一周快讯：本周表观文献精选（2018.4.14）

GFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1

Charles Vadnais, Riyan Chen, Jennifer Fraszczak, Zhenbao Yu, Jonathan Boulais, Jordan Pinder, Daria Frank, Cyrus Khandanpour, Josée Hébert, Graham Dellaire, Jean-François Côté, Stéphane Richard, Alexandre Orthwein, Elliot Drobetsky & Tarik Möröy

原文链接：

http://www.nature.com/articles/s41467-018-03817-5

原文摘要：

GFI1 is a transcriptional regulator expressed in lymphoid cells, and an “oncorequisite” factor required for development and maintenance of T-lymphoid leukemia. GFI1 deletion causes hypersensitivity to ionizing radiation, for which the molecular mechanism remains unknown. Here, we demonstrate that GFI1 is required in T cells for the regulation of key DNA damage signaling and repair proteins. Specifically, GFI1 interacts with the arginine methyltransferase PRMT1 and its substrates MRE11 and 53BP1. We demonstrate that GFI1 enables PRMT1 to bind and methylate MRE11 and 53BP1, which is necessary for their function in the DNA damage response. Thus, our results provide evidence that GFI1 can adopt non-transcriptional roles, mediating the post-translational modification of proteins involved in DNA repair. These findings have direct implications for treatment responses in tumors overexpressing GFI1 and suggest that GFI1’s activity may be a therapeutic target in these malignancies.

Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation

Hui Li, Qi Yao, Alberto Garcia Mariscal, Xudong Wu, Justus Hülse, Esben Pedersen, Kristian Helin , Ari Waisman ， Caroline Vinkel, Simon Francis Thomsen, Alexandra Avgustinova, Salvador Aznar Benitah , Paola Lovato, Hanne Norsgaard, Mette Sidsel Mortensen,Lone Veng, Björn Rozell & Cord Brakebusch

原文链接：

http://www.nature.com/articles/s41467-018-03704-z

原文摘要：

The chronic skin inflammation psoriasis is crucially dependent on the IL-23/IL-17 cytokine axis. Although IL-23 is expressed by psoriatic keratinocytes and immune cells, only the immune cell-derived IL-23 is believed to be disease relevant. Here we use a genetic mouse model to show that keratinocyte-produced IL-23 is sufficient to cause a chronic skin inflammation with an IL-17 profile. Furthermore, we reveal a cell-autonomous nuclear function for the actin polymerizing molecule N-WASP, which controls IL-23 expression in keratinocytes by regulating the degradation of the histone methyltransferases G9a and GLP, and H3K9 dimethylation of the IL-23 promoter. This mechanism mediates the induction of IL-23 by TNF, a known inducer of IL-23 in psoriasis. Finally, in keratinocytes of psoriatic lesions a decrease in H3K9 dimethylation correlates with increased IL-23 expression, suggesting relevance for disease. Taken together, our data describe a molecular pathway where epigenetic regulation of keratinocytes can contribute to chronic skin inflammation.

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Stefan Gräf , Matthias Haime , [……] Emilia M. Swietlik,

原文链接：

http://www.nature.com/articles/s41467-018-03672-4

原文摘要：

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types

Hilary K. Finucane , Yakir A. Reshef , Verneri Anttila, Kamil Slowikowski , Alexander Gusev , Andrea Byrnes, Steven Gazal, Po-Ru Loh, Caleb Lareau, Noam Shoresh, Giulio Genovese, Arpiar Saunders, Evan Macosko, Samuela Pollack, The Brainstorm Consortium, John R. B. Perry, Jason D. Buenrostro, Bradley E. Bernstein, Soumya Raychaudhuri, Steven McCarroll，Benjamin M. Neale & Alkes L. Price

原文链接：

http://www.nature.com/articles/s41588-018-0081-4

原文摘要：

We introduce an approach to identify disease-relevant tissues and cell types by analyzing gene expression data together with genome-wide association study (GWAS) summary statistics. Our approach uses stratified linkage disequilibrium (LD) score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We applied our approach to gene expression data from several sources together with GWAS summary statistics for 48 diseases and traits (average N = 169,331) and found significant tissue-specific enrichments (false discovery rate (FDR)

