Human molecular genetics最新文献_第4页

LRP8 inhibits bladder cancer cell ferroptosis by activating the Wnt/β-catenin-SCD1 positive feedback loop.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-24 DOI: 10.1093/hmg/ddaf024

Yong Zhao, Guohong Shi, Xiang Huang, Zhongyuan Zhang, Kaijun Liao, Hao Xiong, Zhiqiang Feng, Shihui Mao, Xu Zhang

{"title":"LRP8 inhibits bladder cancer cell ferroptosis by activating the Wnt/β-catenin-SCD1 positive feedback loop.","authors":"Yong Zhao, Guohong Shi, Xiang Huang, Zhongyuan Zhang, Kaijun Liao, Hao Xiong, Zhiqiang Feng, Shihui Mao, Xu Zhang","doi":"10.1093/hmg/ddaf024","DOIUrl":"https://doi.org/10.1093/hmg/ddaf024","url":null,"abstract":"Background: Advanced bladder cancer (bc) patients often have poor prognoses due to issues such as recurrence and drug resistance. The discovery of ferroptosis has opened new avenues for bc treatment; however, the specific regulatory mechanisms remain to be explored. This study aimed to investigate the mechanisms influencing ferroptosis in bc cells, with a particular focus on the role of low-density lipoprotein receptor-related protein 8 (LRP8).Methods: We utilized reverse transcription-quantitative polymerase chain reaction and western blot to assess the expression of LRP8 in bc cells, activation of the Wnt/β-catenin signaling pathway, and the expression of genes related to fatty acid synthesis. We measured changes in ferroptosis levels by evaluating mitochondrial membrane potential, Fe2+, malondialdehyde, and reactive oxygen species levels. A xenograft mouse model was employed to validate the impact of LRP8 on bc progression.Results: Cell experiments demonstrated a significant upregulation of LRP8 expression in bc cells. Knockdown of LRP8 induced ferroptosis in bc cells, a process directly triggered by the inhibition of the Wnt/β-catenin signaling pathway. Activation of the Wnt/β-catenin signaling pathway mediated by LRP8 upregulated the expression of stearoyl-CoA desaturase 1 (SCD1), subsequently leading to the suppression of ferroptosis. In vivo experiments indicated that LRP8 knockdown significantly impaired bc growth, accompanied by inhibition of the Wnt/β-catenin-SCD1 axis.Conclusion: LRP8 mediates the synthesis of monounsaturated fatty acids through the Wnt/β-catenin-SCD1 positive feedback loop, thereby inhibiting ferroptosis in bc cells. These findings provide a promising target for the regulation of ferroptosis in bc cells.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The impact of TRPV4 pathogenic mutations on barrier integrity.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-18 DOI: 10.1093/hmg/ddaf023

Gabriela Sampaio, Taylor Ismaili, Ali Torkamani, David G Breckenridge, Ashley Katana, David B Goldstein, Sunil Sahdeo

引用次数: 0

A TAF11 variant contributes to non-syndromic cleft lip only through modulating neural crest cell migration. TAF11变异仅通过调节神经嵴细胞迁移来促进非综合征性唇裂。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddae188

Dandan Li, Yu Tian, Barbara Vona, Xin Yu, Junyan Lin, Lan Ma, Shu Lou, Xiaofeng Li, Guirong Zhu, Yuting Wang, Mulong Du, Lin Wang, Yongchu Pan

