least three paternally expressed genes (Pegs: Peg9/Dlk1, Peg11/Rtl1, and Dio3) and four maternally expressed genes (Megs: Meg3/Gtl2, antiPeg11/antiRlt1, Meg8/Rian, and Meg9/Mirg). Gtl2(lacZ) (Gene trap locus 2) mice have a transgene (TG) insertion 2.3 kb upstream from the Meg3/Gtl2 promoter and show about 40% growth retardation when the TG-inserted allele is paternally derived. Quantitative RT-PCR experiments showed that the expression levels of Pegs in this region were reduced below 50%. These results are consistent with the observed phenotype in Gtl2lacZ mice, because at least two Pegs(Peg9/Dlk1 and Dio3) have growth-promoting effects. The aberrant induction of Megs from silent paternal alleles was also observed in association with changes in the DNA methylation level of a differentially methylated region (DMR) located around Meg3/Gtl2 exon 1. Interestingly, a 60 approximately 80% reduction in all Megs was observed when the TG was maternally derived, although the pups showed no apparent growth or morphological abnormalities. Therefore, the paternal or maternal inheritance of the TG results in the down-regulation in cis of either Pegs or Megs, respectively, suggesting that the TG insertion influences the mechanism regulating the entire imprinted region.

Animals↗

PubMed2026

IGH::FENDRR and specific KRAS mutations define a novel B-ALL molecular subtype with poor chemotherapy response.

Large-scale sequencing efforts have defined up to 27 diagnostic subtypes in B-cell precursor acute lymphoblastic leukemia (B-ALL), leaving few samples unclassified. Extended genomic and transcriptomic profiling in routine diagnostics broadens the sample collection, enabling identification of novel subtypes. We analyzed 4857 patients with B-ALL from 3 cohorts and identified a group of 20 patients (age, 18-66 years; median, 34 years) characterized by a previously undescribed IGH::FENDRR rearrangement exclusive to this subtype (n = 17/20), KRAS p.A146T/V/P mutations (n = 17/20 vs n = 86/4857; P< .001), and distinct DNA methylation/gene expression profiles, including overexpression of the lncRNA FENDRR and the transcription factor FOXF1 (FOXF1/FENDRR) as well as JAK/STAT and RAS/MAPK signaling signatures. A gene expression machine learning classifier accurately identified FOXF1/FENDRR cases in 2 independent cohorts. Patients treated according to German Multicenter Study Group for Adult ALL (GMALL)/Group for Research in Adult ALL (GRAALL) protocols showed very poor chemotherapy response with 8 of 13 exhibiting induction failure or minimal residual disease (MRD) ≥10-3 and 8 of 12 remaining MRD positive after first consolidation/salvage. Intensification including blinatumomab (n = 10) and/or allogeneic stem cell transplantation (n = 12) resulted in ongoing molecular remission in 13 of 16 patients. FOXF1/FENDRR represents a novel B-ALL subtype which might benefit from early immunotherapeutic treatment or targeted interventions.

Humans↗

PubMed2006

Loss of imprinting at the Dlk1-Gtl2 locus caused by insertional mutagenesis in the Gtl2 5' region.