Highly parallel genome variant engineering with CRISPR–Cas9

Meru J. Sadhu, Joshua S. Bloom Laura Day, Jake J. Siegel, Sriram Kosuri & Leonid Kruglyak

原文链接：

http://www.nature.com/articles/s41588-018-0087-y

原文摘要：

Understanding the functional effects of DNA sequence variants is of critical importance for studies of basic biology, evolution, and medical genetics; however, measuring these effects in a high-throughput manner is a major challenge. One promising avenue is precise editing with the CRISPR–Cas9 system, which allows for generation of DNA double-strand breaks (DSBs) at genomic sites matching the targeting sequence of a guide RNA (gRNA). Recent studies have used CRISPR libraries to generate many frameshift mutations genome wide through faulty repair of CRISPR-directed breaks by nonhomologous end joining (NHEJ)1. Here, we developed a CRISPR-library-based approach for highly efficient and precise genome-wide variant engineering. We used our method to examine the functional consequences of premature-termination codons (PTCs) at different locations within all annotated essential genes in yeast. We found that most PTCs were highly deleterious unless they occurred close to the 3′ end of the gene and did not affect an annotated protein domain. Unexpectedly, we discovered that some putatively essential genes are dispensable, whereas others have large dispensable regions. This approach can be used to profile the effects of large classes of variants in a high-throughput manner.

Histone deacetylase 6 controls Notch3 trafficking and degradation in T-cell acute lymphoblastic leukemia cells

Marica Pinazza, Margherita Ghisi, Sonia Minuzzo, Valentina Agnusdei, Gianluca Fossati, Vincenzo Ciminale, Laura Pezzè, Yari Ciribilli, Giorgia Pilotto, Carolina Venturoli, Alberto Amadori & Stefano Indraccolo

原文链接：

http://www.nature.com/articles/s41388-018-0234-z

原文摘要：

Several studies have revealed that endosomal sorting controls the steady-state levels of Notch at the cell surface in normal cells and prevents its inappropriate activation in the absence of ligands. However, whether this highly dynamic physiologic process can be exploited to counteract dysregulated Notch signaling in cancer cells remains unknown. T-ALL is a malignancy characterized by aberrant Notch signaling, sustained by activating mutations in Notch1 as well as overexpression of Notch3, a Notch paralog physiologically subjected to lysosome-dependent degradation in human cancer cells. Here we show that treatment with the pan-HDAC inhibitor Trichostatin A (TSA) strongly decreases Notch3 full-length protein levels in T-ALL cell lines and primary human T-ALL cells xenografted in mice without substantially reducing NOTCH3 mRNA levels. Moreover, TSA markedly reduced the levels of Notch target genes, including pTα, CR2, and DTX-1, and induced apoptosis of T-ALL cells. We further observed that Notch3 was post-translationally regulated following TSA treatment, with reduced Notch3 surface levels and increased accumulation of Notch3 protein in the lysosomal compartment. Surface Notch3 levels were rescued by inhibition of dynein with ciliobrevin D. Pharmacologic studies with HDAC1, 6, and 8-specific inhibitors disclosed that these effects were largely due to inhibition of HDAC6 in T-ALL cells. HDAC6 silencing by specific shRNA was followed by reduced Notch3 expression and increased apoptosis of T-ALL cells. Finally, HDAC6 silencing impaired leukemia outgrowth in mice, associated with reduction of Notch3 full-length protein in vivo. These results connect HDAC6 activity to regulation of total and surface Notch3 levels and suggest HDAC6 as a potential novel therapeutic target to lower Notch signaling in T-ALL and other Notch3-addicted tumors.

A pilot study of ultra-deep targeted sequencing of plasma DNA identifies driver mutations in hepatocellular

carcinoma，Ismail Labgaa, Carlos Villacorta-Martin, Delia D’Avola, Amanda J. Craig, Johann von Felden, Sebastiao N. Martins-Filho, Daniela Sia, Ashley Stueck, Stephen C. Ward, M. Isabel Fiel, Milind Mahajan, Parissa Tabrizian, Swan N. Thung, Celina Ang, Scott L. Friedman, Josep M. Llovet, Myron Schwartz & Augusto Villanueva

原文链接：

http://www.nature.com/articles/s41388-018-0206-3

原文摘要：