Loss of Mettl3 enhances liver tumorigenesis by inducing hepatocyte dedifferentiation and hyperproliferation.

While a few works have shown that Mettl3 plays oncogenic roles in hepatocellular carcinoma (HCC), its function in early HCC tumorigenesis remains unclear. In Mettl3flox/flox; Alb-Cre knockout mice, Mettl3 loss leads to aberrant hepatocyte homeostasis and liver damage. Importantly, Mettl3 deletion dramatically accelerates liver tumorigenesis in various HCC mouse models. Depletion of Mettl3 in adult Mettl3flox/flox mice through TBG-Cre administration also enhances liver tumor development, while overexpression of Mettl3 inhibits hepatocarcinogenesis. Mechanistically, aggravated tumorigenesis upon Mettl3 deletion is a consequence of hepatocyte dedifferentiation and hyperproliferation via m6A-mediated modulation on Hnf4α and cell cycle genes. In contrast, by using Mettl3flox/flox; Ubc-Cre mice, depletion of Mettl3 in established HCC ameliorates tumor progression. Additionally, Mettl3 is overexpressed in HCC tumors compared with adjacent non-tumor tissues. The present findings define a tumor-suppressive role of Mettl3 in liver tumorigenesis, indicating its potentially opposite stage-dependent functions in HCC initiation versus progression.

Corrigendum: Assessing the Function of the ZFP90 Variant rs1170426 in SLE and the Association Between SLE Drug Target and Susceptibility Genes.

[This corrects the article DOI: 10.3389/fimmu.2021.611515.].

Assessing the Function of the ZFP90 Variant rs1170426 in SLE and the Association Between SLE Drug Target and Susceptibility Genes.

A genome-wide association study (GWAS) has discovered that a polymorphism in the ZFP90 gene is associated with systemic lupus erythematosus (SLE). In this study, we explored the candidate function of a ZFP90 variant (rs1170426) in the context of SLE and detected the relationship between SLE susceptible genes and SLE drug target genes. First, we investigated the regulatory role of rs1170426 on ZFP90 expression by expression quantitative trait loci (eQTL) analysis in peripheral blood mononuclear cells (PBMCs), T, B, and monocytes cells and annotated the regulatory function of rs1170426 using bioinformatic databases. Second, we compared the case-control difference in ZFP90 expression levels. Third, we analyzed the association of genotype and ZFP90 expression levels with SLE clinical characters. Last, we showed the interaction of SLE susceptibility genes with SLE drug target genes. Subjects with the risk allele "C" of rs1170426 had lower expression levels of ZFP90 in PBMCs (P = 0.006) and CD8+ T cells (P = 0.003) from controls. SLE cases also had lower expression levels compared with controls (P = 2.78E-9). After correction for multiple testing, the ZFP90 expression levels were related to serositis (FDR p = 0.004), arthritis (FDR p = 0.020), hematological involvement (FDR p = 0.021), and increased C-reactive protein (CRP) (FDR p = 0.005) in cases. Furthermore, the SLE susceptible genes and the recognized SLE drug target genes were more likely to act upon each other compared with non-SLE genetic genes (OR = 2.701, P = 1.80E-5). These findings suggest that ZFP90 might play a role in the pathogenesis of SLE, and SLE genetics would contribute to therapeutic drug discovery.

Combined coagulation/decantation-ozone/hydrogen peroxide-biological aerated filter process for advanced treatment of bio-treated leachate from Chinese herbal medicine residue.