BACKGROUND: The Dlk1 and Gtl2 genes define a region of mouse chromosome 12 that is subject to genomic imprinting, the parental allele-specific expression of a gene. Although imprinted genes play important roles in growth and development, the mechanisms by which imprinting is established and maintained are poorly understood. Differentially methylated regions (DMRs), which carry methylation on only one parental allele, are involved in imprinting control at many loci. The Dlk1-Gtl2 region contains three known DMRs, the Dlk1 DMR in the 3' region of Dlk1, the intergenic DMR 15 kb upstream of Gtl2, and the Gtl2 DMR at the Gtl2 promoter. Three mouse models are analyzed here that provide new information about the regulation of Dlk1-Gtl2 imprinting. RESULTS: A previously existing insertional mutation (Gtl2lacZ), and a targeted deletion in which the Gtl2 upstream region was replaced by a Neo cassette (Gtl2Delta5'Neo), display partial lethality and dwarfism upon paternal inheritance. Molecular characterization shows that both mutations cause loss of imprinting and changes in expression of the Dlk1, Gtl2 and Meg8/Rian genes. Dlk1 levels are decreased upon paternal inheritance of either mutation, suggesting Dlk1 may be causative for the lethality and dwarfism. Loss of imprinting on the paternal chromosome in both Gtl2lacZ and Gtl2Delta5'Neo mice is accompanied by the loss of paternal-specific Gtl2 DMR methylation, while maternal loss of imprinting suggests a previously unknown regulatory role for the maternal Gtl2 DMR. Unexpectedly, when the Neo gene is excised, Gtl2Delta5' animals are of normal size, imprinting is unchanged and the Gtl2 DMR is properly methylated. The exogenous DNA sequences integrated upstream of Gtl2 are therefore responsible for the growth and imprinting effects. CONCLUSION: These data provide further evidence for the coregulation of the imprinted Dlk1 and Gtl2 genes, and support a role for Dlk1 as an important neonatal growth factor. The ability of the Gtl2lacZ and Gtl2Delta5'Neo mutations to cause long-range changes in imprinting and gene expression suggest that regional imprinting regulatory elements may lie in proximity to the integration site.

Animals↗

PubMed2026

Comparative transcriptome analysis of Qinchuan and Wagyu cattle reveals lnc11599 as a negative regulator of intramuscular fat deposition.

BACKGROUND: Intramuscular fat (IMF) content is a critical factor determining beef quality, influenced by various factors including breed and age. However, the regulatory role of long non-coding RNAs (lncRNAs) in IMF deposition remains unclear. METHODS: This study investigated IMF deposition in the longissimus dorsi muscle of one- and two-year-old Qinchuan and Wagyu cattle through histological examination and fat content measurement. Based on transcriptome sequencing data of intramuscular fat tissue, differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify lncRNAs associated with IMF deposition. The effects of a key candidate lncRNA on the adipogenic differentiation of cattle intramuscular preadipocytes were further examined. RESULTS: Results showed that Wagyu cattle exhibited stronger IMF deposition capacity than Qinchuan cattle across all age groups, with IMF content increasing with age in both breeds. We identified 7,910 lncRNAs from intramuscular fat tissue transcriptome data, including 6,455 novel lncRNAs. Through integrated differential expression analysis and WGCNA, 88 lncRNAs closely associated with IMF deposition were screened from two-year-old Qinchuan and Wagyu cattle. Notably, lnc11599 was significantly upregulated in Qinchuan cattle intramuscular fat tissue, but its expression decreased during intramuscular preadipocyte differentiation. Functional experiments demonstrated that lnc11599 knockdown enhanced adipogenic differentiation capacity, manifested as a highly significant increase in lipid accumulation, upregulation of key adipogenic genes at the mRNA level, together with increases in total fatty acid content and unsaturated fatty acid proportion. CONCLUSIONS: This study established the lncRNA expression profiles in intramuscular fat tissue of Qinchuan and Wagyu cattle across different developmental stages, and demonstrated that lnc11599 acts as a negative regulator of intramuscular fat deposition. These findings provide new directions for elucidating the mechanisms of cattle IMF deposition and offer potential targets for genetic improvement of beef quality.

Animals↗

PubMed2024

Stemness related lncRNAs signature for the prognosis and tumor immune microenvironment of ccRCC patients.

Long non-coding RNAs (lncRNAs) and cancer stem cells (CSCs) are crucial for the growth, migration, recurrence, and medication resistance of tumors. However, the impact of lncRNAs related to stemness on the outcome and tumor immune microenvironment (TIME) in clear cell renal cell carcinoma (ccRCC) is still unclear. In this study, we aimed to predict the outcome and TIME of ccRCC by constructing a stem related lncRNAs (SRlncRNAs) signature. We firstly downloaded ccRCC patients' clinical data and RNA sequencing data from UCSC and TCGA databases, and abtained the differentially expressed lncRNAs highly correlated with stem index in ccRCC through gene expression differential analysis and Pearson correlation analysis. Then, we selected suitable SRlncRNAs for constructing a prognostic signature of ccRCC patients by LASSO Cox regression. Further, we used nomogram and Kaplan Meier curves to evaluate the SRlncRNA signature for the prognose in ccRCC. At last, we used ssGSEA and GSVA to evaluate the correlation between the SRlncRNAs signature and TIME in ccRCC. Finally, We obtained a signtaure based on six SRlncRNAs, which are correlated with TIME and can effectively predict the ccRCC patients' prognosis. The SRlncRNAs signature may be a noval prognostic indicator in ccRCC.

Humans↗

PubMed2024

Serum lncRNA ITGB2-AS1 and ICAM-1 as novel biomarkers for rheumatoid arthritis and osteoarthritis diagnosis.

BACKGROUND: The complete circulating long non-coding RNAs (lncRNAs) signature of rheumatoid arthritis (RA) and osteoarthritis (OA) is still uncovered. The lncRNA integrin subunit beta 2 (ITGB2)-anti-sense RNA 1 (ITGB2-AS1) affects ITGB2 expression; however, there is a gap in knowledge regarding its expression and clinical usefulness in RA and OA. This study investigated the potential of serum ITGB2-AS1 as a novel diagnostic biomarker and its correlation with ITGB2 expression and its ligand intercellular adhesion molecule-1 (ICAM-1), disease activity, and severity in RA and primary knee OA patients. SUBJECTS: Forty-three RA patients, 35 knee OA patients, and 22 healthy volunteers were included. RESULTS: Compared with healthy controls, serum ITGB2-AS1 expression was upregulated in RA patients but wasn't significantly altered in knee OA patients, whereas serum ICAM-1 protein levels were elevated in both diseases. ITGB2-AS1 showed discriminative potential for RA versus controls (AUC = 0.772), while ICAM-1 displayed diagnostic potential for both RA and knee OA versus controls (AUC = 0.804, 0.914, respectively) in receiver-operating characteristic analysis. In the multivariate analysis, serum ITGB2-AS1 and ICAM-1 were associated with the risk of developing RA, while only ICAM-1 was associated with the risk of developing knee OA. A panel combining ITGB2-AS1 and ICAM-1 showed profound diagnostic power for RA (AUC = 0.9, sensitivity = 86.05%, and specificity = 91.67%). Interestingly, serum ITGB2-AS1 positively correlated with disease activity (DAS28) in RA patients and with ITGB2 mRNA expression in both diseases, while ICAM-1 positively correlated with ITGB2 expression in knee OA patients. CONCLUSION: Our study portrays serum ITGB2-AS1 as a novel potential diagnostic biomarker of RA that correlates with disease activity. A predictive panel combining ITGB2-AS1 and ICAM-1 could have clinical utility in RA diagnosis. We also spotlight the association of ICAM-1 with knee OA diagnosis. The correlation of serum ITGB2-AS1 with ITGB2 expression in both diseases may be insightful for further mechanistic studies.

Humans↗

PubMed2024

Construction of an immunogenic cell death-related LncRNA signature to predict the prognosis of patients with lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most common malignant diseases worldwide. This study aimed to construct an immunogenic cell death (ICD)-related long non-coding RNA (lncRNA) signature to effectively predict the prognosis of LUAD. METHODS: The RNA-sequencing and clinical data of LUAD were downloaded from The Cancer Genome Atlas (TCGA). Least absolute shrinkage and selection operator (LASSO) and stepwise multivariate Cox proportional hazard regression analysis were utilized to construct lncRNA signature. Then, the reliability of the signature was evaluated in the training, validation and whole cohorts. The differences in the immune landscape and drug sensitivity between the low- and high-risk groups were analyzed. Finally, the expression level of the selected ICD-related lncRNAs in LUAD cell lines via reverse transcription quantitative PCR (RT-qPCR). CCK-8 and transwell assays were performed to study biological function of AC245014.3. RESULTS: A signature consisting of 5 ICD-related lncRNAs was constructed. Kaplan Meier (K-M) survival analysis showed shorter overall survival (OS) in high-risk group. The receiver operating characteristic (ROC) curves and Multivariate Cox regression analysis showed the signature was good predictive and independent prognostic factor in LUAD. Moreover, the high-risk group had a lower level of antitumor immunity and was less sensitive to some chemotherapeutics and targeted drugs. Finally, the expression level of selected ICD-related lncRNAs was validated in LUAD cell lines by RT-qPCR. Knockdown of AC245014.3 significantly suppressed LUAD proliferation, migration and invasion. CONCLUSIONS: In this study, an ICD-related lncRNA signature was constructed, which could accurately predict the prognosis of LUAD patients and guide clinical treatment.

