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Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood.

13 hours 58 minutes ago
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Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood.

J Med Genet. 2019 05;56(5):340-346

Authors: Shalata A, Lauhasurayotin S, Leibovitz Z, Li H, Hebert D, Dhanraj S, Hadid Y, Mahroum M, Bajar J, Egenburg S, Arad A, Shohat M, Haddad S, Bakry H, Moshiri H, Scherer SW, Tzur S, Dror Y

Abstract
BACKGROUND: Dandy-Walker malformation features agenesis/hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of posterior fossa. Although Dandy-Walker malformation is relatively common and several genes were linked to the syndrome, the genetic cause in the majority of cases is unknown.
OBJECTIVE: To identify the mutated gene responsible for Dandy-Walker malformation, kidney disease and bone marrow failure in four patients from two unrelated families.
METHODS: Medical assessment, sonographic, MRI and pathological studies were used to define phenotype. Chromosomal microarray analysis and whole-exome sequence were performed to unravel the genotype.
RESULTS: We report four subjects from two unrelated families with homozygous mutations in the Exocyst Complex Component 3-Like-2 gene (EXOC3L2).EXOC3L2 functions in trafficking of post-Golgi vesicles to the plasma membrane. In the first family a missense mutation in a highly conserved amino acid, p.Leu41Gln, was found in three fetuses; all had severe forms of Dandy-Walker malformation that was detectable by prenatal ultrasonography and confirmed by autopsy. In the second family, the affected child carried a nonsense mutation, p.Arg72*, and no detected protein. He had peritrigonal and cerebellar white matter abnormalities with enlargement of the ventricular trigones, developmental delay, pituitary hypoplasia, severe renal dysplasia and bone marrow failure.
CONCLUSION: We propose that biallelic EXOC3L2 mutations lead to a novel syndrome that affects hindbrain development, kidney and possibly the bone marrow.

PMID: 30327448 [PubMed - indexed for MEDLINE]

Using Reactome to build an autophagy mechanism knowledgebase.

13 hours 58 minutes ago
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Using Reactome to build an autophagy mechanism knowledgebase.

Autophagy. 2020 Jun 02;:1-12

Authors: Varusai TM, Jupe S, Sevilla C, Matthews L, Gillespie M, Stein L, Wu G, D'Eustachio P, Metzakopian E, Hermjakob H

Abstract
The 21st century has revealed much about the fundamental cellular process of autophagy. Autophagy controls the catabolism and recycling of various cellular components both as a constitutive process and as a response to stress and foreign material invasion. There is considerable knowledge of the molecular mechanisms of autophagy, and this is still growing as new modalities emerge. There is a need to investigate autophagy mechanisms reliably, comprehensively and conveniently. Reactome is a freely available knowledgebase that consists of manually curated molecular events (reactions) organized into cellular pathways (https://reactome.org/). Pathways/reactions in Reactome are hierarchically structured, graphically presented and extensively annotated. Data analysis tools, such as pathway enrichment, expression data overlay and species comparison, are also available. For customized analysis, information can also be programmatically queried. Here, we discuss the curation and annotation of the molecular mechanisms of autophagy in Reactome. We also demonstrate the value that Reactome adds to research by reanalyzing a previously published work on genome-wide CRISPR screening of autophagy components.
ABBREVIATIONS: CMA: chaperone-mediated autophagy; GO: Gene Ontology; MA: macroautophagy; MI: microautophagy; MTOR: mechanistic target of rapamycin kinase; SQSTM1: sequestosome 1.

PMID: 32486891 [PubMed - as supplied by publisher]

Early change in reward and punishment sensitivity as a predictor of response to antidepressant treatment for major depressive disorder: a CAN-BIND-1 report.

1 day 13 hours ago
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Early change in reward and punishment sensitivity as a predictor of response to antidepressant treatment for major depressive disorder: a CAN-BIND-1 report.

Psychol Med. 2019 07;49(10):1629-1638

Authors: Allen TA, Lam RW, Milev R, Rizvi SJ, Frey BN, MacQueen GM, Müller DJ, Uher R, Kennedy SH, Quilty LC

Abstract
BACKGROUND: In an effort to optimize patient outcomes, considerable attention is being devoted to identifying patient characteristics associated with major depressive disorder (MDD) and its responsiveness to treatment. In the current study, we extend this work by evaluating whether early change in these sensitivities is associated with response to antidepressant treatment for MDD.
METHODS: Participants included 210 patients with MDD who were treated with 8 weeks of escitalopram and 112 healthy comparison participants. Of the original 210 patients, 90 non-responders received adjunctive aripiprazole for an additional 8 weeks. Symptoms of depression and anhedonia were assessed at the beginning of treatment and 8 weeks later in both samples. Reward and punishment sensitivity were assessed using the BIS/BAS scales measured at the initiation of treatment and 2 weeks later.
RESULTS: Individuals with MDD exhibited higher punishment sensitivity and lower reward sensitivity compared with healthy comparison participants. Change in reward sensitivity during the first 2 weeks of treatment was associated with improved depressive symptoms and anhedonia following 8 weeks of treatment with escitalopram. Similarly, improvement in reward responsiveness during the first 2 weeks of adjunctive therapy with aripiprazole was associated with fewer symptoms of depression at post-treatment.
CONCLUSIONS: Findings highlight the predictive utility of early change in reward sensitivity during antidepressant treatment for major depression. In a clinical setting, a lack of change in early reward processing may signal a need to modify a patient's treatment plan with alternative or augmented treatment approaches.

PMID: 30220263 [PubMed - indexed for MEDLINE]

AcrIF9 tethers non-sequence specific dsDNA to the CRISPR RNA-guided surveillance complex.

1 day 13 hours ago
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AcrIF9 tethers non-sequence specific dsDNA to the CRISPR RNA-guided surveillance complex.

Nat Commun. 2020 Jun 01;11(1):2730

Authors: Hirschi M, Lu WT, Santiago-Frangos A, Wilkinson R, Golden SM, Davidson AR, Lander GC, Wiedenheft B

Abstract
Bacteria have evolved sophisticated adaptive immune systems, called CRISPR-Cas, that provide sequence-specific protection against phage infection. In turn, phages have evolved a broad spectrum of anti-CRISPRs that suppress these immune systems. Here we report structures of anti-CRISPR protein IF9 (AcrIF9) in complex with the type I-F CRISPR RNA-guided surveillance complex (Csy). In addition to sterically blocking the hybridization of complementary dsDNA to the CRISPR RNA, our results show that AcrIF9 binding also promotes non-sequence-specific engagement with dsDNA, potentially sequestering the complex from target DNA. These findings highlight the versatility of anti-CRISPR mechanisms utilized by phages to suppress CRISPR-mediated immune systems.

PMID: 32483187 [PubMed - in process]

BCL6 Evolved to Enable Stress Tolerance in Vertebrates and Is Broadly Required by Cancer Cells to Adapt to Stress.

2 days 13 hours ago
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BCL6 Evolved to Enable Stress Tolerance in Vertebrates and Is Broadly Required by Cancer Cells to Adapt to Stress.

Cancer Discov. 2019 05;9(5):662-679

Authors: Fernando TM, Marullo R, Pera Gresely B, Phillip JM, Yang SN, Lundell-Smith G, Torregroza I, Ahn H, Evans T, Győrffy B, Privé GG, Hirano M, Melnick AM, Cerchietti L

Abstract
Several lines of evidence link the canonical oncogene BCL6 to stress response. Here we demonstrate that BCL6 evolved in vertebrates as a component of the HSF1-driven stress response, which has been co-opted by the immune system to support germinal center formation and may have been decisive in the convergent evolution of humoral immunity in jawless and jawed vertebrates. We find that the highly conserved BTB corepressor binding site of BCL6 mediates stress adaptation across vertebrates. We demonstrate that pan-cancer cells hijack this stress tolerance mechanism to aberrantly express BCL6. Targeting the BCL6 BTB domain in cancer cells induces apoptosis and increases susceptibility to repeated doses of cytotoxic therapy. The chemosensitization effect upon BCL6 BTB inhibition is dependent on the derepression of TOX, implicating modulation of DNA repair as a downstream mechanism. Collectively, these data suggest a form of adaptive nononcogene addiction rooted in the natural selection of BCL6 during vertebrate evolution. SIGNIFICANCE: We demonstrate that HSF1 drives BCL6 expression to enable stress tolerance in vertebrates. We identify an HSF1-BCL6-TOX stress axis that is required by cancer cells to tolerate exposure to cytotoxic agents and points toward BCL6-targeted therapy as a way to more effectively kill a wide variety of solid tumors.This article is highlighted in the In This Issue feature, p. 565.