To reach discharge limit, further treatment of bio-treated leachate from Chinese herbal medicine residue (BLCHMR) was very imperative. In this study, performance of combined coagulation/decantation-ozone/hydrogen peroxide (O3/H2O2)-biological aerated filter (BAF) technology used to further treat BLCHMR was investigated with pilot-scale experiment. Under optimal conditions, the COD (40-44 mg/L) and color (13-17 time) in treated BLCHMR indicated that combined process can efficiently treat BLCHMR. O3/H2O2 had good performance not only in mineralization and decomposing of organic matter but also in decolorization of BLCHMR. For dissolved organic matter (DOM), O3/H2O2 reacted with non-biodegradable fraction preferentially and oxidized different molecular weight (MW) fractions equally. O3/H2O2-BAF generated more higher MW DOM (namely F2 fraction) than BAF alone. Meanwhile, O3/H2O2 mainly influenced the amount and biodegradability on DOM but not the removal rate on DOM. Accordingly, the helpful influence on O3/H2O2 perhaps can be owed to the generalized influence on DOM but not the specific influence on improved biodegradability. Finally, inspiring (namely very low) cost (respectively, 0.3419 $/per ton bio-treated leachate and 0.5766 $/Kg COD removed) was achieved in the combined process.

The decreased expression of IKBKE in systemic lupus erythematosus.

OBJECTIVE: The IKBKE has been proven to be associated with systemic lupus erythematosus (SLE) in a genome-wide association study (GWAS) conducted by our group. The objective of the recent study is to investigate the contribution of IKBKE functional variants (rs2297550) to SLE. METHODS: We detected the regulatory effect of rs2297550 on IKBKE expression by expression quantitative trait loci (eQTL) study. Then, we investigated the differences of IKBKE mRNA expression levels in peripheral blood mononuclear cells (PBMCs) between 135 SLE patients and 130 healthy controls using quantitative real-time PCR (qRT-PCR). We further analyzed the association of SLE clinical characteristics with IKBKE mRNA expression and rs2297550 polymorphisms. RESULTS: The results of eQTL indicated the genotype "GG" of single-nucleotide polymorphism (SNP) rs2297550 was associated with lower expression levels of IKBKE (P = 0.022) in normal controls. Compared with the healthy control group, the expression levels of IKBKE mRNA in patients with SLE were significantly decreased (P = 2.32 × 10-12). In clinical characteristics, we found that IKBKE mRNA expression levels were associated with vasculitis (P = 0.015) and increased C-reactive protein (CRP) (P = 0.021) in SLE patients. CONCLUSION: In this study, we not only detected that the variant rs2297550 of IKBKE may be closely related to SLE, but also proposed functional hypotheses for the association signals. Key Points • The rs2297550 is located in a region with transcriptional regulatory function and may regulate the expression of IKBKE via these regulatory elements. • The genotype "GG" of SNP rs2297550 was associated with lower expression levels of IKBKE. • The expression of IKBKE mRNA was decreased in SLE patients compared with healthy controls. • IKBKE contributes to the clinical characteristics of SLE.

Exome-Wide Rare Loss-of-Function Variant Enrichment Study of 21,347 Han Chinese Individuals Identifies Four Susceptibility Genes for Psoriasis.

Most psoriasis-related genes or loci identified by GWAS represent common clusters and are located in noncoding regions of the human genome, providing only limited evidence for the roles of rare coding variants in psoriasis. Two exome-wide case-control genotyping data sets (11,245 cases and 11,177 controls) were obtained from our previous study. Quality controls were established for each data set, and the markers remaining in each set were annotated using ANNOVAR. Gene-based analysis was performed on the annotation results. A total of 250 and 35 genes in the Exome_Fine and Exome_Asian array cohorts, respectively, exceeded the threshold (P < 4.43 × 10-6). Merged gene-based analysis was then conducted on the same set of SNPs from seven genes common to both arrays, and the chi-square test was used to confirm all gene-based results. Ultimately, four susceptibility genes were identified: BBS7 (Pcombine = 1.38 × 10-29), GSTCD (Pcombine = 8.35 × 10-47), LIPK (Pcombine = 1.02 × 10-19), and PPP4R3B (Pcombine = 1.79 × 10-33). This study identified four susceptibility genes for psoriasis via a gene-based method using rare variants, contributing to our understanding of the pathogenesis of psoriasis.

