Dataset Information

Global Gene Expression Profiling and Transcription Factor Network Analysis of Cognitive Aging in Monozygotic Twins.

ABSTRACT: Cognitive aging is one of the major problems worldwide, especially as people get older. This study aimed to perform global gene expression profiling of cognitive function to identify associated genes and pathways and a novel transcriptional regulatory network analysis to identify important regulons. We performed single transcript analysis on 400 monozygotic twins using an assumption-free generalized correlation coefficient (GCC), linear mixed-effect model (LME) and kinship model and identified six probes (one significant at the standard FDR < 0.05 while the other results were suggestive with 0.18 ≤ FDR ≤ 0.28). We combined the GCC and linear model results to cover diverse patterns of relationships, and meaningful and novel genes like APOBEC3G, H6PD, SLC45A1, GRIN3B, and PDE4D were detected. Our exploratory study showed the downregulation of all these genes with increasing cognitive function or vice versa except the SLC45A1 gene, which was upregulated with increasing cognitive function. Linear models found only H6PD and SLC45A1, the other genes were captured by GCC. Significant functional pathways (FDR < 3.95e-10) such as focal adhesion, ribosome, cysteine and methionine metabolism, Huntington's disease, eukaryotic translation elongation, nervous system development, influenza infection, metabolism of RNA, and cell cycle were identified. A total of five regulons (FDR< 1.3e-4) were enriched in a transcriptional regulatory analysis in which CTCF and REST were activated and SP3, SRF, and XBP1 were repressed regulons. The genome-wide transcription analysis using both assumption-free GCC and linear models identified important genes and biological pathways implicated in cognitive performance, cognitive aging, and neurological diseases. Also, the regulatory network analysis revealed significant activated and repressed regulons on cognitive function.

SUBMITTER: Mohammadnejad A

PROVIDER: S-EPMC8236849 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Introduction: Nasopharyngeal carcinoma (NPC) is an epithelial tumor with high incidence in southern China and Southeast Asia. Oncogene mutation patterns in NPC have yet to be fully elucidated. It is also unclear if the inheritance of oncogene mutations contribute to the development of NPC. Using a multigene cancer exome sequencing panel, we sought to investigate oncogenes that were shared between both NPCs that developed in a pair of monozygotic female twins. We also examined these patterns, in the context of germline variants found in their unaffected brother. Case Summary: Twin A was first diagnosed with Stage I poorly differentiated NPC in 1988 and underwent radiation therapy with complete remission. Her cancer relapsed in 1991 as lung metastasis. She underwent left thoracotomy followed by systemic chemotherapy with cisplastin/5FU. In 2000, she had recurrence of cancer to her cervical lymph nodes again for which she received chemoradiation that resulted in complete remission. Her sister, Twin B was diagnosed with Stage I poorly differentiated NPC twenty years later (2008) and received radiation with complete remission. Both monozygotic twins were of southern Chinese ethnicity and had an unaffected brother. Methods: Archival formalin fixed paraffin embedded tumor tissue was retrieved from excision specimens of the two twins. A blood specimen was obtained from the unaffected brother. DNA was extracted and amplified using primer pairs targeted to 50 oncogenes selected by the Wellcome Trust Sanger Genomic Institute. Samples were barcoded and sequenced on a PGM™ semiconductor sequencer (Life Technologies, Foster City, CA). Results: Sequence of the twin NPCs identified similar mutations on KIT (1708A > C; M541L; rs3822214) and HRAS (269T > C; H27H; rs249860) with a closely related novel TP53 variants of 587G > A; R196Q and 567C > T; A189A between twin A and twin B, respectively. Both TP53 variants were located near the Zinc binding regions of the TP53 protein (P04637). The unaffected brother showed a similar HRAS mutation (269T > C; H27H; rs249860). All siblings possessed a complex inframe deletion on Exon 12 of PDGFRA (AGCCCAGATGGACATG; S566_E571delinsR; rs121913271). Conclusions: An intriguing relationship between these two twins affected by nasopharyngeal carcainoma was identified by multigene targeted exome sequencing. A possible inheritance pattern was also elucidated in their unaffected brother. This cluster of genes suggests a possible role for tyrosine kinase inhibitors as molecularly targeted therapies in NPC. Further analysis by tumor-normal comparisons may work toward confirming an effector pathway that could broaden our understanding of this aggressive tumor.