PMID: 30777872 [PubMed - indexed for MEDLINE]

Visualization of drug target interactions in the contexts of pathways and networks with ReactomeFIViz.

2 days 13 hours ago
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Visualization of drug target interactions in the contexts of pathways and networks with ReactomeFIViz.

F1000Res. 2019;8:908

Authors: Blucher AS, McWeeney SK, Stein L, Wu G

Abstract
The precision medicine paradigm is centered on therapies targeted to particular molecular entities that will elicit an anticipated and controlled therapeutic response. However, genetic alterations in the drug targets themselves or in genes whose products interact with the targets can affect how well a drug actually works for an individual patient. To better understand the effects of targeted therapies in patients, we need software tools capable of simultaneously visualizing patient-specific variations and drug targets in their biological context. This context can be provided using pathways, which are process-oriented representations of biological reactions, or biological networks, which represent pathway-spanning interactions among genes, proteins, and other biological entities. To address this need, we have recently enhanced the Reactome Cytoscape app, ReactomeFIViz, to assist researchers in visualizing and modeling drug and target interactions. ReactomeFIViz integrates drug-target interaction information with high quality manually curated pathways and a genome-wide human functional interaction network. Both the pathways and the functional interaction network are provided by Reactome, the most comprehensive open source biological pathway knowledgebase. We describe several examples demonstrating the application of these new features to the visualization of drugs in the contexts of pathways and networks. Complementing previous features in ReactomeFIViz, these new features enable researchers to ask focused questions about targeted therapies, such as drug sensitivity for patients with different mutation profiles, using a pathway or network perspective.

PMID: 31372215 [PubMed - indexed for MEDLINE]

CReSCENT: CanceR Single Cell ExpressioN Toolkit.

2 days 13 hours ago
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CReSCENT: CanceR Single Cell ExpressioN Toolkit.

Nucleic Acids Res. 2020 Jun 01;:

Authors: Mohanraj S, Díaz-Mejía JJ, Pham MD, Elrick H, Husić M, Rashid S, Luo P, Bal P, Lu K, Patel S, Mahalanabis A, Naidas A, Christensen E, Croucher D, Richards LM, Shooshtari P, Brudno M, Ramani AK, Pugh TJ

Abstract
CReSCENT: CanceR Single Cell ExpressioN Toolkit (https://crescent.cloud), is an intuitive and scalable web portal incorporating a containerized pipeline execution engine for standardized analysis of single-cell RNA sequencing (scRNA-seq) data. While scRNA-seq data for tumour specimens are readily generated, subsequent analysis requires high-performance computing infrastructure and user expertise to build analysis pipelines and tailor interpretation for cancer biology. CReSCENT uses public data sets and preconfigured pipelines that are accessible to computational biology non-experts and are user-editable to allow optimization, comparison, and reanalysis for specific experiments. Users can also upload their own scRNA-seq data for analysis and results can be kept private or shared with other users.

PMID: 32479601 [PubMed - as supplied by publisher]

Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE subanalysis (DEVOTE 10).

5 days 10 hours ago
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Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE subanalysis (DEVOTE 10).

Diabetes Obes Metab. 2019 06;21(6):1437-1444

Authors: Brown-Frandsen K, Emerson SS, McGuire DK, Pieber TR, Poulter NR, Pratley RE, Zinman B, Ranthe MF, Grøn R, Lange M, Moses AC, Örsy P, Buse JB, DEVOTE Study Group

