Dual-specificity histone demethylase KIAA1718 （KDM7A） regulates neural differentiation through FGF4

histone H3 离氨酸的 Dimethylations 9 和离氨酸 27 是与抄写压抑联系的重要 epigenetic 标记。这里，我们作为为这二个镇压标记特定的新奇 histone demethylase 识别了 KIAA1718 (KDM7A ) 。用老鼠胚胎的干细胞，我们证明那 KIAA1718 表情在神经区别的早阶段增加了。基因击倒堵住的神经区别和效果被野类型的人的基因，并且不由催化地不活跃的异种救。另外， KIAA1718 的 overexpression 加速了神经区别。我们提供 KDM7A 的支持 neural 区别效果通过 FGF4 的直接 transcriptional 激活被调停的证据，一个信号分子在神经区别含有。因此，我们的学习识别了通过 FGF4 调整神经区别的双特性的 histone demethylase。

PHF8 is a histone H3K9me2 demethylase regulating rRNA synthesis

histone H3 离氨酸 9 的 Dimethylation (H3K9me2 ) 是与抄写压抑联系的一个重要 epigenetic 标记。这里，我们识别了 PHF8， JmjC-domain-containing 蛋白质，为这个镇压标记特定的 histone demethylase。Recombinant 全身的野类型蛋白质能把 methylation 从 H3K9me2 移开，但是到丙氨酸 H247A 的保存 histidine 的变化废除 demethylase 活动。Overexpressed 外长的 PHF8 是 colocalized， B23 染色。内长的 PHF8 也是有 B23 和 fibrillarin 的 colocalized，二生长得很好的核蛋白质，建议那 PHF8 在核是局部性的并且可以调整 rRNA 抄写。确实， PHF8 跳了到 rDNA 基因的倡导者区域。减少的 PHF8 击倒 rRNA 的表示，和基因的 overexpression 导致了 rRNA 的 upregulation 抄本。附随地， H3K9me2 水平在 PHF8 击倒的房间在 rDNA 基因的倡导者区域被提高并且当野类型然而并非催化地不活跃的 H247A 变异的 PHF8 是 overexpressed 时，显著地减少了。因此，我们的学习为调整 rRNA 抄写的 H3K9me2 识别了 histone demethylase。

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。

The androgen receptor in hormone-refractory prostate cancer

先进前列腺癌症对防碍发信号的雄激素受体(AR ) 的荷尔蒙治疗应答。然而，当将近所有瘤进行到，效果是短命的一荷尔蒙倔强(HR ) 说，疾病的一个致命的阶段。直觉地，因为堵住的荷尔蒙治疗或还原剂 AR 活动不在对待 HR 瘤是有效的， AR 不应该被包含。然而，仍然有一致， AR 玩在 HR 前列腺癌症(HRPC ) 的一个必要角色因为 AR 发信号在 HR 瘤仍然是功能的。发信号的 AR 能通过几机制在 HR 瘤被激活。首先，细胞内部的信号 transduction 小径的激活能敏化 AR 阉割雄激素的层次。另外，在 AR 的变化能改变 AR ligand 特性，从而允许它被非类固醇或反雄激素激活。最后，野类型的 AR 的 overexpression 敏化自己到雄激素的低集中。因此，指向 AR 发信号的药能仍然在对待 HRPC 是有效的。

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。

The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation

Interleukin(IL)17-producing T helper(Th17)cells play critical roles in the clearance of extracellular bacteria and fungi as well as the pathogenesis of various autoimmune diseases,such as multiple sclerosis,psoriasis,and ulcerative colitis.Although a global transcriptional regulatory network of Th17 cell differentiation has been mapped recently,the participation of epigenetic modifications in the differentiation process has yet to be elucidated.We demonstrated here that histone H3 lysine-27(H3K27)demethylation,predominantly mediated by the H3K27 demethylase Jmjd3,crucially regulated Th17 cell differentiation.Activation of naı¨ve CD41 T cells immediately induced high expression of Jmjd3.Genetic depletion of Jmjd3 in CD41 T cells specifically impaired Th17 cell differentiation both in vitro and in vivo.Ectopic expression of Jmjd3 largely rescued the impaired differentiation of Th17 cells in vitro in Jmjd3-deficientCD41 T cells.Importantly,Jmjd3-deficient mice were resistant to the induction of experimental autoimmune encephalomyelitis(EAE).Furthermore,inhibition of the H3K27 demethylase activity with the specific inhibitor GSK-J4 dramatically suppressed Th17 cell differentiation in vitro.At the molecular level,Jmjd3 directly bound to and reduced the level of H3K27 trimethylation(me3)at the genomic sites ofRorc,which encodes the masterTh17 transcription factorRorgt,and Th17 cytokine genes such as Il17,Il17f,and Il22.Therefore,our studies established acritical role of Jmjd3-mediatedH3K27demethylation inTh17 cell differentiation andsuggest that Jmjd3 can be a novel therapeutic target for suppressing autoimmune responses.

Knockout of glutathione peroxidase 5 down-regulates the piRNAs in the caput epididymidis of aged mice

The mammalian epididymis not only plays a fun dame ntal role in the maturati on of spermatozoa,but also provides protecti on agai nst various stressors.The foremost among these is the threat posed by oxidative stress,which arises from an imbalance in reactive oxygen species and can elicit damage to cellular lipids,proteins,and nucleic acids.In mice,the risk of oxidative damage to spermatozoa is mitigated through the expression and secretion of glutathione peroxidase 5(GPX5)as a major luminal scavenger in the proximal caput epididymidal segment.Accordingly,the loss of GPX5^-/-mediated protection leads to impaired DNA integrity in the spermatozoa of aged Gpx57 mice.To explore the underlying mechanism,we have conducted transcriptomic analysis of caput epididymidal epithelial cells from aged(13 months old)Gpx5^-/-m mice.This analysis revealed the dysregulation of several thousand epididymal mRNA transcripts,in eluding the downregulation of a subgroup of piRNA pathway gen es,in aged Gpx5^-/-mice.In agreeme nt with these fin dings,we also observed the loss of piRNAs,which potentially bind to the P-element-induced wimpy testis(PlWI)-like proteins PIWIL1 and PIWIL2.The absence of these piRNAs was correlated with the elevated mRNA levels of their putative gene targets in the caput epididymidis of Gpx5^-/-mice.Importantly,the oxidative stress response genes tend to have more targeting piRNAs,and many of them were among the top increased genes upon the loss of GPX5^-/-.Taken together,our findings suggest the existence of a previously uncharacterized somatic piRNA pathway in the mammalian epididymis and its possible invoIvement in the aging and oxidative stress-mediated responses.

JMJD3 promotes chondrocyte proliferation and hypertrophy during endochondral bone formation in mice

JMJD3(KDM6B)is an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression.However,the function of JMJD3 in vivo is not well understood.Here we show that JMJD3 is highly expressed in cells of the chondrocyte lineage,especially in prehypertrophic and hypertrophic chondrocytes,during endochondral ossification.Homozygous deletion of Jmjd3 results in severely decreased proliferation and delayed hypertrophy of chondrocytes,and thereby marked retardation of endochondral ossification in mice.Genetically,JMJD3 associates with RUNX2 to promote proliferation and hypertrophy of chondrocytes.Biochemically,JMJD3 associates with and enhances RUNX2 activity by derepression of Runx2 and Ihh transcription throughits H3K27me3 demethylase activity.These results demonstrate that JMJD3 is a key epigenetic regulator in the process of cartilage maturation during endochondral bone formation.