Structural insights into a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans

Histone 离氨酸 methylation 能被 JmjC 包含域的蛋白质在 sequence-state-specific 和 methylation-state-specific 举止移开。然而，底层特性怎么样，决定，酶怎么被调整，大部分是未知的。我们最近发现了那 ceKDM7A，一个哲学博士 -- 并且 JmjC 包含域的蛋白质，是为 H3K9me2 特定的 histone demethylase， H3K27me2，和 PHD 摸绑定到 H3K4me3 指南在 vivo 的 demethylation 活动。为了为酶的活动和 PHD 的功能提供结构的卓见进分子的机制，摸，我们与包含 H3K4me3， H3K9me2，和 H3K27me2 修正的各种各样的联合的单身者或二肽一起在 apo 形式并且在建筑群解决了酶的六水晶结构。结构显示 H3K9me2 和 H3K27me2 以一种类似的方式与 ceKDM7A 交往，并且肽绑定特性被特定的相互作用的一个网络决定。结构的几何测量也揭示了与 PHD 手指和 H3K9me2 界限联系到 JmjC 领域的那 H3K4me3 从二个分开的分子，建议 trans-histone 肽绑定机制。因此，我们的全身的结构的研究重要地由催化领域而且更多揭示底层识别不仅，为 H3K9me2 和 H3K27me2 的 ceDKM7A 的双特性的分子的机制。

Coordinated regulation of active and repressive histone methylations by a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans

H3K9me2 和 H3K27me2 是与抄写压抑联系的重要 epigenetic 标记，当 H3K4me3 与抄写激活被联系时。活跃、压抑的 histone methylations 以一种互相独占的方式散布，这被显示出，但是内在的机制糟糕被理解。这里，我们识别了 ceKDM7A，一个哲学博士(植物 homeodomain )- 并且 JmjC 包含域的蛋白质，为 H3K9me2 和 H3K27me2 特定的 histone demethylase。我们进一步证明 ceKDM7A 的 PHD 领域在染色体宽的水平绑了 H3K4me3 和与 ceKDM7A co 局部性的 H3K4me3。到 H3K4me3 的 PHD 域绑定的混乱在 vivo 减少了 demethylase 活动，并且 ceKDM7A 的损失减少了它的联系目标基因的表达式。这些结果显示 ceKDM7A 被招募到倡导者到 demethylate H3K9me2 和 H3K27me2 并且通过 PHD 领域的绑定激活基因表示到 H3K4me3。因此，我们的学习识别双特性的 histone demethylase 并且提供新奇卓见进 histone methylation 的规定。

Comprehensive molecular profiling of extrahepatic cholangiocarcinoma in Chinese population and potential targets for clinical practice

Background:Cholangiocarcinoma(CCA)is a diverse group of malignancies arising from the intra-or extrahepatic biliary epithelium and characterized by its late diagnosis and fatal outcome.Extrahepatic cholangiocarcinoma(ECC)accounts for 90%of CCA.However,little is known about the comprehensive genomic alterations of ECC in Chinese population for providing clinical managements especially targeted therapy.Methods:Comprehensive genomic profiling(CGP)was performed with next generation sequencing panel on paraffin-embedded tumor from a cohort of 80 Chinese ECC patients.Results:The most frequently altered genes were TP53(68%),KRAS(46%),SMAD4(22%),ARID1A(20%)and CDKN2A(19%).Mutual exclusivity was observed between multiple genes including ARID1A:TP53,KRAS:LRP1B and NF2:TP53.Genetic alterations with potential therapeutic implications were identified in 43%of patients.The top three actionable alterations include CDKN2A(n=11),BRAF(n=5)and ERBB2(n=4).Potentially actionable alterations were mainly enriched in the G1-S transition,homologous recombination repair,MAPK/ERK pathway.Conclusions:This is the largest data set of ECC cases providing a comprehensive view on genetic alterations in Chinese population which differs significantly from a US cohort,and indicates the potential clinical implications for targeted therapies.

PGC-1α overexpression promotes mitochondrial biogenesis to protect auditory cells against cisplatin-induced cytotoxicity

Cisplatin(CDDP)-induced ototoxicity is one of the common adverse effects of cisplatin chemotherapy.Thus far,effective approaches for attenuating hearing loss are unavailable in clinical practice.Mitochondrial biogenesis acts as a master element of mitochondrial health and is necessary for mitochondrial quality control.The current study examined whether mitochondrial biogenesis is involved in CDDP-induced ototoxicity.Herein,we showed that CDDP damaged mitochondrial function and caused death of House Ear Institute-Organ of Corti 1(HEI-OC1)cells by impairing mitochondrial biogenesis.Moreover,overexpression of peroxisome proliferatoractivated receptor-g coactivator-1a,a key factor in mitochondrial biogenesis,promoted mitochondrial biogenesis in HEI-OC1 cells and protected them against CDDP-induced cytotoxicity.These findings suggest that mitochondrial biogenesis is involved in the pathology of CDDP cytotoxicity of HEI-OC1 cells,and activation of peroxisome proliferator-activated receptor-g coactivator-1a can be considered a potential therapeutic strategy to attenuate CDDP-mediated ototoxicity.