{"title":"A TAF11 variant contributes to non-syndromic cleft lip only through modulating neural crest cell migration.","authors":"Dandan Li, Yu Tian, Barbara Vona, Xin Yu, Junyan Lin, Lan Ma, Shu Lou, Xiaofeng Li, Guirong Zhu, Yuting Wang, Mulong Du, Lin Wang, Yongchu Pan","doi":"10.1093/hmg/ddae188","DOIUrl":"10.1093/hmg/ddae188","url":null,"abstract":"The NC_000006.12: g.34887814C>G variant in TAF11 was identified as a potential functional variant in a Chinese pedigree including two non-syndromic cleft lip only (NSCLO) cases. Applying Chromatin Immunoprecipitation (ChIP), Electrophoretic mobility shift and super-shift assays, we found that the mutant G allele recruited more STAT1 and STAT3, and increased the expression of TAF11. RNA sequencing, GO and KEGG pathway enrichment, ChIP and dual-luciferase reporter assays revealed that TAF11 downregulated CDH1 and CTNND1 in the cell adhesion pathway by binding to their promoter regions and inhibiting transcriptional activities. Alcian blue staining, time-lapse photography, whole-mount in situ hybridization, phospho-Histone H3 immunofluorescence and TUNEL assays indicated that TAF11 and taf11 overexpression (TAF11OE and taf11OE, respectively) contributed to disturbed migration of cranial neural crest cells and abnormal craniofacial development, as well as increased death and deformity rates in zebrafish. In conclusion, a functionally relevant TAF11 variant, affecting cell migration via modulating CDH1 and CTNND1, was associated with etiology of NSCLO.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"392-401"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retraction of: Protective effects of mitophagy enhancers against amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer disease. 撤回：有丝分裂促进剂对阿尔茨海默病中淀粉样β诱导的线粒体和突触毒性的保护作用。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddae149

引用次数: 0

Integrated multi-omics analysis revealed the molecular networks and potential targets of cellular senescence in Alzheimer's disease. 综合多组学分析揭示了阿尔茨海默病细胞衰老的分子网络和潜在靶点。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddae189

Yudi Xu, Shutong Liu, Zhaokai Zhou, Hongzhuo Qin, Yuyuan Zhang, Ge Zhang, Hongxuan Ma, Xinwei Han, Huimin Liu, Zaoqu Liu

{"title":"Integrated multi-omics analysis revealed the molecular networks and potential targets of cellular senescence in Alzheimer's disease.","authors":"Yudi Xu, Shutong Liu, Zhaokai Zhou, Hongzhuo Qin, Yuyuan Zhang, Ge Zhang, Hongxuan Ma, Xinwei Han, Huimin Liu, Zaoqu Liu","doi":"10.1093/hmg/ddae189","DOIUrl":"10.1093/hmg/ddae189","url":null,"abstract":"Cellular senescence (CS) is a hallmark of Alzheimer's disease (AD). However, the mechanisms through which CS contributes to AD pathogenesis remain poorly understood. We found that CS level in AD was higher compared with the healthy control group. Transcriptome-based differential expression analysis identified 113 CS-related genes in blood and 410 in brain tissue as potential candidate genes involved in AD. To further explore the causal role of these genes, an integrative mendelian randomization analysis was conducted, combining AD genome-wide association study summary statistics with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) data from blood samples, which identified five putative AD-causal genes (CENPW, EXOSC9, HSPB11, SLC44A2, and SLFN12) and 18 corresponding DNA methylation probes. Additionally, integrative analysis between eQTLs and mQTLs from blood uncovered two genes and 12 corresponding regulatory elements involved in AD. Furthermore, two genes (CDKN2B and ITGAV) were prioritized as putative causal genes in brain tissue and were validated through in vitro experiments. The multi-omics integration study revealed the potential role and underlying biological mechanisms of CS driven by genetic predisposition in AD. This study contributed to fundamental understanding of CS in AD pathogenesis and facilitated the identification of potential therapeutic targets for AD prevention and treatment.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"381-391"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integration of multiomic data identifies core-module of inherited-retinal diseases. 整合多组数据识别遗传性视网膜疾病的核心模块。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddaf001

Ajeet Singh, Rinki Ratnapriya

引用次数: 0

Functional characterization of OXTR-associated enhancers.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddaf022

Dianne Laboy Cintrón, Rory R Sheng, Nadav Ahituv

引用次数: 0

Transcriptomic analysis of human cartilage identified potential therapeutic targets for hip osteoarthritis. 人软骨转录组学分析确定了髋关节骨关节炎的潜在治疗靶点。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddae200

Jingyi Huang, Ming Liu, Andrew Furey, Proton Rahman, Guangju Zhai

{"title":"Transcriptomic analysis of human cartilage identified potential therapeutic targets for hip osteoarthritis.","authors":"Jingyi Huang, Ming Liu, Andrew Furey, Proton Rahman, Guangju Zhai","doi":"10.1093/hmg/ddae200","DOIUrl":"10.1093/hmg/ddae200","url":null,"abstract":"Cartilage degradation is the hallmark of osteoarthritis (OA). The purpose of this study was to identify and validate differentially expressed genes (DEGs) in human articular cartilage that could serve as potential therapeutic targets for hip OA. We performed transcriptomic profiling in a discovery cohort (12 OA-free and 72 hip OA-affected cartilage) and identified 179 DEGs between OA-free and OA-affected cartilage after correcting for multiple testing (P < 2.97 × 10-6). Pathway and network analyses found eight hub genes to be associated with hip OA (ASPN, COL1A2, MXRA5, P3H1, PCOLCE, SDC1, SPARC, and TLR2), which were all confirmed using qPCR in a validation cohort (36 OA-free and 62 hip OA-affected cartilage) (P < 6.25 × 10-3). Our data showed that dysregulation of extracellular matrix formation and imbalance in the proportion of collagen chains may contribute to the development of hip OA, and SDC1 could be a promising potential therapeutic target. These findings provided a better understanding of the molecular mechanisms for hip OA and may assist in developing targeted treatment strategies.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"444-453"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retraction of: Absence of ALOX5 gene prevents stress-induced memory deficits, synaptic dysfunction and tauopathy in a mouse model of Alzheimer's disease. 撤回：在阿尔茨海默病小鼠模型中，ALOX5 基因缺失可预防应激诱导的记忆缺陷、突触功能障碍和牛磺酸病变。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddae114

引用次数: 0

Q241R mutation of Braf causes neurological abnormalities in a mouse model of cardio-facio-cutaneous syndrome, independent of developmental malformations. Braf的Q241R突变导致心脏-面部-皮肤综合征小鼠模型的神经异常，独立于发育畸形。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddae196

Akira Moriya, Shin-Ichi Inoue, Fumihito Saitow, Moe Keitoku, Noato Suzuki, Etsumi Oike, Eriko Urano, Eiko Matsumoto, Hidenori Suzuki, Yoko Aoki, Hiroshi Ohnishi

{"title":"Q241R mutation of Braf causes neurological abnormalities in a mouse model of cardio-facio-cutaneous syndrome, independent of developmental malformations.","authors":"Akira Moriya, Shin-Ichi Inoue, Fumihito Saitow, Moe Keitoku, Noato Suzuki, Etsumi Oike, Eriko Urano, Eiko Matsumoto, Hidenori Suzuki, Yoko Aoki, Hiroshi Ohnishi","doi":"10.1093/hmg/ddae196","DOIUrl":"10.1093/hmg/ddae196","url":null,"abstract":"Constitutively active mutants of BRAF cause cardio-facio-cutaneous (CFC) syndrome, characterized by growth and developmental defects, cardiac malformations, facial features, cutaneous manifestations, and mental retardation. An animal model of human CFC syndrome, the systemic BrafQ241R/+ mutant mouse, has been reported to exhibit multiple CFC syndrome-like phenotypes. In this study, we analyzed the effects of Braf mutations on neural function, separately from their effects on developmental processes. To this end, we generated Braf mutant mice expressing BRAFQ241R specifically in mature excitatory neurons (n-BrafQ241R/+). We found no growth retardation or cardiac malformations in n-BrafQ241R/+ mice, indicating normal development. Behavioral analysis revealed that n-BrafQ241R/+ mice exhibited reduced home cage activity and learning disability, which were similar to those of systemic BrafQ241R/+ mice. The active form of ERK was increased in the hippocampus of n-BrafQ241R/+ mice, whereas basal synaptic transmission and synaptic plasticity in hippocampal Schaffer collateral-CA1 synapses seems to be normal. Transcriptome analysis of the hippocampal tissue revealed significant changes in the expression of genes involved in regulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway, synaptic function and memory formation. These data suggest that the neuronal dysfunction observed in the systemic CFC mouse model is due to the disruption of homeostasis of the RAS/MAPK signaling pathway by the activated Braf mutant after maturation, rather than abnormal development of the brain. A similar mechanism may be possible in human CFC syndrome.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"418-434"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0