一周快讯：本周表观文献精选（2018.3.24）

RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia

Jason X. Cheng, Li Chen, Yuan Li, Adam Cloe, Ming Yue, Jiangbo Wei, Kenneth A. Watanabe, Jamile M. Shammo, John Anastasi, Qingxi J. Shen, Richard A. Larson, Chuan He, Michelle M. Le Beau & ames W. Vardiman

原文链接：

http://www.nature.com/articles/s41467-018-03513-4

原文摘要：

The roles of RNA 5-methylcytosine (RNA:m5C) and RNA:m5C methyltransferases (RCMTs) in lineage-associated chromatin organization and drug response/resistance are unclear. Here we demonstrate that the RCMTs, namely NSUN3 and DNMT2, directly bind hnRNPK, a conserved RNA-binding protein. hnRNPK interacts with the lineage-determining transcription factors (TFs), GATA1 and SPI1/PU.1, and with CDK9/P-TEFb to recruit RNA-polymerase-II at nascent RNA, leading to formation of 5-Azacitidine (5-AZA)-sensitive chromatin structure. In contrast, NSUN1 binds BRD4 and RNA-polymerase-II to form an active chromatin structure that is insensitive to 5-AZA, but hypersensitive to the BRD4 inhibitor JQ1 and to the downregulation of NSUN1 by siRNAs. Both 5-AZA-resistant leukaemia cell lines and clinically 5-AZA-resistant myelodysplastic syndrome and acute myeloid leukaemia specimens have a significant increase in RNA:m5C and NSUN1-/BRD4-associated active chromatin. This study reveals novel RNA:m5C/RCMT-mediated chromatin structures that modulate 5-AZA response/resistance in leukaemia cells, and hence provides a new insight into treatment of leukaemia.

Structure of Schlafen13 reveals a new class of tRNA/rRNA- targeting RNase engaged in translational control

Jin-Yu Yang, Xiang-Yu Deng, Yi-Sheng Li, Xian-Cai Ma, Jian-Xiong Feng, Bing Yu, Yang Chen, Yi-Ling Luo, Xi Wang, Mei-Ling Chen, Zhi-Xin Fang, Fu-Xiang Zheng, Yi-Ping Li, Qian Zhong, Tie-Bang Kang,Li-Bing Song, Rui-Hua Xu, Mu-Sheng Zeng, Wei Chen, Hui Zhang, Wei Xie & Song Gao

原文链接：

http://www.nature.com/articles/s41467-018-03544-x

原文摘要：

Cleavage of transfer (t)RNA and ribosomal (r)RNA are critical and conserved steps of translational control for cells to overcome varied environmental stresses. However, enzymes that are responsible for this event have not been fully identified in high eukaryotes. Here, we report a mammalian tRNA/rRNA-targeting endoribonuclease: SLFN13, a member of the Schlafen family. Structural study reveals a unique pseudo-dimeric U-pillow-shaped architecture of the SLFN13 N′-domain that may clamp base-paired RNAs. SLFN13 is able to digest tRNAs and rRNAs in vitro, and the endonucleolytic cleavage dissevers 11 nucleotides from the 3′-terminus of tRNA at the acceptor stem. The cytoplasmically localised SLFN13 inhibits protein synthesis in 293T cells. Moreover, SLFN13 restricts HIV replication in a nucleolytic activity-dependent manner. According to these observations, we term SLFN13 RNase S13. Our study provides insights into the modulation of translational machinery in high eukaryotes, and sheds light on the functional mechanisms of the Schlafen family.

nc886 is induced by TGF-β and suppresses the microRNA pathway in ovarian cancer

Ji-Hye Ahn, Hyun-Sung Lee, Ju-Seog Lee, Yeon-Su Lee, Jong-Lyul Park, Seon-Young Kim, Jung-Ah Hwang, Nawapol Kunkeaw, Sung Yun Jung, Tae Jin Kim, Kwang-Soo Lee, Sung Ho Jeon, Inhan Lee,Betty H. Johnson, Jung-Hye Choi & Yong Sun Lee

