一周快讯：本周表观文献精选（2017.10.1-10.14）

Dynamic landscape and regulation of RNA editing in mammal

Meng How Tan, Qin Li, Raghuvaran Shanmugam, Robert Piskol, Jennefer Kohler, Amy N. Young, Kaiwen Ivy Liu, Rui Zhang, Gokul Ramaswami, Kentaro Ariyoshi,       Ankita Gupte, Liam P. Keegan et al.

https://www.nature.com/nature/journal/v550/n7675/full/nature24041.html

Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules. Although many editing sites have recently been discovered, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.

（ doi :10.1038/nature24041）

Single-cell epigenomics: Recording the past and predicting the future

Gavin Kelsey, Oliver Stegle, Wolf Reik

http://science.sciencemag.org/content/358/6359/69

Single-cell multi-omics has recently emerged as a powerful technology by which different layers of genomic output—and hence cell identity and function—can be recorded simultaneously. Integrating various components of the epigenome into multi-omics measurements allows for studying cellular heterogeneity at different time scales and for discovering new layers of molecular connectivity between the genome and its functional output. Measurements that are increasingly available range from those that identify transcription factor occupancy and initiation of transcription to long-lasting and heritable epigenetic marks such as DNA methylation. Together with techniques in which cell lineage is recorded, this multilayered information will provide insights into a cell’s past history and its future potential. This will allow new levels of understanding of cell fate decisions, identity, and function in normal development, physiology, and disease.

（ DOI: 10.1126/science.aan6826）

Landscape of X chromosome inactivation across human tissues

Taru Tukiainen,         Alexandra-Chloé Villani,  Angela Yen,      Manuel A. Rivas,      Jamie L. Marshall, Rahul Satija,       Matt Aguirre,   Laura Gauthier,        Mark Fleharty, Andrew Kirby,  Beryl B. Cummings, Stephane E. Castel, Konrad J. Karczewski,         François Aguet,        Andrea Byrnes, GTEx Consortium, Tuuli Lappalainen,    Aviv Regev,       Kristin G. Ardlie,       Nir Hacohen  & Daniel G. MacArthur

https://www.nature.com/nature/journal/v550/n7675/full/nature24265.html

X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of ‘escape’ from inactivation varying between genes and individuals1, 2. The extent to which XCI is shared between cells and tissues remains poorly characterized3, 4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity6, 7. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.

（ DOI: 10.1038/nature24265）

Silencio/CG9754 connects the Piwi–piRNA complex to the cellular heterochromatin machinery

Grzegorz Sienski, Julia Batki, Kirsten-André Senti, Derya Dönertas, Laszlo Tirian, Katharina Meixner, and Julius Brennecke

http://genesdev.cshlp.org/content/29/21/2258

The repression of transposable elements in eukaryotes often involves their transcriptional silencing via targeted chromatin modifications. In animal gonads, nuclear Argonaute proteins of the PIWI clade complexed with small guide RNAs (piRNAs) serve as sequence specificity determinants in this process. How binding of nuclear PIWI– piRNA complexes to nascent transcripts orchestrates heterochromatin formation and transcriptional silencing is unknown. Here, we characterize CG9754/Silencio as an essential piRNA pathway factor that is required for Piwimediated transcriptional silencing in Drosophila. Ectopic targeting of Silencio to RNA or DNA is sufficient to elicit silencing independently of Piwi and known piRNA pathway factors. Instead, Silencio requires the H3K9 methyltransferase Eggless/SetDB1 for its silencing ability. In agreement with this, SetDB1, but not Su(var)3-9, is required for Piwi-mediated transcriptional silencing genome-wide. Due to its interaction with the target-engaged Piwi– piRNA complex, we suggest that Silencio acts as linker between the sequence specificity factor Piwi and the cellular heterochromatin machinery.

（ doi: 10.1101/gad.271908.115）

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