Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the car...Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers(TNBCs).Methods:The Cancer Genome Atlas database was used to quantify the expression of MEIOB.Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC.The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro.Patient-derived xenograft(PDX)models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.Results:We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors,especially TNBCs.Its activation was significantly associated with poor survival in breast cancer patients[overall,hazard ratio(HR)=1.90(1.16–2.06);TNBCs:HR=7.05(1.16–41.80)].In addition,we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells.Further analysis showed that MEIOB participated in DSB repair in TNBCs.However,in contrast to its function in meiosis,it mediated homologous recombination deficiency(HRD)through the activation of poly ADP-ribose polymerase(PARP)1 by interacting with YBX1.Furthermore,activated MEIOB was shown to confer sensitivity to PARP inhibitors,which was confirmed in PDX models.Conclusions:MEIOB played an oncogenic role in TNBC through its involvement in HRD.In addition,dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors,so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.展开更多
Background Understanding the genetic basis of male reproduction in mammals remains challenging.Commercial pig populations offer a unique model for studying fertility,as semen traits are routinely recorded using high-t...Background Understanding the genetic basis of male reproduction in mammals remains challenging.Commercial pig populations offer a unique model for studying fertility,as semen traits are routinely recorded using high-throughput systems.Results In a large-scale GWAS of 15 semen traits based on 286,314 ejaculates collected from 2,954 boars of a purebred pig line,we identified 10 QTL,including four loci with recessive deleterious alleles.Several lead SNPs affected multiple semen traits.For example,a SNP on SSC6 was significantly associated with distal cytoplasmic droplets and with effects on tail abnormalities and sperm motility in a follow up analysis.The allele frequencies of some loci were different in older boar's,most likely due to culling based on poor semen quality.Using WGS,we identified six missense variants in high linkage disequilibrium(LD)with lead SNPs in genes related to sperm production(e.g.,MEIOB,CFAP74 and UBE2B).Remarkably,the frequency of some alleles with predicted deleterious effects on semen traits increased between 2013 and 2019.Conclusions Our results highlight loci with major effects on semen quality,some of which are linked to functional variants in key genes involved in spermatogenesis.The information from this study can be used to select against deleterious alleles affecting semen characteristics in pigs and provides valuable insight into the genetics of mammalian male fertility.展开更多
Dear Editor,Male infertility comprises 50%of infertility cases globally,and one of the most severe forms is non-obstructive azoospermia(NOA),which affects approximately 10%–15%of infertile men.1 Genetic factors play ...Dear Editor,Male infertility comprises 50%of infertility cases globally,and one of the most severe forms is non-obstructive azoospermia(NOA),which affects approximately 10%–15%of infertile men.1 Genetic factors play an important role in the pathogenesis of NOA.Recent research progress has increasingly elucidated the pathogenesis of NOA.Multiple studies,particularly those using whole-exome sequencing,have identified an increasing number of pathogenic genes,including meiosis specific with OB-fold(MEIOB),telomere repeat binding bouquet formation protein 1(TERB1),and ubiquitin-specific peptidase 26(USP26)2–4 associated with NOA.These findings have greatly advanced our understanding of the molecular mechanisms underlying the failure of spermatogenesis.However,the genetic etiology of NOA for a considerable number of patients remains to be identified.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.81902836 and 81572602)the China Postdoctoral Science Foundation(Grant Nos.2017M610339 and 2018M630584)。
文摘Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers(TNBCs).Methods:The Cancer Genome Atlas database was used to quantify the expression of MEIOB.Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC.The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro.Patient-derived xenograft(PDX)models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.Results:We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors,especially TNBCs.Its activation was significantly associated with poor survival in breast cancer patients[overall,hazard ratio(HR)=1.90(1.16–2.06);TNBCs:HR=7.05(1.16–41.80)].In addition,we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells.Further analysis showed that MEIOB participated in DSB repair in TNBCs.However,in contrast to its function in meiosis,it mediated homologous recombination deficiency(HRD)through the activation of poly ADP-ribose polymerase(PARP)1 by interacting with YBX1.Furthermore,activated MEIOB was shown to confer sensitivity to PARP inhibitors,which was confirmed in PDX models.Conclusions:MEIOB played an oncogenic role in TNBC through its involvement in HRD.In addition,dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors,so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.
基金the GEroNIMO(Genome and Epigenome Enabled Breeding in Monogastics)project.The GEroNIMO project has received funding from the European Union’s Horizon 2020 research and innovation program under Grant Agreement No 101000236。
文摘Background Understanding the genetic basis of male reproduction in mammals remains challenging.Commercial pig populations offer a unique model for studying fertility,as semen traits are routinely recorded using high-throughput systems.Results In a large-scale GWAS of 15 semen traits based on 286,314 ejaculates collected from 2,954 boars of a purebred pig line,we identified 10 QTL,including four loci with recessive deleterious alleles.Several lead SNPs affected multiple semen traits.For example,a SNP on SSC6 was significantly associated with distal cytoplasmic droplets and with effects on tail abnormalities and sperm motility in a follow up analysis.The allele frequencies of some loci were different in older boar's,most likely due to culling based on poor semen quality.Using WGS,we identified six missense variants in high linkage disequilibrium(LD)with lead SNPs in genes related to sperm production(e.g.,MEIOB,CFAP74 and UBE2B).Remarkably,the frequency of some alleles with predicted deleterious effects on semen traits increased between 2013 and 2019.Conclusions Our results highlight loci with major effects on semen quality,some of which are linked to functional variants in key genes involved in spermatogenesis.The information from this study can be used to select against deleterious alleles affecting semen characteristics in pigs and provides valuable insight into the genetics of mammalian male fertility.
基金supported by Fundamental Research Funds for the Central Institutes(2023GJZD01).
文摘Dear Editor,Male infertility comprises 50%of infertility cases globally,and one of the most severe forms is non-obstructive azoospermia(NOA),which affects approximately 10%–15%of infertile men.1 Genetic factors play an important role in the pathogenesis of NOA.Recent research progress has increasingly elucidated the pathogenesis of NOA.Multiple studies,particularly those using whole-exome sequencing,have identified an increasing number of pathogenic genes,including meiosis specific with OB-fold(MEIOB),telomere repeat binding bouquet formation protein 1(TERB1),and ubiquitin-specific peptidase 26(USP26)2–4 associated with NOA.These findings have greatly advanced our understanding of the molecular mechanisms underlying the failure of spermatogenesis.However,the genetic etiology of NOA for a considerable number of patients remains to be identified.