JAK2 and PTPRC mRNA expression in peripheral blood mononuclear cells from patients with systemic lupus erythematosus.

In this study, we aimed to explore the expression levels of JAK2 and PTPRC in peripheral blood mononuclear cells (PBMCs) from SLE patients and controls, detect the effects of SLE activity on genes mRNA expression, and find the association between genes mRNA expression and clinical manifestations of patients. We performed quantitative real-time PCR (qRT-PCR) to test differences in the expression levels of JAK2 and PTPRC in PBMCs extracted from 135 patients with SLE and 130 healthy controls. Furthermore, we detected the regulatory effect of SNPs on gene expression by expression quantitative trait loci (eQTL). We also tested whether the genes mRNA expression was affected with the SLE activity and analyzed the relationship between genes mRNA expression and clinical manifestations of patients. The mRNA expression levels of JAK2 in SLE patients were significantly higher than those in healthy controls (P = 0.005), and PTPRC mRNA expression levels were significantly decreased (P < 0.001). However, no other statistical significance was detected. We found that the elevated JAK2 mRNA expression and the decreased PTPRC mRNA expression may play suggestive roles in the pathogenesis of SLE.Key Points• The JAK2 mRNA expression levels in SLE patients were significantly higher than those in healthy controls.• The PTPRC mRNA expression levels in SLE were decreased.• JAK2 and PTPRC mRNA expression may play suggestive roles in the pathogenesis of SLE.

The association of the UHRF1BP1 gene with systemic lupus erythematosus was replicated in a Han Chinese population from mainland China.

Single-nucleotide polymorphisms (SNPs) in the UHRF gene have been shown to be associated with systemic lupus erythematosus (SLE) in European and Hong Kong Chinese, but statistically significant evidence for association has not been found in a mainland Han Chinese population. Therefore, we selected SNP rs13205210 located in UHRF1BP1 as a candidate association from our previously published genome-wide association study (GWAS) data of SLE (1,047 cases and 1,205 controls from a mainland Han Chinese population) to explore the association between the UHRF1BP1 gene and SLE. We conducted a large-scale replication study in an additional independent sample of 3,509 cases and 8,246 controls from a mainland Han Chinese population. Real-time PCR was used to determine gene expression differences in peripheral blood mononuclear cells (PBMCs) from cases and controls. As a result, we replicated the association between the UHRF1BP1 gene and SLE (rs13205210, missense, Pmeta  = 2.26E-17, odds ratio = 1.41) by a meta-analysis of our previous GWAS and this replication study involving a total of 4,556 cases and 9,451 controls. The UHRF1BP1 mRNA expression level in PBMCs was significantly decreased in patients with SLE compared with that in healthy controls. SNP rs13205210 exhibited an expression quantitative trait loci effect on the UHRF1BP1 gene in PBMCs from patients. In conclusion, this study not only suggests that the UHRF1BP1 gene was associated with SLE in a mainland Han Chinese population, but also implied that it might be a common genetic factor contributing to SLE susceptibility in multiple populations.

DNA methylation profile of psoriatic skins from different body locations.

Aim: To understand whether the anatomical location of origin plays a role in shaping the DNA methylation (DNAm) landscape of psoriatic skins. Patients & methods: A number of 108 psoriatic and 57 control skin samples were grouped based on their anatomical locations. Two group t-tests were used to identify those differentially methylated sites and regions. Target region methylation loci were validated by bisulfate conversion sequencing. The correlations of DNAm with pathological features, DNAm and gene expression were also interrogated. Results: Our analysis revealed 315 location-specific differentially methylated sites for back, 291 for the extremities and 801 for abdomen. Moreover, we observed that the extremity-specific loci cg21942490 located on HOXA9 is associated with hyperkeratosis. We further observed that HOXA5 and KIAA1949 are differential methylation regions. Conclusion: Our study shown evidence of anatomical location-dependent DNAm pattern in psoriasis skins, and thus provided new insights into the pathogenesis of this disease.

