查看更多>>摘要：Histone H3 Lys36(H3K36)methylation and its associated modifiers are crucial for DNA double-strand break(DSB)repair,but the me-chanism governing whether and how different H3K36 methylation forms impact repair pathways is unclear.Here,we unveil the distinct roles of H3K36 dimethylation(H3K36me2)and H3K36 trimethylation(H3K36me3)in DSB repair via non-homologous end joining(NHEJ)or homologous recombination(HR).Yeast cells lacking H3K36me2 or H3K36me3 exhibit reduced NHEJ or HR efficiency.yKu70 and Rfa1 bind H3K36me2-or H3K36me3-modified peptides and chromatin,respectively.Disrupting these interactions impairs yKu70 and Rfa1 recruit-ment to damaged H3K36me2-or H3K36me3-rich loci,increasing DNA damage sensitivity and decreasing repair efficiency.Conversely,H3K36me2-enriched intergenic regions and H3K36me3-enriched gene bodies independently recruit yKu70 or Rfa1 under DSB stress.Importantly,human KU70 and RPA1,the homologs of yKu70 and Rfa1,exclusively associate with H3K36me2 and H3K36me3 in a con-served manner.These findings provide valuable insights into how H3K36me2 and H3K36me3 regulate distinct DSB repair pathways,highlighting H3K36 methylation as a critical element in the choice of DSB repair pathway.
查看更多>>摘要：The adaptation of insects to environments relies on a sophisticated set of behaviors controlled by molecular and physiological processes.Over the past several decades,accumulating studies have unveiled the roles of non-coding RNAs(ncRNAs)in regulating insect behaviors.ncRNAs assume particularly pivotal roles in the behavioral plasticity of insects by rapidly responding to environmental stimuli.ncRNAs also contribute to the maintenance of homeostasis of insects by fine-tuning the expression of target genes.However,a comprehensive review of ncRNAs'roles in regulating insect behaviors has yet to be conducted.Here,we present the recent progress in our understanding of how ncRNAs regulate various insect behaviors,including flight and movement,social behavior,reproduction,learning and memory,and feeding.We refine the intricate mechanisms by which ncRNAs modulate the function of neural,motor,reproductive,and other physiological systems,as well as gene expression in insects like fruit flies,social insects,locusts,and mosquitos.Furthermore,we discuss potential avenues for future studies in ncRNA-mediated insect behaviors.
查看更多>>摘要：Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation.It occurs when multiple redox-active enzymes are ectopically expressed or show abnormal function.Hence,the precise regulation of ferroptosis-related molecules is mediated across multiple levels,including transcriptional,posttranscriptional,translational,and epigenetic levels.N6-methyladenosine(m6 A)is a highly evolutionarily conserved epigenetic modification in mammals.The m6A modification is commonly linked to tumor pro-liferation,progression,and therapy resistance because it is involved in RNA metabolic processes.Intriguingly,accumulating evidence suggests that dysregulated ferroptosis caused by the m6A modification drives tumor development.In this review,we summarized the roles of m6A regulators in ferroptosis-mediated malignant tumor progression and outlined the m6A regulatory mechanism involved in ferroptosis pathways.We also analyzed the potential value and application strategies of targeting m6A/ferroptosis pathway in the clinical diagnosis and therapy of tumors.
查看更多>>摘要：Detecting genes that affect specific traits(such as human diseases and crop yields)is important for treating complex diseases and improving crop quality.A genome-wide association study(GWAS)provides new insights and directions for understanding complex traits by identifying important single nucleotide polymorphisms.Many GWAS summary statistics data related to various complex traits have been gathered recently.Studies have shown that GWAS risk loci and expression quantitative trait loci(eQTLs)often have a lot of overlaps,which makes gene expression gradually become an important intermediary to reveal the regulatory role of GWAS.In this review,we review three types of gene-trait association detection methods of integrating GWAS summary statistics and eQTLs data,namely colocalization methods,tran-scriptome-wide association study-oriented approaches,and Mendelian randomization-related methods.At the theoretical level,we dis-cussed the differences,relationships,advantages,and disadvantages of various algorithms in the three kinds of gene-trait association detection methods.To further discuss the performance of various methods,we summarize the significant gene sets that influence high-density lipoprotein,low-density lipoprotein,total cholesterol,and triglyceride reported in 16 studies.We discuss the performance of various algorithms using the datasets of the four lipid traits.The advantages and limitations of various algorithms are analyzed based on experi-mental results,and we suggest directions for follow-up studies on detecting gene-trait associations.