Abstract
AIM: To compare the associations between concomitant liraglutide use versus no liraglutide use and the risk of major adverse cardiovascular events (MACE) and all-cause mortality among patients receiving basal insulin (either insulin degludec [degludec] or insulin glargine 100 units/mL [glargine U100]) in the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE).
MATERIALS AND METHODS: Patients with type 2 diabetes and high cardiovascular risk were randomized 1:1 to degludec or glargine U100. Hazard ratios for MACE/mortality were calculated using a Cox regression model adjusted for treatment and time-varying liraglutide use at any time during the trial, without interaction. Sensitivity analyses were adjusted for baseline covariates including, but not limited to, age, sex, smoking and prior cardiovascular disease.
RESULTS: At baseline, 436/7637 (5.7%) patients were treated with liraglutide; after baseline, 187/7637 (2.4%) started and 210/7637 (2.7%) stopped liraglutide. Mean liraglutide exposure from randomization was 530.2 days. Liraglutide use versus no liraglutide use was associated with significantly lower hazard rates for MACE [0.62 (0.41; 0.92)95%CI ] and all-cause mortality [0.50 (0.29; 0.88)95%CI ]. There was no significant difference in the rate of severe hypoglycaemia with versus without liraglutide use. Multiple sensitivity analyses yielded similar results.
CONCLUSIONS: Use of liraglutide was associated with significantly lower risk of MACE and death in patients with type 2 diabetes and high cardiovascular risk using basal insulin.

PMID: 30793465 [PubMed - indexed for MEDLINE]

Spectral Diversification and Trans-Species Allelic Polymorphism during the Land-to-Sea Transition in Snakes.

5 days 10 hours ago
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Spectral Diversification and Trans-Species Allelic Polymorphism during the Land-to-Sea Transition in Snakes.

Curr Biol. 2020 May 19;:

Authors: Simões BF, Gower DJ, Rasmussen AR, Sarker MAR, Fry GC, Casewell NR, Harrison RA, Hart NS, Partridge JC, Hunt DM, Chang BS, Pisani D, Sanders KL

Abstract
Snakes are descended from highly visual lizards [1] but have limited (probably dichromatic) color vision attributed to a dim-light lifestyle of early snakes [2-4]. The living species of front-fanged elapids, however, are ecologically very diverse, with ∼300 terrestrial species (cobras, taipans, etc.) and ∼60 fully marine sea snakes, plus eight independently marine, amphibious sea kraits [1]. Here, we investigate the evolution of spectral sensitivity in elapids by analyzing their opsin genes (which are responsible for sensitivity to UV and visible light), retinal photoreceptors, and ocular lenses. We found that sea snakes underwent rapid adaptive diversification of their visual pigments when compared with their terrestrial and amphibious relatives. The three opsins present in snakes (SWS1, LWS, and RH1) have evolved under positive selection in elapids, and in sea snakes they have undergone multiple shifts in spectral sensitivity toward the longer wavelengths that dominate below the sea surface. Several relatively distantly related Hydrophis sea snakes are polymorphic for shortwave sensitive visual pigment encoded by alleles of SWS1. This spectral site polymorphism is expected to confer expanded "UV-blue" spectral sensitivity and is estimated to have persisted twice as long as the predicted survival time for selectively neutral nuclear alleles. We suggest that this polymorphism is adaptively maintained across Hydrophis species via balancing selection, similarly to the LWS polymorphism that confers allelic trichromacy in some primates. Diving sea snakes thus appear to share parallel mechanisms of color vision diversification with fruit-eating primates.

PMID: 32470360 [PubMed - as supplied by publisher]

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen.

6 days 9 hours ago
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Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen.

J Am Soc Nephrol. 2019 10;30(10):2000-2016

Authors: Salem RM, Todd JN, Sandholm N, Cole JB, Chen WM, Andrews D, Pezzolesi MG, McKeigue PM, Hiraki LT, Qiu C, Nair V, Di Liao C, Cao JJ, Valo E, Onengut-Gumuscu S, Smiles AM, McGurnaghan SJ, Haukka JK, Harjutsalo V, Brennan EP, van Zuydam N, Ahlqvist E, Doyle R, Ahluwalia TS, Lajer M, Hughes MF, Park J, Skupien J, Spiliopoulou A, Liu A, Menon R, Boustany-Kari CM, Kang HM, Nelson RG, Klein R, Klein BE, Lee KE, Gao X, Mauer M, Maestroni S, Caramori ML, de Boer IH, Miller RG, Guo J, Boright AP, Tregouet D, Gyorgy B, Snell-Bergeon JK, Maahs DM, Bull SB, Canty AJ, Palmer CNA, Stechemesser L, Paulweber B, Weitgasser R, Sokolovska J, Rovīte V, Pīrāgs V, Prakapiene E, Radzeviciene L, Verkauskiene R, Panduru NM, Groop LC, McCarthy MI, Gu HF, Möllsten A, Falhammar H, Brismar K, Martin F, Rossing P, Costacou T, Zerbini G, Marre M, Hadjadj S, McKnight AJ, Forsblom C, McKay G, Godson C, Maxwell AP, Kretzler M, Susztak K, Colhoun HM, Krolewski A, Paterson AD, Groop PH, Rich SS, Hirschhorn JN, Florez JC, SUMMIT Consortium, DCCT/EDIC Research Group, GENIE Consortium

Abstract
BACKGROUND: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.
METHODS: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.
RESULTS: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).
CONCLUSIONS: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

PMID: 31537649 [PubMed - indexed for MEDLINE]

Introducing the Canadian Women's Heart Health Alliance ATLAS on the Epidemiology, Diagnosis, and Management of Cardiovascular Diseases in Women.

6 days 9 hours ago
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Introducing the Canadian Women's Heart Health Alliance ATLAS on the Epidemiology, Diagnosis, and Management of Cardiovascular Diseases in Women.

CJC Open. 2020 May;2(3):145-150

Authors: Norris CM, Yip CYY, Nerenberg KA, Jaffer S, Grewal J, Levinsson ALE, Mulvagh SL

Abstract
Despite a global understanding that indicators and outcomes of cardiovascular disease (CVD) are known to differ between men and women, uptake of the recognition of sex and gender influences on the clinical care of women has been slow or absent. The Canadian Women's Heart Health Alliance (CWHHA) was established as a network of experts and advocates to develop and disseminate evidence-informed strategies to transform clinical practice and augment collaborative action on women's cardiovascular health in Canada. As an initial project, the CWHHA membership undertook an environmental scan of CVD in women in Canada from which a scientific statement could be developed to summarize critical sex- and gender-specific issues in CVD. This comprehensive review of the evidence focused on the sex- and gender-specific differences in comorbidity, risk factors, disease awareness, presentation, diagnosis, and treatment across the entire spectrum of CVD. In the process of creating the review, it was recognized that the team of CWHHA experts had also assembled an expansive collection of original research articles that were synthesized into detailed chapters reporting on the present state of the evidence unique to each cardiovascular condition in women. This work comprises an "ATLAS" on the epidemiology, diagnosis, and management of CVD in women. The overall goal of the ATLAS is to create a living document that will help clinicians and the public recognize the unique aspects of women's heart health care and provide policy makers with information they need to ensure equitable care for women with CVD.

PMID: 32462128 [PubMed]

Modeling Cellular Response in Large-Scale Radiogenomic Databases to Advance Precision Radiotherapy.

1 week ago
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Modeling Cellular Response in Large-Scale Radiogenomic Databases to Advance Precision Radiotherapy.

Cancer Res. 2019 12 15;79(24):6227-6237

Authors: Manem VS, Lambie M, Smith I, Smirnov P, Kofia V, Freeman M, Koritzinsky M, Abazeed ME, Haibe-Kains B, Bratman SV

Abstract
Radiotherapy is integral to the care of a majority of patients with cancer. Despite differences in tumor responses to radiation (radioresponse), dose prescriptions are not currently tailored to individual patients. Recent large-scale cancer cell line databases hold the promise of unravelling the complex molecular arrangements underlying cellular response to radiation, which is critical for novel predictive biomarker discovery. Here, we present RadioGx, a computational platform for integrative analyses of radioresponse using radiogenomic databases. We fit the dose-response data within RadioGx to the linear-quadratic model. The imputed survival across a range of dose levels (AUC) was a robust radioresponse indicator that correlated with biological processes known to underpin the cellular response to radiation. Using AUC as a metric for further investigations, we found that radiation sensitivity was significantly associated with disruptive mutations in genes related to nonhomologous end joining. Next, by simulating the effects of different oxygen levels, we identified putative genes that may influence radioresponse specifically under hypoxic conditions. Furthermore, using transcriptomic data, we found evidence for tissue-specific determinants of radioresponse, suggesting that tumor type could influence the validity of putative predictive biomarkers of radioresponse. Finally, integrating radioresponse with drug response data, we found that drug classes impacting the cytoskeleton, DNA replication, and mitosis display similar therapeutic effects to ionizing radiation on cancer cell lines. In summary, RadioGx provides a unique computational toolbox for hypothesis generation to advance preclinical research for radiation oncology and precision medicine. SIGNIFICANCE: The RadioGx computational platform enables integrative analyses of cellular response to radiation with drug responses and genome-wide molecular data. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/24/6227/F1.large.jpg.See related commentary by Spratt and Speers, p. 6076.