Noninvasive analysis of skin proteins in healthy Chinese subjects using an Orbitrap Fusion Tribrid mass spectrometer.

OBJECTIVE: The objective of this study was to perform noninvasive analysis of skin proteins in a healthy Chinese population using label-free nanoflow liquid chromatography-mass spectrometry (nLC-MS). MATERIALS AND METHODS: Five consecutive tape strippings were obtained from the volar forearm skin of healthy Chinese subjects. Proteins were extracted, and trypsin-digested peptides were analyzed by a nanochromatography instrument coupled to an Orbitrap Fusion Tribrid mass spectrometer. Data-dependent acquisition allowed protein identification, which was performed by using Proteome Discoverer software (v2.2). RESULTS: In this study, we identified 80 common proteins that were expressed in the skin of healthy Chinese volunteers and divided these proteins into 16 categories, including keratins, cornified envelope proteins, and enzymes associated with substance metabolism. These proteins were closely associated with multiple functions of the skin barrier. CONCLUSION: This study provides a noninvasive method to analyze healthy human epidermal proteins, which are closely associated with the skin barrier. In addition, this study provides a reference for further studies on the application of proteomic technologies to investigate the role of human epidermal proteins in health and disease.

Safety and Efficacy of Methotrexate for Chinese Adults With Psoriasis With and Without Psoriatic Arthritis.

Importance: It is necessary to determine whether psoriasis responds to methotrexate in the same manner in patients with and without psoriatic arthritis. Objective: To evaluate the effectiveness and safety of methotrexate in treating patients with psoriasis with and without psoriatic arthritis. Design, Setting, and Participants: In this prospective, single-arm, interventional study, a total of 235 patients with psoriasis, 107 without psoriatic arthritis and 128 with psoriatic arthritis who were receiving methotrexate therapy from April 1, 2015, to December 31, 2017, were recruited from the outpatient department of a hospital at a large Chinese university. There were no significant demographic or clinical differences between the subgroups with the exception of diabetes. Interventions: A 12-week course of low-dosage oral methotrexate (7.5-15 mg weekly). Main Outcomes and Measures: Changes in disease severity, adverse events, blood cell counts, and liver and renal function. Results: A total of 235 patients with psoriasis (166 male [66.0%]; mean [SD] age, 49.6 [15.1] years) received methotrexate treatment for 12 weeks. The 90% reduction from baseline Psoriasis Area Severity Index response was significantly lower in patients with psoriatic arthritis than in patients without psoriatic arthritis at week 8 (4 0f 128 [3.1%] vs 12 of 107 [11.2%]; P = .02) and week 12 (19 of 128 [14.8%] vs 27 of 107 [25.2%]; P = .049). Furthermore, the incidence of adverse events, including dizziness (12 of 128 [9.4%] vs 1 of 107 [0.9%]; P = .007), gastrointestinal symptoms (32 of 128 [25.0%] vs 13 of 107 [12.1%]; P = .01), and hepatoxicity (34 of 128 [26.6%] vs 16 of 107 [15.0%]; P = .04), was significantly higher in patients with psoriatic arthritis than in patients without psoriatic arthritis. Methotrexate-induced elevation of alanine aminotransferase levels was associated with body mass index (mean [SD] body mass index, 26 [4] in patients with [P = .04] vs 26 [4] in those without [P = .005] psoriatic arthritis) and smoking (17 of 34 [50.0%] in patients with [P = .02] vs 9 of 16 [56.3%] in those without [P = .04] psoriatic arthritis). Conclusions and Relevance: In this study, methotrexate was well tolerated and effective in treating psoriasis. It was more effective, with fewer adverse effects, in patients with psoriasis who did not have psoriatic arthritis than in patients who presented with both psoriasis and psoriatic arthritis. Therefore, methotrexate can be recommended as first-line treatment for psoriasis without arthritis.