查看更多>>摘要：CFIRL is a long noncoding RNA(lncRNA),we previously identified as the most significantly upregulated lncRNA in the failing hearts of patients with dilated cardiomyopathy(DCM).In this study,we determined the function of CFIRL and its role in DCM.Real-time polymerase chain reaction and in situ hybridization assays revealed that CFIRL was primarily localized in the nucleus of cardiac fibroblasts and robustly increased in failing hearts.Global knockdown or fibroblast-specific knockout of CFIRL attenuated transverse aortic constriction(TAC)-induced cardiac dysfunction and fibrosis in vivo.Overexpression of CFIRL in vitro promoted fibroblast proliferation and aggravated an-giotensin Ⅱ-induced differentiation to myofibroblasts.CFIRL knockdown attenuated these effects.Mechanistically,RNA pull-down assay and gene expression profiling revealed that CFIRL recruited ENO1,a newly identified noncanonical transcriptional factor,to activate IL-6 transcription.IL-6 exerted a paracrine effect on cardiomyocytes to promote cardiac hypertrophy,which can be prevented by CFIRL knockdown.These findings uncover the critical role of CFIRL,a fibroblast-associated lncRNA,in heart failure by facilitating crosstalk between fibroblasts and cardiomyocytes.CFIRL knockdown might be a potent strategy to prevent cardiac remodeling in heart failure,particularly in DCM.
查看更多>>摘要：Metabolically healthy obesity refers to obese individuals who do not develop metabolic disorders.These people store fat in subcutaneous adipose tissue(SAT)rather than in visceral adipose tissue(VAT).However,the molecules participating in this specific scenario remain elusive.Rab18,a lipid droplet(LD)-associated protein,mediates the contact between the endoplasmic reticulum(ER)and LDs to facilitate LD growth and maturation.In the present study,we show that the protein level of Rab18 is specifically upregulated in the SAT of obese people and mice.Rab18 adipocyte-specific knockout(Rab1 8 AKO)mice had a decreased volume ratio of SAT to VAT compared with wild-type mice.When subjected to high-fat diet(HFD),Rab1 8 AKO mice had increased ER stress and inflammation,reduced adiponectin,and decreased triacylglycerol(TAG)accumulation in SAT.In contrast,TAG accumulation in VAT,brown adipose tissue(BAT)or liver of Rab18 AKO mice had a moderate increase without ER stress stimulation.Rab18 AKO mice developed insulin resistance and systematic in-flammation.Rab18 AKO mice maintained body temperature in response to acute and chronic cold induction with a thermogenic SAT,similar to the counterpart mice.Furthermore,Rab1 8-deficient 3T3-L1 adipocytes were more prone to palmitate-induced ER stress,in-dicating the involvement of Rab18 in alleviating lipid toxicity.Rab1 8 AKO mice provide a good animal model to investigate metabolic disorders such as impaired SAT.In conclusion,our studies reveal that Rab18 is a key and specific regulator that maintains the proper functions of SAT by alleviating lipid-induced ER stress.
查看更多>>摘要：Liver disease,a major health concern worldwide,is a serious and progressive disorder.Herein,we not only established a mouse model of DEN+CCl4-induced primary liver disease but also collected clinical human samples to investigate longitudinal alterations in the gut my-cobiome.As liver disease advanced,gut integrity was disrupted,and the mycobiota was disturbed in the mouse models.The metabolites associated with hepatocellular carcinoma(HCC)differed from those associated with the cirrhotic phase as follows:levels of stercobilin and aflatoxin B1 dialcohol were reduced,while levels of triterpenoids,bafilomycin A1,and DHEA were increased in the HCC group.The abundance of the phylum Chytridiomycota increased as the chronic liver disease progressed and was then replaced by the phylum Asco-mycota in HCC.Based on the results from clinical human samples,the genus Candida(Ascomycota)(in humans)and the genus Kazachstania(Ascomycota)(in mice)occupied a dominant position in the HCC group,while other fungi were depleted.The increased abundance of C.albicans and depletion of S.cerevisiae may be hallmarks of the progression of liver cirrhosis to early HCC.Moreover,the administration of C.albicans and S.cerevisiae in the LC-HCC progression could accelerate or retard the progression of HCC.Therefore,gut fungi have the potential to serve as a noninvasive clinical biomarker and even a treatment method.
