2014 Vol. 5(11)

Applications of RNA interference highthroughput screening technology in cancer biology and virology
Shan Gao, Chen Yang, Shan Jiang, Xiao-Ning Xu, Xin Lu, You-Wen He, Annie Cheung, Hui Wang
2014, 5(11): 805-815. doi: 10.1007/s13238-014-0076-6
RNA interference (RNAi) is an ancient intra-cellular mechanism that regulates gene expression and cell function. Large-scale gene silencing using RNAi highthroughput screening (HTS) has opened an exciting frontier to systematically study gene function in mammalian cells. This approach enables researchers to identify gene function in a given biological context and will provide considerable novel insight. Here, we review RNAi HTS strategies and applications using case studies in cancer biology and virology.
Tackling the tumor microenvironment: what challenge does it pose to anticancer therapies?
Fei Chen, Xinyi Qi, Min Qian, Yue Dai, Yu Sun
2014, 5(11): 816-826. doi: 10.1007/s13238-014-0097-1
Cancer is a highly aggressive and devastating disease, and impediments to a cure arise not just from cancer itself. Targeted therapies are difficult to achieve since the majority of cancers are more intricate than ever imagined. Mainstream methodologies including chemotherapy and radiotherapy as routine clinical regimens frequently fail, eventually leading to pathologies that are refractory and incurable. One major cause is the gradual to rapid repopulation of surviving cancer cells during intervals of multiple-dose administration. Novel stressresponsive molecular pathways are increasingly unmasked and show promise as emerging targets for advanced strategies that aim at both de novo and acquired resistance. We highlight recent data reporting that treatments particularly those genotoxic can induce highly conserved damage responses in non-cancerous constituents of the tumor microenvironment (TMEN). Master regulators, including but not limited to NF-kB and C/EBP-β, are implicated and their signal cascades culminate in a robust, chronic and genome-wide secretory program, forming an activated TMEN that releases a myriad of soluble factors. The damage-elicited but essentially off target and cell non-autonomous secretory phenotype of host stroma causes adverse consequences, among which is acquired resistance of cancer cells. Harnessing signals arising from the TMEN, a pathophysiological niche frequently damaged by medical interventions, has the potential to promote overall efficacy and improve clinical outcomes provided that appropriate actions are ingeniously integrated into contemporary therapies. Thereby, anticancer regimens should be well tuned to establish an innovative clinical avenue, and such advancement will allow future oncological treatments to be more specific, accurate, thorough and personalized.
Molecules and mechanisms controlling the active DNA demethylation of the mammalian zygotic genome
Jun-Yu Ma, Teng Zhang, Wei Shen, Heide Schatten, Qing Yuan Sun
2014, 5(11): 827-836. doi: 10.1007/s13238-014-0095-3
The active DNA demethylation in early embryos is essential for subsequent development. Although the zygotic genome is globally demethylated, the DNA methylation of imprinted regions, part of repeat sequences and some gamete-specific regions are maintained. Recent evidence has shown that multiple proteins and biological pathways participate in the regulation of active DNA demethylation, such as TET proteins, DNA repair pathways and DNA methyltransferases. Here we review the recent understanding regarding proteins associated with active DNA demethylation and the regulatory networks controlling the active DNA demethylation in early embryos.
Research articles
The PHD1 finger of KDM5B recognizes unmodified H3K4 during the demethylation of histone H3K4me2/3 by KDM5B
Yan Zhang, Huirong Yang, Xue Guo, Naiyan Rong, Yujiao Song, Youwei Xu, Wenxian Lan, Xu Zhang, Maili Liu, Yanhui Xu, Chunyang Cao
2014, 5(11): 837-850. doi: 10.1007/s13238-014-0078-4
KDM5B is a histone H3K4me2/3 demethylase. The PHD1 domain of KDM5B is critical for demethylation, but the mechanism underlying the action of this domain is unclear. In this paper, we observed that PHD1KDM5B interacts with unmethylated H3K4me0. Our NMR structure of PHD1KDM5B in complex with H3K4me0 revealed that the binding mode is slightly different from that of other reported PHD fingers. The disruption of this interaction by double mutations on the residues in the interface (L325A/D328A) decreases the H3K4me2/3 demethylation activity of KDM5B in cells by approximately 50% and increases the transcriptional repression of tumor suppressor genes by approximately twofold. These findings imply that PHD1KDM5B may help maintain KDM5B at target genes to mediate the demethylation activities of KDM5B.