原文链接：

http://www.nature.com/articles/s41467-018-03556-7

原文摘要：Transforming growth factor-β (TGF-β) signaling and microRNAs (miRNAs) are important gene regulatory components in cancer. Usually in advanced malignant stages, TGF-β signaling is elevated but global miRNA expression is suppressed. Such a gene expression signature is well illustrated in a fibrosis (or mesenchymal) subtype of ovarian cancer (OC) that is of poor prognosis. However, the interplay between the two pathways in the OC subtype has not yet been elucidated. nc886 is a recently identified non-coding RNA implicated in several malignancies. The high expression of nc886 is associated with poor prognosis in 285 OC patients. Herein, we find that in OC nc886 expression is induced by TGF-β and that nc886 binds to Dicer to inhibit miRNA maturation. By preventing the miRNA pathway, nc886 emulates TGF-β in gene expression patterns and potentiates cell adhesion, migration, invasion, and drug resistance. Here we report nc886 to be a molecular link between the TGF-β and miRNA pathways.

Understanding Alzheimer Disease at the Interface between Genetics and Transcriptomics

Jan Verheijen，Kristel Sleegers

原文链接：

http://www.cell.com/trends/genetics/fulltext/S0168-9525(18)30042-8

原文摘要：

Due to risk gene pleiotropy, difficulty in finding functional variants, and poor reflection of physiological complexity in genetic analysis, translation of new genetic findings for Alzheimer disease (AD) into functional mechanisms has been difficult.

Transcriptomic analysis has provided additional support for previously identified risk genes while also identifying novel associated genes, helping to elucidate mechanisms of disease.

Refinement of transcriptomics through 2nd and 3rd generation sequencing, single-cell sequencing and bioinformatics is revealing mechanisms involved in AD in previously unattainable detail, including brain region- and cell-type-specific expression changes and molecular processes such as transcript rescue events, challenging the direct interpretation of an association between genetic variant and phenotype.

Transcriptome analysis in postmortem brain has uncovered central biological pathways and central regulator ‘hub’ genes in disease, for example, SPI.1 and TYROBP in the brain immune response.

Over 25 genes are known to affect the risk of developing Alzheimer disease (AD), the most common neurodegenerative dementia. However, mechanistic insights and improved disease management remains limited, due to difficulties in determining the functional consequences of genetic associations. Transcriptomics is increasingly being used to corroborate or enhance interpretation of genetic discoveries. These approaches, which include second and third generation sequencing, single-cell sequencing, and bioinformatics, reveal allele-specific events connecting AD risk genes to expression profiles, and provide converging evidence of pathophysiological pathways underlying AD. Simultaneously, they highlight brain region- and cell-type-specific expression patterns, and alternative splicing events that affect the straightforward relation between a genetic variant and AD, re-emphasizing the need for an integrated approach of genetics and transcriptomics in understanding AD.

Genetic and pharmacological inhibition of Cdk1 provides neuroprotection towards ischemic neuronal death

Quentin Marlier, Florian Jibassia, Sébastien Verteneuil, Jérôme Linden, Philipp Kaldis, Laurent Meijer, Laurent Nguyen, Renaud Vandenbosch & Brigitte Malgrange

原文链接：

http://www.nature.com/articles/s41420-018-0044-7

原文摘要：

Cell cycle proteins are mainly expressed by dividing cells. However, it is well established that these molecules play additional non-canonical activities in several cell death contexts. Increasing evidence shows expression of cell cycle regulating proteins in post-mitotic cells, including mature neurons, following neuronal insult. Several cyclin-dependent kinases (Cdks) have already been shown to mediate ischemic neuronal death but Cdk1, a major cell cycle G2/M regulator, has not been investigated in this context. We therefore examined the role of Cdk1 in neuronal cell death following cerebral ischemia, using both in vitro and in vivo genetic and pharmacological approaches. Exposure of primary cortical neurons cultures to 4 h of oxygen–glucose deprivation (OGD) resulted in neuronal cell death and induced Cdk1 expression. Neurons from Cdk1-cKO mice showed partial resistance to OGD-induced neuronal cell death. Addition of R-roscovitine to the culture medium conferred neuroprotection against OGD-induced neuronal death. Transient 1-h occlusion of the cerebral artery (MCAO) also leads to Cdk1 expression and activation. Cdk1-cKO mice displayed partial resistance to transient 1-h MCAO. Moreover, systemic delivery of R-roscovitine was neuroprotective following transient 1-h MCAO. This study demonstrates that promising neuroprotective therapies can be considered through inhibition of the cell cycle machinery and particularly through pharmacological inhibition of Cdk1.