一周快讯：本周表观文献精选（2018.1.27）

Science Signaling：ATM directs DNA damage responses and proteostasis via genetically separable pathways

Ji-Hoon Lee, Michael R. Mand,Chung-Hsuan Kao,Yi Zhou,Seung W. Ryu, Alicia L. Richards, Joshua J. Coon,and Tanya T. Paull

原文链接：

http://stke.sciencemag.org/content/11/512/eaan5598

原文摘要：The protein kinase ATM is a master regulator of the DNA damage response but also responds directly to oxidative stress. Loss of ATM causes ataxia telangiectasia, a neurodegenerative disorder with pleiotropic symptoms that include cerebellar dysfunction, cancer, diabetes, and premature aging. We genetically separated the activation of ATM by DNA damage from that by oxidative stress using separation-of-function mutations. We found that deficient activation of ATM by the Mre11-Rad50-Nbs1 complex and DNA double-strand breaks resulted in loss of cell viability, checkpoint activation, and DNA end resection in response to DNA damage. In contrast, loss of oxidative activation of ATM had minimal effects on DNA damage–related outcomes but blocked ATM-mediated initiation of checkpoint responses after oxidative stress and resulted in deficiencies in mitochondrial function and autophagy. In addition, expression of a variant ATM incapable of activation by oxidative stress resulted in widespread protein aggregation. These results indicate a direct relationship between the mechanism of ATM activation and its effects on cellular metabolism and DNA damage responses in human cells and implicate ATM in the control of protein homeostasis.

LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer

Masoud F. Tavazoie,Ilana Pollack,Raissa Tanqueco,Benjamin N. Ostendorf,Bernardo S. Reis,Foster C. Gonsalves,Isabel Kurth,Celia Andreu-Agullo,Mark L. Derbyshire,Jessica Posada, Shugaku Takeda,Kimia N. Tafreshian,Eric Rowinsky,Michael Szarek,Roger J. Waltzman, Elizabeth A. Mcmillan,Connie Zhao,Monica Mita,Alain Mita,Bartosz Chmielowski,Michael A. Postow,Antoni Ribas,Daniel Mucida,Sohail F. Tavazoie

原文链接：

http://www.cell.com/cell/fulltext/S0092-8674(17)31506-4

原文摘要： Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)—an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients.

Detection and localization of surgically resectable cancers with a multi-analyte blood test

Joshua D. Cohen, Lu Li,Yuxuan Wang, Christopher Thoburn ,Bahman Afsari,Ludmila Danilova,Christopher Douville, Ammar A. Javed, Fay Wong ,Austin Mattox ,Ralph. H. Hruban, Christopher L. Wolfgang ,Michael G. Goggins, Marco Dal Molin ,Tian-Li Wang ,Richard Roden3,9, Alison P. Klein, Janine Ptak,  Lisa Dobbyn ,Joy Schaefer, Natalie Silliman, Maria Popoli, Joshua T. Vogelstein, James D. Browne ,Robert E. Schoen, Randall E. Brand ,Jeanne Tie, Peter Gibbs ,Hui-Li Wong, Aaron S. Mansfield,  Jin Jen,  Samir M. Hanash,  Massimo Falconi, Peter J. Allen, Shibin, Chetan Bettegowda, Luis Diaz, Cristian Tomasetti, Kenneth W. Kinzler, Bert Vogelstein, Anne Marie Lennon, Nickolas Papadopoulos

原文链接：

http://science.sciencemag.org/content/early/2018/01/17/science.aar3247

原文摘要：Earlier detection is key to reducing cancer deaths. Here we describe a blood test that can detect eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA. We applied this test, called CancerSEEK, to 1,005 patients with non-metastatic, clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive in a median of 70% of the eight cancer types. The sensitivities ranged from 69% to 98% for the detection of five cancer types (ovary, liver, stomach, pancreas, and esophagus) for which there are no screening tests available for average-risk individuals. The specificity of CancerSEEK was > 99%: only 7 of 812 healthy controls scored positive. In addition, CancerSEEK localized the cancer to a small number of anatomic sites in a median of 83% of the patients.

Genetic determinants and epigenetic effects of pioneer-factor occupancy

Julie Donaghey, Sudhir Thakurela , Jocelyn Charlton, Jennifer S. Chen, Zachary D. Smith, Hongcang Gu, Ramona Pop, Kendell Clement, Elena K. Stamenova, Rahul Karnik, David R. Kelley , Casey A. Gifford, Davide Cacchiarelli, John L. Rinn, Andreas Gnirke, Michael J. Ziller& Alexander Meissner

原文链接：

http://www.nature.com/articles/s41588-017-0034-3

原文摘要：Transcription factors (TFs) direct developmental transitions by binding to target DNA sequences, influencing gene expression and establishing complex gene-regultory networks. To systematically determine the molecular components that enable or constrain TF activity, we investigated the genomic occupancy of FOXA2, GATA4 and OCT4 in several cell types. Despite their classification as pioneer factors, all three TFs exhibit cell-type-specific binding, even when supraphysiologically and ectopically expressed. However, FOXA2 and GATA4 can be distinguished by low enrichment at loci that are highly occupied by these factors in alternative cell types. We find that expression of additional cofactors increases enrichment at a subset of these sites. Finally, FOXA2 occupancy and changes to DNA accessibility can occur in G1-arrested cells, but subsequent loss of DNA methylation requires DNA replication.