PMID: 31558563 [PubMed - indexed for MEDLINE]

Cistrome Partitioning Reveals Convergence of Somatic Mutations and Risk Variants on Master Transcription Regulators in Primary Prostate Tumors.

1 week ago
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Cistrome Partitioning Reveals Convergence of Somatic Mutations and Risk Variants on Master Transcription Regulators in Primary Prostate Tumors.

Cancer Cell. 2019 12 09;36(6):674-689.e6

Authors: Mazrooei P, Kron KJ, Zhu Y, Zhou S, Grillo G, Mehdi T, Ahmed M, Severson TM, Guilhamon P, Armstrong NS, Huang V, Yamaguchi TN, Fraser M, van der Kwast T, Boutros PC, He HH, Bergman AM, Bristow RG, Zwart W, Lupien M

Abstract
Thousands of noncoding somatic single-nucleotide variants (SNVs) of unknown function are reported in tumors. Partitioning the genome according to cistromes reveals the enrichment of somatic SNVs in prostate tumors as opposed to adjacent normal tissue cistromes of master transcription regulators, including AR, FOXA1, and HOXB13. This parallels enrichment of prostate cancer genetic predispositions over these transcription regulators' tumor cistromes, exemplified at the 8q24 locus harboring both risk variants and somatic SNVs in cis-regulatory elements upregulating MYC expression. However, Massively Parallel Reporter Assays reveal that few SNVs can alter the transactivation potential of individual cis-regulatory elements. Instead, similar to inherited risk variants, SNVs accumulate in cistromes of master transcription regulators required for prostate cancer development.

PMID: 31735626 [PubMed - indexed for MEDLINE]

Functional Enhancers Shape Extrachromosomal Oncogene Amplifications.

1 week ago
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Functional Enhancers Shape Extrachromosomal Oncogene Amplifications.

Cell. 2019 11 27;179(6):1330-1341.e13

Authors: Morton AR, Dogan-Artun N, Faber ZJ, MacLeod G, Bartels CF, Piazza MS, Allan KC, Mack SC, Wang X, Gimple RC, Wu Q, Rubin BP, Shetty S, Angers S, Dirks PB, Sallari RC, Lupien M, Rich JN, Scacheri PC

Abstract
Non-coding regions amplified beyond oncogene borders have largely been ignored. Using a computational approach, we find signatures of significant co-amplification of non-coding DNA beyond the boundaries of amplified oncogenes across five cancer types. In glioblastoma, EGFR is preferentially co-amplified with its two endogenous enhancer elements active in the cell type of origin. These regulatory elements, their contacts, and their contribution to cell fitness are preserved on high-level circular extrachromosomal DNA amplifications. Interrogating the locus with a CRISPR interference screening approach reveals a diversity of additional elements that impact cell fitness. The pattern of fitness dependencies mirrors the rearrangement of regulatory elements and accompanying rewiring of the chromatin topology on the extrachromosomal amplicon. Our studies indicate that oncogene amplifications are shaped by regulatory dependencies in the non-coding genome.

PMID: 31761532 [PubMed - indexed for MEDLINE]

Eye Movements and White Matter are Associated with Emotional Control in Children Treated for Brain Tumors.

1 week ago
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Eye Movements and White Matter are Associated with Emotional Control in Children Treated for Brain Tumors.

J Int Neuropsychol Soc. 2020 May 27;:1-15

Authors: Moxon-Emre I, Taylor MJ, Farb NAS, Oyefiade AA, Taylor MD, Bouffet E, Laughlin S, Skocic J, de Medeiros CB, Mabbott DJ

Abstract
OBJECTIVE: Children treated for brain tumors often experience social and emotional difficulties, including challenges with emotion regulation; our goal was to investigate the attention-related component processes of emotion regulation, using a novel eye-tracking measure, and to evaluate its relations with emotional functioning and white matter (WM) organization.
METHOD: Fifty-four children participated in this study; 36 children treated for posterior fossa tumors, and 18 typically developing children. Participants completed two versions of an emotion regulation eye-tracking task, designed to differentiate between implicit (i.e., automatic) and explicit (i.e., voluntary) subprocesses. The Emotional Control scale from the Behavior Rating Inventory of Executive Function was used to evaluate emotional control in daily life, and WM organization was assessed with diffusion tensor imaging.
RESULTS: We found that emotional faces captured attention across all groups (F(1,51) = 32.18, p < .001, η2p = .39). However, unlike typically developing children, patients were unable to override the attentional capture of emotional faces when instructed to (emotional face-by-group interaction: F(2,51) = 5.58, p = .006, η2p = .18). Across all children, our eye-tracking measure of emotion regulation was modestly associated with the parent-report emotional control score (r = .29, p = .045), and in patients it was associated with WM microstructure in the body and splenium of the corpus callosum (all t > 3.03, all p < .05).
CONCLUSIONS: Our findings suggest that an attention-related component process of emotion regulation is disrupted in children treated for brain tumors, and that it may relate to their emotional difficulties and WM organization. This work provides a foundation for future theoretical and mechanistic investigations of emotional difficulties in brain tumor survivors.

PMID: 32456730 [PubMed - as supplied by publisher]

Author Correction: Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response.

1 week ago
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Author Correction: Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response.

Nat Commun. 2020 May 26;11(1):2683

Authors: Szewczyk MM, Ishikawa Y, Organ S, Sakai N, Li F, Halabelian L, Ackloo S, Couzens AL, Eram M, Dilworth D, Fukushi H, Harding R, Dela Seña CC, Sugo T, Hayashi K, McLeod D, Zepeda C, Aman A, Sánchez-Osuna M, Bonneil E, Takagi S, Al-Awar R, Tyers M, Richard S, Takizawa M, Gingras AC, Arrowsmith CH, Vedadi M, Brown PJ, Nara H, Barsyte-Lovejoy D

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 32457299 [PubMed - in process]

MKRN2 Physically Interacts with GLE1 to Regulate mRNA Export and Zebrafish Retinal Development.

1 week ago
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MKRN2 Physically Interacts with GLE1 to Regulate mRNA Export and Zebrafish Retinal Development.

Cell Rep. 2020 May 26;31(8):107693

Authors: Wolf EJ, Miles A, Lee ES, Nabeel-Shah S, Greenblatt JF, Palazzo AF, Tropepe V, Emili A

Abstract
The mammalian mRNA nuclear export process is thought to terminate at the cytoplasmic face of the nuclear pore complex through ribonucleoprotein remodeling. We conduct a stringent affinity-purification mass-spectrometry-based screen of the physical interactions of human RNA-binding E3 ubiquitin ligases. The resulting protein-interaction network reveals interactions between the RNA-binding E3 ubiquitin ligase MKRN2 and GLE1, a DEAD-box helicase activator implicated in mRNA export termination. We assess MKRN2 epistasis with GLE1 in a zebrafish model. Morpholino-mediated knockdown or CRISPR/Cas9-based knockout of MKRN2 partially rescue retinal developmental defects seen upon GLE1 depletion, consistent with a functional association between GLE1 and MKRN2. Using ribonomic approaches, we show that MKRN2 binds selectively to the 3' UTR of a diverse subset of mRNAs and that nuclear export of MKRN2-associated mRNAs is enhanced upon knockdown of MKRN2. Taken together, we suggest that MKRN2 interacts with GLE1 to selectively regulate mRNA nuclear export and retinal development.