Project description:BackgroundBroadly, much of variance in immune system phenotype has been linked to the influence of non-heritable factors rather than genetics. In particular, two non-heritable factors: aging and human cytolomegavirus (CMV) infection, have been known to account for significant inter-individual immune variance. However, many specific relationships between them and immune composition remain unclear, especially between individuals over narrower age ranges. Further exploration of these relationships may be useful for informing personalized intervention development.ResultsTo address this need, we evaluated 41 different cell type frequencies by mass cytometry and identified their relationships with aging and CMV seropositivity. Analyses were done using 60 healthy individuals, including 23 monozygotic twin pairs, categorized into young (12-31 years) and middle-aged (42-59 years). Aging and CMV discordance were associated with increased immune diversity between monozygotic twins overall, and particularly strongly in various T cell populations. Notably, we identified 17 and 11 cell subset frequencies as relatively influenced and uninfluenced by non-heritable factors, respectively, with results that largely matched those from studies on older-aged cohorts. Next, CD4+ T cell frequency was shown to diverge with age in twins, but with lower slope than in demographically similar non-twins, suggesting that much inter-individual variance in this cell type can be attributed to interactions between genetic and environmental factors. Several cell frequencies previously associated with memory inflation, such as CD27- CD8+ T cells and CD161+ CD4+ T cells, were positively correlated with CMV seropositivity, supporting findings that CMV infection may incur rapid aging of the immune system.ConclusionsOur study confirms previous findings that aging, even within a relatively small age range and by mid-adulthood, and CMV seropositivity, both contribute significantly to inter-individual immune diversity. Notably, we identify several key immune cell subsets that vary considerably with aging, as well as others associated with memory inflation which correlate with CMV seropositivity.

Project description:BackgroundMoyamoya disease (MMD) is characterized by progressive stenosis of intracranial arteries in the circle of Willis with unknown etiology even after the identification of a Moyamoya susceptible gene, RNF213. Recently, differences in epigenetic regulations have been investigated by a case-control study in MMD. Here, we employed a disease discordant monozygotic twin-based study design to unmask potential confounders.MethodsCirculating genome-wide microRNA (miRNome) profiling was performed in MMD-discordant monozygotic twins, non-twin-MMD patients, and non-MMD healthy volunteers by microarray followed by qPCRvalidation, using blood samples. Differential plasma-microRNAs were further quantified in endothelial cells differentiated from iPS cell lines (iPSECs) derived from another independent non-twin cohort. Lastly, their target gene expression in the iPSECs was analyzed.ResultsMicroarray detected 309 plasma-microRNAs in MMD-discordant monozygotic twins that were also detected in the non-twin cohort. Principal component analysis of the plasma-microRNA expression level demonstrated distinct 2 groups separated by MMD and healthy control in the twin- and non-twin cohorts. Of these, differential upregulations of hsa-miR-6722-3p/- 328-3p were validated in the plasma of MMD (absolute log2 expression fold change (logFC) > 0.26 for the twin cohort; absolute logFC > 0.26, p < 0.05, and q < 0.15 for the non-twin cohort). In MMD derived iPSECs, hsa-miR-6722-3p/- 328-3p showed a trend of up-regulation with a 3.0- or higher expression fold change. Bioinformatics analysis revealed that 41 target genes of miR-6722-3p/- 328-3p were significantly down-regulated in MMD derived iPSECs and were involved in STAT3, IGF-1-, and PTEN-signaling, suggesting a potential microRNA-gene expression interaction between circulating plasma and endothelial cells.ConclusionsOur MMD-discordant monozygotic twin-based study confirmed a novel circulating microRNA signature in MMD as a potential diagnostic biomarker minimally confounded by genetic heterogeneity. The novel circulating microRNA signature can contribute for the future functional microRNA analysis to find new diagnostic and therapeutic target of MMD.

Dataset Information

Global Gene Expression Profiling and Transcription Factor Network Analysis of Cognitive Aging in Monozygotic Twins.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets