Correlation between DNA methylation and gene expression in the brains of patients with bipolar disorder and schizophrenia.

OBJECTIVES: Aberrant DNA methylation and gene expression have been reported in postmortem brain tissues of psychotic patients, but until now there has been no systematic evaluation of synergistic changes in methylation and expression on a genome-wide scale in brain tissue. METHODS: In this study, genome-wide methylation and expression analyses were performed on cerebellum samples from 39 patients with schizophrenia, 36 patients with bipolar disorder, and 43 unaffected controls, to screen for a correlation between gene expression and CpG methylation. RESULTS: Out of 71,753 CpG gene pairs (CGPs) tested across the genome, 204 were found to significantly correlate with gene expression after correction for multiple testing [p < 0.05, false discovery rate (FDR) q < 0.05]. The correlated CGPs were tested for disease-associated expression and methylation by comparing psychotic patients with bipolar disorder and schizophrenia to healthy controls. Four of the identified CGPs were found to significantly correlate with the differential expression and methylation of genes encoding phosphoinositide-3-kinase, regulatory subunit 1 (PIK3R1), butyrophilin, subfamily 3, member A3 (BTN3A3), nescient helix-loop-helix 1 (NHLH1), and solute carrier family 16, member 7 (SLC16A7) in psychotic patients (p < 0.05, FDR q < 0.2). Additional expression and methylation datasets were used to validate the relationship between DNA methylation, gene expression, and neuropsychiatric diseases. CONCLUSIONS: These results suggest that the identified differentially expressed genes with an aberrant methylation pattern may represent novel candidate factors in the etiology and pathology of neuropsychiatric disorders.

Disseminated Mycoplasma Orale Infection in Patients With Phosphoinositide-3-Kinase Regulatory Subunit 1 Mutations.

Mycoplasma orale is a rare cause of invasive infection in immunodeficient hosts. Phosphatidylinositol 3-kinase, regulatory subunit 1 (PI3KR1) mutations predispose patients to sinopulmonary infections, alongside bronchiectasis autoimmunity and lymphoproliferation. We report 2 cases of PI3KR1 deficiency with invasive M orale and effective treatment options.

Long Non-coding RNA RMST Worsens Ischemic Stroke via MicroRNA-221-3p/PIK3R1/TGF-ß Signaling Pathway.

Much efforts have been made to probe the mechanism underlying ischemic stroke (IS). This study was proposed to uncover the role of long non-coding RNA rhabdomyosarcoma 2 related transcript (RMST) in IS through microRNA-221-3p (miR-221-3p)/phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1)/transforming growth factor-ß (TGF-ß) axis. Neurological behavioral function, pathological changes in brain tissue, oxidative stress, and inflammation responses in middle cerebral artery occlusion (MCAO) mice were tested. RMST, miR-221-3p, PIK3R1, and TGF-ß signaling-related protein expression in brain tissues of MCAO mice were detected. RMST and PIK3R1 were elevated, miR-221-3p was downregulated, and TGF-ß pathway was activated in mice after MCAO. Restored miR-221-3p or depleted RMST improved neurological behavioral functions, relieved pathological injury in brain tissue, and repressed oxidative stress and inflammation in mice after MCAO. Depleted PIK3R1 or restored miR-221-3p offsets the negative effects of overexpressed RMST on mice with MCAO. The present work highlights that RMST augments IS through reducing miR-221-3p-mediated regulation of PIK3R1 and activating TGF-ß pathway.

Exosomal MicroRNA-221-3p Confers Adriamycin Resistance in Breast Cancer Cells by Targeting PIK3R1.