PMID: 32460013 [PubMed - as supplied by publisher]

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

1 week 1 day ago
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Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

J Clin Invest. 2019 07 02;129(8):3171-3184

Authors: Roberts JD, Murphy NP, Hamilton RM, Lubbers ER, James CA, Kline CF, Gollob MH, Krahn AD, Sturm AC, Musa H, El-Refaey M, Koenig S, Aneq MÅ, Hoorntje ET, Graw SL, Davies RW, Rafiq MA, Koopmann TT, Aafaqi S, Fatah M, Chiasson DA, Taylor MR, Simmons SL, Han M, van Opbergen CJ, Wold LE, Sinagra G, Mittal K, Tichnell C, Murray B, Codima A, Nazer B, Nguyen DT, Marcus FI, Sobriera N, Lodder EM, van den Berg MP, Spears DA, Robinson JF, Ursell PC, Green AK, Skanes AC, Tang AS, Gardner MJ, Hegele RA, van Veen TA, Wilde AA, Healey JS, Janssen PM, Mestroni L, van Tintelen JP, Calkins H, Judge DP, Hund TJ, Scheinman MM, Mohler PJ

Abstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.

PMID: 31264976 [PubMed - indexed for MEDLINE]

MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2.

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MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2.

Epigenetics Chromatin. 2019 10 10;12(1):63

Authors: Martínez de Paz A, Khajavi L, Martin H, Claveria-Gimeno R, Tom Dieck S, Cheema MS, Sanchez-Mut JV, Moksa MM, Carles A, Brodie NI, Sheikh TI, Freeman ME, Petrotchenko EV, Borchers CH, Schuman EM, Zytnicki M, Velazquez-Campoy A, Abian O, Hirst M, Esteller M, Vincent JB, Malnou CE, Ausió J

Abstract
BACKGROUND: MeCP2-a chromatin-binding protein associated with Rett syndrome-has two main isoforms, MeCP2-E1 and MeCP2-E2, differing in a few N-terminal amino acid residues. Previous studies have shown brain region-specific expression of these isoforms which, in addition to their different cellular localization and differential expression during brain development, suggest that they may also have non-overlapping molecular mechanisms. However, differential functions of MeCP2-E1 and E2 remain largely unexplored.
RESULTS: Here, we show that the N-terminal domains (NTD) of MeCP2-E1 and E2 modulate the ability of the methyl-binding domain (MBD) to interact with DNA as well as influencing the turn-over rates, binding dynamics, response to neuronal depolarization, and circadian oscillations of the two isoforms. Our proteomics data indicate that both isoforms exhibit unique interacting protein partners. Moreover, genome-wide analysis using ChIP-seq provide evidence for a shared as well as a specific regulation of different sets of genes.
CONCLUSIONS: Our study supports the idea that Rett syndrome might arise from simultaneous impairment of cellular processes involving non-overlapping functions of MECP2 isoforms. For instance, MeCP2-E1 mutations might impact stimuli-dependent chromatin regulation, while MeCP2-E2 mutations could result in aberrant ribosomal expression. Overall, our findings provide insight into the functional complexity of MeCP2 by dissecting differential aspects of its two isoforms.

PMID: 31601272 [PubMed - indexed for MEDLINE]

WormBase: a modern Model Organism Information Resource.

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WormBase: a modern Model Organism Information Resource.

Nucleic Acids Res. 2020 01 08;48(D1):D762-D767

Authors: Harris TW, Arnaboldi V, Cain S, Chan J, Chen WJ, Cho J, Davis P, Gao S, Grove CA, Kishore R, Lee RYN, Muller HM, Nakamura C, Nuin P, Paulini M, Raciti D, Rodgers FH, Russell M, Schindelman G, Auken KV, Wang Q, Williams G, Wright AJ, Yook K, Howe KL, Schedl T, Stein L, Sternberg PW

Abstract
WormBase (https://wormbase.org/) is a mature Model Organism Information Resource supporting researchers using the nematode Caenorhabditis elegans as a model system for studies across a broad range of basic biological processes. Toward this mission, WormBase efforts are arranged in three primary facets: curation, user interface and architecture. In this update, we describe progress in each of these three areas. In particular, we discuss the status of literature curation and recently added data, detail new features of the web interface and options for users wishing to conduct data mining workflows, and discuss our efforts to build a robust and scalable architecture by leveraging commercial cloud offerings. We conclude with a description of WormBase's role as a founding member of the nascent Alliance of Genome Resources.

PMID: 31642470 [PubMed - indexed for MEDLINE]

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