查看更多>>摘要：Metastasis accounts for the major cause of colorectal cancer(CRC)related mortality due to the lack of effective treatments.In this study,we integrated the single-cell RNA-seq(scRNA-seq)and bulk RNA-seq data and identified the transcriptional coactivator SUB1 homolog(Sac-Saccharomyces cerevisiae)/PC4(positive cofactor 4)associated with CRC metastasis.Elevated SUB1 expression was correlated with advanced tumor stage and poor survival in CRC.In vivo and vitro assays showed that SUBI depletion could inhibit the invasive and metastatic abilities of CRC cells.SUB1 activated NF-κB signaling and its transcriptional target genes CXCL1 and CXCL3 to drive CRC metastasis.Mechanistically,SUB1 integrated with the E3 ubiquitin-protein ligase UBR5 and increased its protein level in CRC cells.Subsequently,the increased UBR5 mainly mediated Lys11-linked polyubiquitination and degradation of NF-κB negative regulator UBXN1,thus to activate the NF-κB signaling.Overall,our study demonstrated that SUB1 promoted CRC progression by modulating UBR5/UBXN1 and activating NF-κB signaling,pro-viding a new therapeutic strategy for treating metastatic CRC through targeting SUB1.
查看更多>>摘要：Generally shortened 3'UTR due to alternative polyadenylation(APA)is widely observed in cancer,but its regulation mechanisms for cancer are not well characterized.Here,with profiling of APA in colorectal cancer tissues and poly(A)signal editing,we firstly identified that the shortened 3'UTR of CTNNIBP1 in colorectal cancer promotes cell proliferation and migration.We found that liquid-liquid phase separation(LLPS)ofPABPN1 is reduced albeit with higher expression in cancer,and the reduction of LLPS leads to the shortened 3'UTR of CTNNBIP1 and promotes cell proliferation and migration.Notably,the splicing factor SNRPD2 upregulated in colorectal cancer,can interact with glutamic-proline(EP)domain of PABPN1,and then disrupt LLPS of PABPN1,which attenuates the repression effect of PABPN1 on the proximal poly(A)sites.Our results firstly reveal a new regulation mechanism of APA by disruption of LLPS of PABPN1,suggesting that regulation of APA by interfering LLPS of 3'end processing factor may have the potential as a new way for the treatment of cancer.
查看更多>>摘要：Ovarian cancer is the most lethal and aggressive gynecological cancer with a high recurrencerate and is often diagnosed late.In ovarian cancer,multiple metabolic enzymes of lipid metabolism are abnormally expressed,resulting in metabolism disorder.As a characteristic pathway in polyunsaturated fatty acid(PUFA)metabolism,arachidonic acid(AA)metabolism is disturbed in ovarian cancer.Therefore,we established a 10-gene signature model to evaluate the prognostic risk of PUFA-related genes.This 10-gene signature has strong robustness and can play a stable predictive role in datasets of various platforms(TCGA,ICGC,and GSE17260).The high association between the risk subgroups and clinical characteristics indicated a good performance of the model.Our data further indicated that the high expression of LTA4H was positively correlated with poor prognosis in ovarian cancer.Deficiency of LTA4H enhanced sensitivity to Cisplatin and modified the characteristics of immune cell infiltration in ovarian cancer.Additionally,our results indicate that CCL5 was involved in the aberrant metabolism of the AA/LTA4H axis,which contributes to the reduction of tumor-infiltrating CD8+T cells and immune escape in ovarian cancer.These findings provide new insights into the prognosis and potential target of LTA4H/CCL5 in treating ovarian cancer.
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