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Increased levels of fetal hemoglobin (HbF: α2γ2) can ameliorate the clinical severity of the β‐hemoglobinopathies. Microarray analysis represents a powerful approach to identify novel genetic factors regulating the γ‐globin gene. Gene expression profiling was previously performed on 14 individuals with high or normal HbF levels to identify the genetic factors that control γ‐globin gene expression. To obtain more accurate and reliable results, our results were combined with public microarray dataset GSE22109 deposited in the Gene Expression Omnibus database. Annotation of case versus control samples was taken directly from the microarray documentation. The differentially expressed genes (DEGs) were obtained and were deeply analyzed by bioinformatics methods. Combined with our own chip expression data, potential genes HBE1, TFRC, and CSF2 were selected out for subsequent qRT‐PCR validation. A total of 184 DEGs were identified from GSE22109 and the protein–protein interaction network was constructed. Gene set enrichment analysis showed that the hematopoietic cell lineage pathway overlaps in the two datasets. HBE1, CSF2, and TFRC were confirmed by qRT‐PCR. Our results suggest novel candidate genes and pathways associated with the γ‐globin gene expression. [ABSTRACT FROM AUTHOR]

Foetal haemoglobin (HbF) plays a dominant role in ameliorating the morbidity and mortality of β-thalassaemia. A better understanding of the loci and genes involved in HbF expression would be beneficial for the treatment of β-thalassaemia major. However, the genes associated with HbF expression remain largely unknown. In this study, we first explored large-scale data sets and examined the human genome for evidence of positive natural selection to screen out single nucleotide polymorphisms (SNPs). A genetic analysis of HbF levels was conducted in a Chinese cohort of patients with β-thalassaemia to confirm the bioinformatics results. A total of 1141 subjects with β-thalassaemia were recruited. The results showed that the SNP rs11759328 in the ARHGAP18 gene was significantly associated with HbF levels (Ρ = 5.1 × 10−4). ARHGAP18 belongs to the RhoGAP family and controls angiogenesis, cellular morphology and motility. Second, after determining that ARHGAP18 was highly expressed in the human K562 cell line, we used lentiviral-mediated small interfering RNA to knock down ARHGAP18 expression and subsequently assessed cell proliferation and apoptosis using cell proliferation assays and flow cytometry, respectively. ARHGAP18 downregulation in K562 cells significantly increased HBG1/2 expression and apoptosis, but proliferation was not significantly affected in vitro. Our data suggest that ARHGAP18, which was located by the SNP rs11759328 via positive selection, plays a potential role in regulating HbF expression in β-thalassaemia and may be a promising therapeutic target. Knockout studies of ARHGAP18 warrant further investigation into its aetiology in HbF. [ABSTRACT FROM AUTHOR]

Highlights: [•] MEK1 controls both YAP expression and activity independent of ERK and Hippo pathway. [•] MEK1 regulates YAP independent of transcription. [•] MEK1 interacts and correlates with YAP expression in liver cancers. [•] MEK1 controls BTRC expression, which may serve as a novel YAP protector. [•] The interaction between YAP and MEK1 promotes tumorigenesis in liver cancer. [ABSTRACT FROM AUTHOR]

Fetal hemoglobin (HbF) plays a dominant role in ameliorating morbidity and mortality of hemoglobinopathies. The authors performed a replicated study following the genome-wide association study (GWAS) guidelines to identify the genetic mechanics that influence HbF. The authors recruited and phenotyped 312 unrelated β-thalassemia subjects. Single-nucleotide polymorphism (SNP) analysis was performed by using polymerase chain reaction (PCR)/restriction enzymes. Four independent regions of interest were identified: HBS1L-MYB intergenic region, BCL11A locus, β-globin gene cluster, and the CSNK2A1 gene. There were 10 SNPs associated with HbF levels. In addition, haplotypes of HBS1L-MYB and BCL11A were identified and showed association with HbF production. Three independent regions, including HBS1L-MYB intergenic region, BCL11A locus, and β-globin gene cluster, were associated with HbF levels. This study can significantly improve the GWAS findings in Chinese cohorts and is useful for further research in the field of common predictors of the erythropoiesis. [ABSTRACT FROM AUTHOR]