Humans↗

PubMed2025

Comprehensive analysis of diagnostic biomarkers related to histone acetylation in acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) has become a serious disease that endangers human health, with high morbidity and mortality. Numerous studies have reported histone acetylation can result in the occurrence of cardiovascular diseases. This article aims to explore the potential biomarkers of histone acetylation regulatory genes (ARGs) in AMI patients. METHODS: Five AMI datasets were downloaded from the Gene Expression Omnibus (GEO) database. Next, ARG-related genes were gathered by gene set variation analysis (GSVA) and Spearman's correlation analysis. Subsequently, weighted gene co-expression network analysis (WGCNA) was performed to identify the module genes related to histone acetylation regulation. In the GSE60993 and GSE48060 datasets, the common differentially expressed genes (DEGs) between AMI and control samples were screened. Importantly, the intersecting genes were obtained by overlapping ARGs-related genes, common DEGs, and module genes. Then, the biomarkers in AMI were determined by machine learning, receiver operating characteristic (ROC) curves, and quantitative PCR (qPCR). In addition, immune analysis, drug prediction, molecular docking, and the lncRNA-miRNA-mRNA regulatory network targeting the biomarkers were analyzed, respectively. RESULTS: Here, a total of 18 intersecting genes were identified by overlapping 7,349 ARGs-related genes, 5,565 module genes, and 25 common DEGs. Further, five biomarkers (AQP9, HLA-DQA1, MCEMP1, NKG7, and S100A12) were obtained, and a nomogram was constructed and verified based on these biomarkers. Notably, the biomarkers were significantly associated with CD8 T cells and neutrophils. In addition, the drugs related to biomarkers were predicted, and ATOGEPANT with the molecular target (S100A12) had a high binding affinity (docking score = -10 kcal/mol). CONCLUSION: AQP9, HLA-DQA1, MCEMP1, NKG7, and S100A12 were identified as biomarkers related to ARGs in AMI, which provides a new perspective to study the relationship between ARGs and AMI.

Humans↗

PubMed2025

Expression analysis of LINC00671 and LINC01913 long non-coding RNAs in gastric cancer patients and their correlation with EMT markers.

BACKGROUND: Long-chain non-coding RNAs (lncRNAs) play various roles in the regulation of gene expression at the levels of transcription and translation, and epigenetic modification. Dysregulation of lncRNAs is associated with various malignancies, including cancer. lncRNAs have been demonstrated to regulate critical biological processes in cancer cells, such as apoptosis, proliferation, migration, and invasion. They also play essential roles in the development of gastric cancer (GC). However, the clinical significance and biological function of many lncRNAs remain unexplored in GC progression. This study aimed to evaluate the expression profiles of LINC00671 and LINC01913 in GC patients and investigate their correlation with epithelial-to-mesenchymal transition (EMT) markers. METHOD: The real-time PCR technique was applied to measure the expression levels of the selected lncRNAs (LINC01913 and LINC00671) and EMT-related mRNAs (MAMLs and MMP-13) in 83 tumor and adjacent normal tissues obtained from GC patients. RESULT: A significant reduction in LINC00671 expression was observed in 55.4% of tumor tissues, while elevated expression of LINC01913 (41%), MMP13 (56.6%), and MAML1 (44.6%) was detected, representing the proportion of samples with dysregulated expression relative to matched normal tissues. Dysregulation of these genes was significantly associated with various clinicopathological features (P < 0.05), supporting a potential link between these lncRNAs and EMT processes in GC. CONCLUSION: The observed associations between LINC00671, LINC01913, and EMT-related genes suggest their potential as prognostic biomarkers for treatment response in GC patients.