MiR-139-5p inhibits migration and invasion of colorectal cancer by downregulating AMFR and NOTCH1
Mingxu Song, Yuan Yin, Jiwei Zhang, Binbin Zhang, Zehua Bian, Chao Quan, Leyuan Zhou, Yaling Hu, Qifeng Wang, Shujuan Ni, Bojian Fei, Weili Wang, Xiang Du, Dong Hua, Zhaohui Huang
2014, 5(11): 851-861. doi: 10.1007/s13238-014-0093-5
MicroRNAs (miRNAs) that exert function by posttranscriptional suppression have recently brought insight in our understanding of the role of non-protein-coding RNAs in carcinogenesis and metastasis. In this study, we described the function and molecular mechanism of miR-139-5p in colorectal cancer (CRC) and its potential clinical application in CRC. We found that miR-139-5p was significantly downregulated in 73.8% CRC samples compared with adjacent noncancerous tissues (NCTs), and decreased miR-139-5p was associated with poor prognosis. Functional analyses demonstrated that ectopic expression of miR-139-5p suppressed CRC cell migration and invasion in vitro and metastasis in vivo. Mechanistic investigations revealed that miR-139-5p suppress CRC cell invasion and metastasis by targeting AMFR and NOTCH1. Knockdown of the two genes phenocopied the inhibitory effect of miR-139-5p on CRC metastasis. Furthermore, the protein levels of the two genes were upregulated in CRC samples compared with NCTs, and inversely correlated with the miR-139-5p expression. Increased NOTCH1 protein expression was correlated with poor prognosis of CRC patients. Together, our data indicate that miR-139-5p is a potential tumor suppressor and prognostic factor for CRC, and targeting miR-139-5p may repress the metastasis of CRC and improve survival.
MicroRNA-495 induces breast cancer cell migration by targeting JAM-A
Minghui Cao, Weiwei Nie, Jing Li, Yujing Zhang, Xin Yan, Xiaoxiang Guan, Xi Chen, Ke Zen, Chen-yu Zhang, Xiaohong Jiang, Dongxia Hou
2014, 5(11): 862-872. doi: 10.1007/s13238-014-0088-2
MicroRNAs (miRNAs) are small, non-coding RNAs that function as post-transcriptional regulators of gene expression. The deregulated expression of miRNAs is associated with a variety of diseases, including breast cancer. In the present study, we found that miR-495 was markedly up-regulated in clinical breast cancer samples by quantitative real time-PCR (qRT-PCR). Junctional adhesion molecule A (JAM-A) was predicted to be a potential target of miR-495 by bioinformatics analysis and was subsequently verified by luciferase assay and Western blotting. JAM-A was found to be negatively correlated with the migration of breast cancer cells through loss-of-function and gain-offunction assays, and the inhibition of JAM-A by miR-495 promoted the migration of MCF-7 and MDA-MB-231 cells. Furthermore, overexpression of JAM-A could restore miR-495-induced breast cancer cell migration. Taken together, our findings suggest that miR-495 could facilitate breast cancer progression through the repression of JAM-A, making this miRNA a potential therapeutic target.
A partial pathway-and network-based transformation reveals the synergistic mechanism of JA and UA against cerebral ischemia-reperfusion injury
Shanshan Guo, Li Guo, Yanan Yu, Bing Li, Yingying Zhang, Haixia Li, Ping Wu, Jie Wang, Ye Yuan, Zhong Wang, Yongyan Wang
2014, 5(11): 873-877. doi: 10.1007/s13238-014-0098-0
Continuous reassortments with local chicken H9N2 virus underlie the human-infecting influenza A (H7N9) virus in the new influenza season, Guangdong, China
Wenbao Qi, Weifeng Shi, Wei Li, Lihong Huang, Huanan Li, Ying Wu, Jinghua Yan, Peirong Jiao, Baoli Zhu, Juncai Ma, George F. Gao, Ming Liao, Di Liu
2014, 5(11): 878-882. doi: 10.1007/s13238-014-0084-6
Retraction note
Retraction Note to: Cryptomycota: the missing link
Krishna Bolla, Elizabeth Jane Ashforth
2014, 5(11): 883-883. doi: 10.1007/s13238-014-0063-y

Current Issue

July, 2020

Volume 11, Issue 7

Pages 465-541

About the cover

Epigenetic modifications, including those on DNA andhistones, have been shown to regulate cellular metabolismby controlling expression of enzymes involved in thecorresponding metabolic pathways. In turn, metabolic fluxinfluences epigenetic regulation by affecting the biosyntheticbalance of enzyme cofactors or donors for certainchromatin modifications. Recently, non-enzymatic covalentmodifications (NECMs) by chemically reactive metaboliteshave been reported to manipulate chromatin architectureand gene transcription through multiple mechanisms. Here,we summarize recent advances in the identification andcharacterization of NECMs on nucleic acids, histones, andtranscription factors, providing an additional mechanistic linkbetween metabolism and epigenetics.

Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang Beijing 100101, China

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