一周快讯：本周表观文献精选（2019.8.26）

Nature：

Reconstituting the transcriptome and DNA methylome landscapes of human implantation

Fan Zhou, Rui Wang, Peng Yuan, Yixin Ren, Yunuo Mao, Rong Li, Ying Lian, Junsheng Li, Lu Wen, Liying Yan, Jie Qiao & Fuchou Tang

原文链接：

https://www.nature.com/articles/s41586-019-1500-0

原文摘要：

Implantation is a milestone event during mammalian embryogenesis. Implantation failure is a considerable cause of early pregnancy loss in humans1. Owing to the difficulty of obtaining human embryos early after implantation in vivo, it remains unclear how the gene regulatory network and epigenetic mechanisms control the implantation process. Here, by combining an in vitro culture system for the development human embryos after implantation and single-cell multi-omics sequencing technologies, more than 8,000 individual cells from 65 human peri-implantation embryos were systematically analysed. Unsupervised dimensionality reduction and clustering algorithms of the transcriptome data show stepwise implantation routes for the epiblast, primitive endoderm and trophectoderm lineages, suggesting robust preparation for the proper establishment of a mother-to-offspring connection during implantation. Female embryos showed initiation of random X chromosome inactivation based on analysis of parental allele-specific expression of X-chromosome-linked genes during implantation. Notably, using single-cell triple omics sequencing analysis, the re-methylation of the genome in cells from the primitive endoderm lineage was shown to be much slower than in cells of both epiblast and trophectoderm lineages during the implantation process, which indicates that there are distinct re-establishment features in the DNA methylome of the epiblast and primitive endoderm—even though both lineages are derived from the inner cell mass. Collectively, our work provides insights into the complex molecular mechanisms that regulate the implantation of human embryos, and helps to advance future efforts to understanding early embryonic development and reproductive medicine.

Molecular Cell：

Regulation of Co-transcriptional Pre-mRNA Splicing by m ⁶ A through the Low-Complexity Protein hnRNPG

Katherine I. Zhou，Hailing Shi，Ruitu Lyu，Chuan He，Marc Parisien，Tao Pan

原文链接：

https://doi.org/10.1016/j.molcel.2019.07.005

原文摘要：

N 6-methyladenosine (m 6A) modification occurs co-transcriptionally and impacts pre-mRNA processing; however, the mechanism of co-transcriptional m 6A-dependent alternative splicing regulation is still poorly understood. Heterogeneous nuclear ribonucleoprotein G (hnRNPG) is an m 6A reader protein that binds RNA through RRM and Arg-Gly-Gly (RGG) motifs. Here, we show that hnRNPG directly binds to the phosphorylated carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII) using RGG motifs in its low-complexity region. Through interactions with the phosphorylated CTD and nascent RNA, hnRNPG associates co-transcriptionally with RNAPII and regulates alternative splicing transcriptome-wide. m 6A near splice sites in nascent pre-mRNA modulates hnRNPG binding, which influences RNAPII occupancy patterns and promotes exon inclusion. Our results reveal an integrated mechanism of co-transcriptional m 6A-mediated splicing regulation, in which an m 6A reader protein uses RGG motifs to co-transcriptionally interact with both RNAPII and m ⁶ A-modified nascent pre-mRNA to modulate RNAPII occupancy and alternative splicing.

Science：

N ⁶ -methyladenosine RNA modification–mediated cellular metabolism rewiring inhibits viral replication

Yang Liu，Yuling You, Zhike Lu, Jiang Yang, Panpan Li, Lun Liu, Henan Xu, Yamei Niu, Xuetao Cao

原文链接：

https://science.sciencemag.org/content/early/2019/08/21/science.aax4468

原文摘要：

Host cell metabolism can be modulated by viral infection, affecting viral survival or clearance. The cellular metabolism rewiring mediated by N ⁶ -methyladenosine (m ⁶ A) modification in virus-host interaction remains largely unknown. Here we report that in response to viral infection, host cells impair the enzymatic activity of RNA m ⁶ A demethylase ALKBH5. This increases the m ⁶ A methylation on α-ketoglutarate dehydrogenase (OGDH) mRNA to reduce its mRNA stability and protein expression. Reduced OGDH decreases the production of metabolite itaconate that is required for viral replication. With reduced OGDH and itaconate production in vivo, ALKBH5-deficient mice display an innate immune response-independent resistance to viral challenge. Our findings reveal that m ⁶ A RNA modification-mediated down-regulation of OGDH-Itaconate pathway reprograms cellular metabolism to inhibit viral replication, proposing potential targets for controlling viral infection.

Nature communications：

PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma

Nathan R. Fons, Ranjini K. Sundaram, Gregory A. Breuer, Sen Peng, Ryan L. McLean, Aravind N. Kalathil, Mark S. Schmidt, Diana M. Carvalho, Alan Mackay, Chris Jones, Ángel M. Carcaboso, Javad Nazarian, Michael E. Berens, Charles Brenner & Ranjit S. Bindra

原文链接：

https://www.nature.com/articles/s41467-019-11732-6

原文摘要：

Pediatric high-grade gliomas are among the deadliest of childhood cancers due to limited knowledge of early driving events in their gliomagenesis and the lack of effective therapies available. In this study, we investigate the oncogenic role of PPM1D, a protein phosphatase often found truncated in pediatric gliomas such as DIPG, and uncover a synthetic lethal interaction between PPM1D mutations and nicotinamide phosphoribosyltransferase (NAMPT) inhibition. Specifically, we show that mutant PPM1D drives hypermethylation of CpG islands throughout the genome and promotes epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in NAD biosynthesis. Notably, PPM1D mutant cells are shown to be sensitive to NAMPT inhibitors in vitro and in vivo, within both engineered isogenic astrocytes and primary patient-derived model systems, suggesting the possible application of NAMPT inhibitors for the treatment of pediatric gliomas. Overall, our results reveal a promising approach for the targeting of PPM1D mutant tumors, and define a critical link between oncogenic driver mutations and NAD metabolism, which can be exploited for tumor-specific cell killing.

Science Signaling：

Reverse signaling by semaphorin 4C elicits SMAD1/5- and ID1/3-dependent invasive reprogramming in cancer cells

Sreeharsha Gurrapu, Giulia Franzolin, Damon Fard, Massimo Accardo, Enzo Medico, Ivana Sarotto, Anna Sapino, Claudio Isella, and Luca Tamagnone

原文链接：

https://stke.sciencemag.org/content/12/595/eaav2041

原文摘要：

Semaphorins are a family of molecular signals that guide cell migration and are implicated in the regulation of cancer cells. In particular, transmembrane semaphorins are postulated to act as both ligands (“forward” mode) and signaling receptors (“reverse” mode); however, reverse semaphorin signaling in cancer is relatively less understood. Here, we identified a previously unknown function of transmembrane semaphorin 4C (Sema4C), acting in reverse mode, to elicit nonconventional TGF-β/BMP receptor activation and selective SMAD1/5 phosphorylation. Sema4C coimmunoprecipitated with TGFBRII and BMPR1, supporting its role as modifier of this pathway. Sema4C reverse signaling led to the increased abundance of ID1/3 transcriptional factors and to extensive reprogramming of gene expression, which suppressed the typical features of the epithelial-mesenchymal transition in invasive carcinoma cells. This phenotype was nevertheless coupled with burgeoning metastatic behavior in vivo, consistent with evidence that Sema4C expression correlates with metastatic progression in human breast cancers. Thus, Sema4C reverse signaling promoted SMAD1/5- and ID1/3-dependent gene expression reprogramming and phenotypic plasticity in invasive cancer cells.