Humans↗

PubMed2026

Genome-wide mapping of stress-responsive lncRNA, uc.104, reveals the chromatin-mediated regulation of stress and plasticity-related genes in the hippocampus of chronic restraint rats.

Chronic stress significantly impacts hippocampal function through transcriptional and epigenetic mechanisms. While the roles of lncRNAs in stress-related transcriptional and epigenetic regulation have recently been recognized, their genome-wide functions controlling the transcriptional network remain largely unclear. Evidence indicates that the lncRNA uc.104 is involved in stress responses; however, its genome-wide chromatin interactions and gene regulatory effects are yet to be explored. To examine this, we combined chromatin isolation by RNA purification sequencing (ChIRP-seq) and RNA sequencing (RNA-seq) in the hippocampus from handled control and chronic restraint stress (CRS) rats. ChIRP-seq identified 6,664 uc.104 binding peaks under CRS, including 6,517 enriched and 149 reduced. Many peaks were mapped to intronic and promoter-proximal regions of protein-coding genes. Integration of ChIRP-seq with RNA-seq data revealed 1,839 differentially expressed genes associated with uc.104 binding sites, with 106 high-confidence overlaps. Several genes (Gabra3, Htr7, Irs1, Gpr37, Clu, Hspa1b, Ppp3r2, Nfasc, Pcdhac2, and Cysltr2) identified as regulatory targets of uc.104, have been directly implicated in stress responses, synaptic plasticity, and neuroinflammation. Gene ontology and Synapse GO (SynGO) analyses revealed significant enrichment for processes involving dendritic spine formation, synapse organization, and pre- and postsynaptic signaling. Protein-protein interaction analysis identified hub genes, including EGFR, CDC42, IGF1R, CTNNB1, CALM1, CALM3, POLR2A, MDM2, TBP, and CSNK1E, several of which have been linked to stress-responsive pathways. Together, our findings reveal that uc.104 binding to chromatin near stress- and synapse-related genes may act as a regulator of stress-responsive transcriptional networks in the hippocampus. By linking uc.104 occupancy to stress and synaptic responsive genes, this study highlights uc.104 as a potential mediator of stress-induced hippocampal malfunctions.

Animals↗

PubMed2003

A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells.

Human pituitary adenomas are the most common intracranial neoplasm. Typically monoclonal in origin, a somatic mutation is a prerequisite event in tumor development. To identify underlying pathogenetic mechanisms in tumor formation, we compared the difference in gene expression between normal human pituitary tissue and clinically nonfunctioning pituitary adenomas by cDNA-representational difference analysis. We cloned a cDNA, the expression of which was absent in these tumors, that represents a novel transcript from the previously described MEG3, a maternal imprinting gene with unknown function. It was expressed in normal human gonadotrophs, from which clinically nonfunctioning pituitary adenomas are derived. Additional investigation by Northern blot and RT-PCR demonstrated that this gene was also not expressed in functioning pituitary tumors as well as many human cancer cell lines. Moreover, ectopic expression of this gene inhibits growth in human cancer cells including HeLa, MCF-7, and H4. Genomic analysis revealed that MEG3 is located on chromosome 14q32.3, a site that has been predicted to contain a tumor suppressor gene involved in the pathogenesis of meningiomas. Taken together, our data suggest that MEG3 may represent a novel growth suppressor, which may play an important role in the development of human pituitary adenomas.

Adenoma↗

PubMed2003

Pituitary tumor pathogenesis--the hunt for novel candidate genes continues.

Explore the source record for details and available documents.

Genome, Human↗

PubMed2005

Hypermethylation of the promoter region is associated with the loss of MEG3 gene expression in human pituitary tumors.

