查看更多>>摘要：Coiled-coil domain containing 3(CCDC3,also called Favine)is a highly conserved protein initially identified as a protein secreted from adipocytes and endothelial cells in the vascular system with endocrine-like functions.Recently,CCDC3 was also found to function as a nuclear tumor suppressor in breast cancers.Although it is still understudied,CCDC3,since its discovery,has been shown to play multiple roles in lipid metabolism,fatty liver,abdominal obesity,anti-inflammation,atherosclerosis,and cancer.This essay is thus composed to offer an overview of these extracellular endocrine-like and intracellular(nuclear)functions of CCDC3.We also discuss the possible underlying cellular and molecular mechanisms of CCDC3,the implications for clinical translation,and the remaining puzzles about this special molecule.
查看更多>>摘要：The organized three-dimensional chromosome architecture in the cell nucleus provides scaffolding for precise regulation of gene expression.When the cell changes its identity in the cell-fate decision-making process,extensive rearrangements of chromo-some structures occur accompanied by large-scale adaptations of gene expression,underscoring the importance of chromosome dynamics in shaping genome function.Over the last two decades,rapid development of experimental methods has provided unprecedented data to characterize the hierarchical structures and dynamic properties of chromosomes.In parallel,these enormous data offer valuable opportunities for developing quantitative computational models.Here,we review a variety of large-scale polymer models developed to investigate the structures and dynamics of chromosomes.Different from the underlying modeling strategies,these approaches can be classified into data-driven('top-down')and physics-based('bottom-up')categories.We discuss their contributions to offering valuable insights into the relationships among the structures,dynamics,and functions of chromosomes and propose the perspective of developing data integration approaches from different experimental technologies and multidisciplinary theoretical/simulation methods combined with different modeling strategies.
查看更多>>摘要：Chemoresistance is a primary cause of treatment failure in pancreatic cancer.Identifying cell surface markers specifically expressed in chemoresistant cancer cells(CCCs)could facilitate targeted therapies to overcome chemoresistance.We performed an antibody-based screen and found that TRA-1-60 and TRA-1-81,two'stemness'cell surface markers,are highly enriched in CCCs.Further-more,TRA-1-60+/TRA-1-81+ cells are chemoresistant compared to TRA-1-60-/TRA-1-81-cells.Transcriptome profiling identified UGT1A10,shown to be both necessary and sufficient to maintain TRA-1-60/TRA-1-81 expression and chemoresistance.From a high-content chemical screen,we identified Cymarin,which downregulates UGT1A10,eliminates TRA-1-60/TRA-1-81 expression,and increases chemosensitivity both in vitro and in vivo.Finally,TRA-1-60/TRA-1-81 expression is highly specific in primary cancer tissue and positively correlated with chemoresistance and short survival,which highlights their potentiality for targeted therapy.Therefore,we discovered a novel CCC surface marker regulated by a pathway that promotes chemoresistance,as well as a leading drug candidate to target this pathway.
查看更多>>摘要：A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause.Here,we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes.We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing(WES)data available for 146 of these patients.The coverage of targeted gene panel sequencing was significantly higher than that of WES.The diagnostic yield in patients sequenced by the panel was 32.9%with subsequent WES leading to three additional diagnoses with two novel genes.In total,178 variants in 83 genes were detected in 146 patients by targeted sequencing.Three of the 178 variants were missed by WES,although the WES-only approach had a similar diagnostic yield.For the 335 samples only receiving targeted sequencing,the diagnostic yield was 32.2%.In conclusion,taking into account the lower costs,shorter turnaround time,and higher quality of data,targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES.Therefore,this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.
查看更多>>摘要：In mitosis,accurate chromosome segregation depends on the kinetochore,a supermolecular machinery that couples dynamic spin-dle microtubules to centromeric chromatin.However,the structure-activity relationship of the constitutive centromere-associated network(CCAN)during mitosis remains uncharacterized.Building on our recent cryo-electron microscopic analyses of human CCAN structure,we investigated how dynamic phosphorylation of human CENP-N regulates accurate chromosome segregation.Our mass spectrometric analyses revealed mitotic phosphorylation of CENP-N by CDK1,which modulates the CENP-L-CENP-N interaction for accurate chromosome segregation and CCAN organization.Perturbation of CENP-N phosphorylation is shown to prevent proper chromosome alignment and activate the spindle assembly checkpoint.These analyses provide mechanistic insight into a previously undefined link between the centromere-kinetochore network and accurate chromosome segregation.
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