Search Results (5)

WD40 repeat and FYVE containing protein 1 (WDFY1) functions in membrane trafficking and protein complex scaffolding. WDFY1 has been studied in the immune system and in different oncogenic conditions. Therefore, comprehensive understanding of WDFY1 regulation mechanisms is much desired. In this study, we analyzed the promoter and 5′- and 3′-untranslated regions (UTRs) of wdfy1 and identified critical sequence elements, transcription factors (TFs), and miRNAs that collaboratively regulate wdfy1 gene expression. A 3.5 kb segment of the mouse wdfy1 promoter and 5′-UTR was cloned into a luciferase expression vector and transfected into HeLa cells. Luciferase assays of promoter deletion mutants revealed approximately four-fold increased activity attributed by a 500 bp distal fragment upstream of the wdfy1 5′-UTR. Four TFs (Sp1, Ap-1, Hes1, and TCF7) were found to be critical for wdfy1 expression with binding sites spread throughout the promoter and 5′-UTR regions. Cloning of a 3.2 kb fragment of wdfy1 3′-UTR into the luciferase expression vector led to an ~3.5-fold decrease in luciferase activity. Complementary siRNA and luciferase assays mutually confirmed our findings. Most importantly, IL-6, a critical cytokine in organ inflammation, was found to promote WDFY1 expression through the upregulation of Sp1 in primary renal mesangial cells. We, therefore, identified a potential inflammation-driven WDFY1 upregulation in mice. Full article

Antimicrobial responses play an important role in maintaining intestinal heath. Recently we reported that miR-511 may regulate TLR4 responses leading to enhanced intestinal inflammation. However, the exact mechanism remained unclear. In this study we investigated the effect of miR-511 deficiency on anti-microbial responses and DSS-induced intestinal inflammation. miR-511-deficient mice were protected from DSS-induced colitis as shown by significantly lower disease activity index, weight loss and histology scores in the miR-511-deficient group. Furthermore, reduced inflammatory cytokine responses were observed in colons of miR-511 deficient mice. In vitro studies with bone marrow-derived M2 macrophages showed reduced TLR3 and TLR4 responses in miR-511-deficient macrophages compared to WT macrophages. Subsequent RNA sequencing revealed Wdfy1 as the potential miR-511 target. WDFY1 deficiency is related to impaired TLR3/TLR4 immune responses and the expression was downregulated in miR-511-deficient macrophages and colons. Together, this study shows that miR-511 is involved in the regulation of intestinal inflammation through downstream regulation of TLR3 and TLR4 responses via Wdfy1. Full article

The management of unsolved inherited retinal dystrophies (IRD) cases is challenging since no standard pipelines have been established. This study aimed to define a diagnostic algorithm useful for the diagnostic routine and to address unsolved cases. Here, we applied a Next-Generation Sequencing-based workflow, including a first step of panel sequencing (PS) followed by clinical-exome sequencing (CES) and whole-exome sequencing (WES), in 46 IRD patients belonging to 42 families. Twenty-six likely causal variants in retinal genes were found by PS and CES. CES and WES allowed proposing two novel candidate loci (WDFY3 and a X-linked region including CITED1), both abundantly expressed in human retina according to RT-PCR and immunohistochemistry. After comparison studies, PS showed the best quality and cost values, CES and WES involved similar analytical efforts and WES presented the highest diagnostic yield. These results reinforce the relevance of panels as a first step in the diagnostic routine and suggest WES as the next strategy for unsolved cases, reserving CES for the simultaneous study of multiple conditions. Standardizing this algorithm would enhance the efficiency and equity of clinical genetics practice. Furthermore, the identified candidate genes could contribute to increase the diagnostic yield and expand the mutational spectrum in these disorders. Full article

Bipolar disorder is a common and severe mental illness with unsolved pathophysiology. A genome-wide association study (GWAS) has been used to find a number of risk genes, but it is difficult for a GWAS to find genes indirectly associated with a disease. To find core hub genes, we introduce a network analysis after the GWAS was conducted. Six thousand four hundred fifty eight single nucleotide polymorphisms (SNPs) with p < 0.01 were sifted out from Wellcome Trust Case Control Consortium (WTCCC) dataset and mapped to 2045 genes, which are then compared with the protein–protein network. One hundred twelve genes with a degree >17 were chosen as hub genes from which five significant modules and four core hub genes (FBXL13, WDFY2, bFGF, and MTHFD1L) were found. These core hub genes have not been reported to be directly associated with BD but may function by interacting with genes directly related to BD. Our method engenders new thoughts on finding genes indirectly associated with, but important for, complex diseases. Full article

E26 transformation-specific-1 (ETS1) and WDFY family member 4 (WDFY4) are closely related with systemic lupus erythematosus. We hypothesized that ETS1 and WDFY4 polymorphisms may contribute to rheumatoid arthritis (RA) susceptibility. We studied ETS1 rs1128334 G/A and WDFY4 rs7097397 A/G gene polymorphisms in 329 patients with RA and 697 controls in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. When the WDFY4 rs7097397 AA homozygote genotype was used as the reference group, the AG genotype was associated with a significantly increased risk for RA. In the dominant model, when the WDFY4 rs7097397 AA homozygote genotype was used as the reference group, the AG/GG genotypes were associated with a significant increased susceptibility to RA. In stratification analyses, a significantly increased risk for RA associated with the WDFY4 rs7097397 AG genotype was evident among female patients, younger patients, C-reactive protein (CRP) negative patients and both anti-cyclic citrullinated peptide antibody (ACPA) positive patients and negative patients compared with the WDFY4 rs7097397 AA genotype. These findings suggested that WDFY4 rs7097397 A/G may be associated with the risk of RA, especially among younger, female patients, CRP-negative patients and both ACPA positive and negative patients. However, our results were obtained from a moderate-sized sample, and therefore this is a preliminary conclusion. To confirm these findings, validation by a larger study from a more diverse ethnic population is needed. Full article