Drug resistance in breast cancer (BC) cells continues to be a stern obstacle hindering BC treatment. Adriamycin (ADR) is a frequently employed chemotherapy agent used to treat BC. The exosomal transfer of microRNAs (miRNAs) has been reported to enhance the drug-resistance of BC cells. Herein, we first sought to elucidate the possible role of the exosomal transfer of miR-221-3p in the drug resistance of MCF-7 cells to ADR. Differentially expressed genes (DEGs) were initially screened through microarray analysis in BC drug resistance-related datasets. Next, the expression of miR-221-3p and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) was quantified in ADR-resistant MCF-7 (MCF-7/ADR) and ADR-sensitive MCF-7 (MCF-7/S) cell lines, after which exosomes were separated and identified in each cell line. Target relationship between miR-221-3p and PIK3R1 was validated by a dual-luciferase reporter assay. Next, the expression of miR-221-3p and PIK3R1 was altered to clarify their effects on the resistance of MCF-7 cells to ADR in vitro and in vivo. PIK3R1 was identified as a BC drug resistance-related DEG, with the regulatory miR-221-3p subsequently obtained. Moreover, the MCF-7/ADR cells exhibited a low expression of PIK3R1 and a high expression of miR-221-3p. Notably, PIK3R1 was identified as a target gene of miR-221-3p. The overexpression of miR-221-3p in MCF-7/ADR cell-derived exosomes promoted ADR resistance in MCF-7/S cells via the PI3K/AKT signaling pathway. The in vitro results were reproducible in in vivo assays. Taken together, drug-resistant BC cell-derived exosomal miR-221-3p can promote the resistance of BC cells to ADR by targeting PIK3R1 via the PI3K/AKT signaling pathway in vitro and in vivo. These findings provide encouraging insights and provide perspectives for further investigation into the BC drug resistance mechanism.

Expression profile and biological function of miR-455-5p in colorectal carcinoma.

Underexpression of microRNA-455-5p (miR-455-5p) in medullary thyroid carcinoma, melanoma, gastric cancer and additional cancer types has been reported, which may be associated with carcinoma development. The present study aimed to evaluate the expression profile and biological role of miR-455-5p in colorectal carcinoma. Carcinoma tissues and adjacent tissue specimens from 40 patients with colorectal cancer were randomly collected. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis was conducted to detect the expression levels of miR-455-5p in colorectal carcinoma and adjacent normal tissues. The biological effects of miR-455-5p on selected colorectal cancer cells were assessed using bromodeoxyuridine assays, wound healing migration assays and flow cytometry. Bioinformatics analysis was implemented to predict the potential target genes of miR-455-5p in colorectal cancer. The expression levels of target genes were further validated by RT-qPCR and western blot analysis of the mRNA and protein levels. The results of the experiments demonstrated that miR-455-5p expression was downregulated in colorectal cancer tissues compared with adjacent normal tissues. In colorectal cancer cells (SW-480, HT-29 and HCT-116), miR-455-5p was observed to inhibit cell proliferation and migration while promoting cell apoptosis. Bioinformatics analysis predicted that the oncogene phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) was one of the top ranked target genes of miR-455-5p in colorectal cancer cells. This association was validated by RT-qPCR and western blotting. In vivo studies revealed that the expression level of miR-455-5p was significantly downregulated in human colorectal cancer. Further in vitro studies suggested that miR-455-5p may prevent the development of colorectal cancer by downregulating the oncogene PIK3R1. It was concluded that miR-455-5p may target and downregulate PIK3R1 in colorectal cancer.

Ossification of the posterior longitudinal ligament related genes identification using microarray gene expression profiling and bioinformatics analysis.

Ossification of the posterior longitudinal ligament (OPLL) is a kind of disease with physical barriers and neurological disorders. The objective of this study was to explore the differentially expressed genes (DEGs) in OPLL patient ligament cells and identify the target sites for the prevention and treatment of OPLL in clinic. Gene expression data GSE5464 was downloaded from Gene Expression Omnibus; then DEGs were screened by limma package in R language, and changed functions and pathways of OPLL cells compared to normal cells were identified by DAVID (The Database for Annotation, Visualization and Integrated Discovery); finally, an interaction network of DEGs was constructed by string. A total of 1536 DEGs were screened, with 31 down-regulated and 1505 up-regulated genes. Response to wounding function and Toll-like receptor signaling pathway may involve in the development of OPLL. Genes, such as PDGFB, PRDX2 may involve in OPLL through response to wounding function. Toll-like receptor signaling pathway enriched genes such as TLR1, TLR5, and TLR7 may involve in spine cord injury in OPLL. PIK3R1 was the hub gene in the network of DEGs with the highest degree; INSR was one of the most closely related genes of it. OPLL related genes screened by microarray gene expression profiling and bioinformatics analysis may be helpful for elucidating the mechanism of OPLL.