MEG3 is a human homolog of the mouse maternal imprinted gene, Gtl2. Gtl2 has been suggested to be involved in fetal and postnatal development and to function as an RNA. Recently our laboratory demonstrated that a cDNA isoform of MEG3, MEG3a, inhibits cell growth in vitro. Interestingly, MEG3 is highly expressed in the normal human pituitary. In striking contrast, no MEG3 expression was detected in human clinically nonfunctioning pituitary tumors. These data indicate that this imprinted gene may be involved in pituitary tumorigenesis. In the present study we investigated the mechanism underlying the absence of MEG3 expression in human clinically nonfunctioning pituitary tumors. No genomic abnormality was detected in the tumors examined. Instead, we found that two 5'-flanking regions, immediately in front of and approximately 1.6-2.1 kb upstream of the first exon, respectively, were hypermethylated in tumors without MEG3 expression compared with the normal pituitary. Reporter assays demonstrated that these two regions are functionally important in gene expression activation. Furthermore, treatment of human cancer cell lines with a methylation inhibitor resulted in MEG3 expression. We conclude that hypermethylation of the MEG3 regulatory region is an important mechanism associated with the loss of MEG3 expression in clinically nonfunctioning pituitary tumors.

Azacitidine↗

PubMed2004

Molecular cloning and characterization of a novel sequence, vof-16, with enhanced expression in permanent ischemic rat brain.

We reported previously that chronic hypoperfusion induced by permanent occlusion of the bilateral common carotid arteries (2VO) in rats caused progressive cognitive deficits and neuronal damage in the hippocampus and the white matter. These changes are similar to those observed in human dementia. Reverse transcription-polymerase chain reaction (RT-PCR) differential display was carried out to identify mRNAs encoding the intrinsic factors involved in permanent ischemia from the 2VO rat brain. Over 20 clones which showed different expression levels in 2VO and sham-operated rats were isolated. One of these, named vof-16, was markedly enhanced the expression by 2VO. The whole sequence of vof-16 mRNA was 2098 nt. The distribution of vof-16 transcripts was examined by RT-PCR and in situ hybridization. The results revealed that vof-16 was abundant in the hippocampus, the tenia tecta, the piriform cortex and the area around the aorta. The expression levels of vof-16 in 2VO and sham-operated rat hippocampus were determined by a quantitative PCR method. The expression was abundant in the hippocampus of rats with cognitive impairment induced by 2VO. In contrast, the expression levels of vof-16 were lower in the 2VO rats with no impairment and in sham-operated rats. These results suggest that the expression levels of vof-16 may be related to the cognitive impairment induced by chronic ischemia after 2VO.

Animals↗

PubMed2006

Post-transcriptional regulation of microRNA expression.

microRNAs (miRNAs) are endogenous, noncoding approximately 22-nucleotide RNA molecules that have recently emerged as fundamental, post-transcriptional regulators of cognate target gene expression. Many mammalian miRNAs are expressed in a tissue-specific manner, a phenomenon that has so far been attributed to transcriptional regulation. We here show by Northern blots and in situ hybridization experiments that the expression of mammalian miRNAs can be regulated at the post-transcriptional level. In particular, miR-138 is spatially restricted to distinct cell types, while its precursor, pre-miR-138-2, is ubiquitously expressed throughout all tissues analyzed. Furthermore, pre-miR-138-2 is exported from the nucleus to the cytoplasm, suggesting that cleavage of this pre-miRNA by Dicer is restricted to certain tissues and cell types. Thus, differential processing of pre-miRNAs might be an alternative mechanism to control miRNA function.

Animals↗

PubMed2026

Non-coding RNA 7SK drives tumor resistance by coupling local oncogenic activation with global transcriptional repression.

The conserved non-coding RNA 7SK is a well-established global transcriptional repressor, yet its context-specific functions in cancer and therapy resistance remain paradoxical. Here, we resolve this paradox by uncovering a dual-axis mechanism through which 7SK drives colorectal cancer (CRC) resistance. By integrating single-cell multi-omics with functional assays, we demonstrate that 7SK not only selectively activates the JUN transcriptional network to fuel tumor proliferation but also reduces global transcriptional entropy to stabilize an immunosuppressive microenvironment and promote immune escape. This "local activation-global suppression" paradigm is conserved across multiple cancer types, positioning 7SK as a potential pan-cancer therapeutic target. Our findings reveal 7SK as a dynamic modulator that balances oncogene-specific transcription with global transcriptional suppression across cancers, providing a new framework for understanding and targeting ncRNA-mediated resistance.

Humans↗

PubMed2025

Genetic analysis of IFNG-AS1 implicates opposite effects to Leishmania guyanensis-cutaneous leishmaniasis: rs4913269 confers protection while rs7134599 enhances susceptibility and correlates with high plasma IL-4 and IL-10 levels.

BACKGROUND: The long non-coding RNA interferon gamma antisense-1 (IFNGAS-1) is essential for Th1 lineage specific expression of IFNG. IFN-γ is a key component cytokine in host immune response against intracellular pathogens like Leishmania. We investigated the association of two genetic variants of IFNGAS-1, rs4913269 and rs7134599, with susceptibility or protection to Leishmania guyanensis- induced cutaneous leishmaniasis (Lg-CL). METHODS: A case-control study involving 1,714 individuals (855 Lg-CL and 859 healthy controls) was conducted in the state of Amazonas, Brazil. Genotyping of rs4913269 and rs7134599 were performed using direct nucleotide sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), respectively. Plasma cytokines concentrations (IL-10, IL-12p70, IL-4, IL-1β and TNF-α) were quantified using multiplex Luminex platform. Logistic regression, linkage disequilibrium (LD), and haplotype analyses were applied to assess genetic associations and cytokine correlations. RESULTS: Individuals with the rs4913269 G/G genotype had a 46% reduced risk of developing Lg-CL, (OR adjusted for age and sex [ORadj] = 0.54; 95% CI 0.39-0.75; Pvadj = 0.0001). Carriers of the rs7134599 A/A genotype had a 130% increased risk of progression to Lg- CL (ORadj = 2.3; 95% CI, 1.6-3.4; P = 0.0001). The rs7134599 A/G genotype also showed a 52% increased risk compared to GG genotype (ORadj = 1.52, 95%CI 1.22-1.89; Pvadj = 0.0002). The rs4913269 G/G genotype was associated with lower levels of IL-10 (P = 0.05) and IL-12p70 (P = 0.009) compared to the C/C genotype. Conversely, the rs7134599 AA genotypes were correlated with higher levels of TNF-α, IL-4, IL-10 and IL-1β in comparison to the GG genotype. LD revealed independent segregation of the variants. CONCLUSIONS: The IFNG-AS1 variants rs4913269 and rs7134599 exert opposing effects on Lg-CL risk and modulate key cytokines involved in disease pathogenesis. These findings underscore the regulatory role in immune responses and increase our understanding of the immunogenetic basis of CL and support the potential IFNG-AS1 as a biomarker for susceptibility.

Humans↗

PubMed2006

Regulated expression of two sets of paternally imprinted genes is necessary for mouse parthenogenetic development to term.

Mouse parthenogenetic embryos (PEs) are developmentally arrested until embryo day (E) 9.5 because of genomic imprinting. However, we have shown that embryos containing genomes from non-growing (ng) and fully grown (fg) oocytes, i.e. ng(wt)/fg(wt) PE (wt, wild type), developed to E13.5. Moreover, parthenogenetic development could be extended to term by further regulation of Igf2 and H19 expression using mice with deletion of the H19 transcription unit (H19Delta13) together with its differentially unit (DMR). To gain an insight into the extended development of the parthenotes to term, we have here investigated the expression levels of paternally imprinted genes in ng(H19Delta13)/fg(wt) PE throughout their development. In ng(H19Delta13)/fg(wt) Pes that died soon after recovery, the expression of Igf2 and H19 was restored to the appropriate levels except for low Igf2 expression in the liver after E15.5. Further, the paternally expressed Dlk1 and Dio3 were repressed, while the expression levels of the maternal Gtl2 and Mirg were twice those of the controls. However, the above-mentioned four genes showed almost normal expression in the surviving ng(H19Delta13)/fg(wt) PEs. The methylation analysis revealed that the intragenic DMR of the Dlk1-Gtl2 domain was hypermethylated in the ng(H19Delta13)/fg(wt) PEs that survived, but not in the PEs that died soon after recovery. The present study suggests that two sets of co-ordinately regulated but oppositely expressed genes, Igf2-H19 and Dlk1-Gtl2, act as a critical barrier to parthenogenetic development in order to render a paternal contribution obligatory for descendants in mammals.

Animals↗