1Q21.1 Duplication Syndrome and Epilepsy Case Report and Review
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Understanding the Impact of 1Q21.1 Copy Number Variant
Understanding the impact of 1q21.1 copy number variant Article (Published Version) Havard, Chansonette, Strong, Emma, Mercier, Eloi, Colnaghi, Rita, Alcantara, Diana Rita Ralha, Chow, Eva, Martell, Sally, Tyson, Christine, Hrynchak, Monica, McGillivray, Barbara, Hamilton, Sara, Marles, Sandra, Mhanni, Aziz, Dawson, Angelika J, Pavlidis, Paul et al. (2011) Understanding the impact of 1q21.1 copy number variant. Orphanet Journal of Rare Diseases, 6 (54). pp. 1-12. ISSN 1750-1172 This version is available from Sussex Research Online: http://sro.sussex.ac.uk/id/eprint/41577/ This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the URL above for details on accessing the published version. Copyright and reuse: Sussex Research Online is a digital repository of the research output of the University. Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available. Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. -
Genetic Screens in Isogenic Mammalian Cell Lines Without Single Cell Cloning
ARTICLE https://doi.org/10.1038/s41467-020-14620-6 OPEN Genetic screens in isogenic mammalian cell lines without single cell cloning Peter C. DeWeirdt1,2, Annabel K. Sangree1,2, Ruth E. Hanna1,2, Kendall R. Sanson1,2, Mudra Hegde 1, Christine Strand 1, Nicole S. Persky1 & John G. Doench 1* Isogenic pairs of cell lines, which differ by a single genetic modification, are powerful tools for understanding gene function. Generating such pairs of mammalian cells, however, is labor- 1234567890():,; intensive, time-consuming, and, in some cell types, essentially impossible. Here, we present an approach to create isogenic pairs of cells that avoids single cell cloning, and screen these pairs with genome-wide CRISPR-Cas9 libraries to generate genetic interaction maps. We query the anti-apoptotic genes BCL2L1 and MCL1, and the DNA damage repair gene PARP1, identifying both expected and uncharacterized buffering and synthetic lethal interactions. Additionally, we compare acute CRISPR-based knockout, single cell clones, and small- molecule inhibition. We observe that, while the approaches provide largely overlapping information, differences emerge, highlighting an important consideration when employing genetic screens to identify and characterize potential drug targets. We anticipate that this methodology will be broadly useful to comprehensively study gene function across many contexts. 1 Genetic Perturbation Platform, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA. 2These authors contributed equally: Peter C. DeWeirdt, -
Chromatin Regulator CHD1 Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Defi Cient Prostate Cancer
Published OnlineFirst May 8, 2020; DOI: 10.1158/2159-8290.CD-19-1352 RESEARCH ARTICLE Chromatin Regulator CHD1 Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Defi cient Prostate Cancer Di Zhao 1 , 2 , Li Cai 1 , Xin Lu 1 , 3 , Xin Liang 1 , 4 , Jiexi Li 1 , Peiwen Chen 1 , Michael Ittmann 5 , Xiaoying Shang 1 , Shan Jiang6 , Haoyan Li 2 , Chenling Meng 2 , Ivonne Flores 6 , Jian H. Song 4 , James W. Horner 6 , Zhengdao Lan 1 , Chang-Jiun Wu6 , Jun Li 6 , Qing Chang 7 , Ko-Chien Chen 1 , Guocan Wang 1 , 4 , Pingna Deng 1 , Denise J. Spring 1 , Y. Alan Wang1 , and Ronald A. DePinho 1 Downloaded from cancerdiscovery.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst May 8, 2020; DOI: 10.1158/2159-8290.CD-19-1352 ABSTRACT Genetic inactivation of PTEN is common in prostate cancer and correlates with poorer prognosis. We previously identifi edCHD1 as an essential gene in PTEN- defi cient cancer cells. Here, we sought defi nitivein vivo genetic evidence for, and mechanistic under- standing of, the essential role of CHD1 in PTEN-defi cient prostate cancer. In Pten and Pten /Smad4 genetically engineered mouse models, prostate-specifi c deletion ofChd1 resulted in markedly delayed tumor progression and prolonged survival. Chd1 deletion was associated with profound tumor microenvironment (TME) remodeling characterized by reduced myeloid-derived suppressor cells (MDSC) and increased CD8+ T cells. Further analysis identifi ed IL6 as a key transcriptional target of CHD1, which plays a major role in recruitment of immunosuppressive MDSCs. -
Megalencephaly and Macrocephaly
277 Megalencephaly and Macrocephaly KellenD.Winden,MD,PhD1 Christopher J. Yuskaitis, MD, PhD1 Annapurna Poduri, MD, MPH2 1 Department of Neurology, Boston Children’s Hospital, Boston, Address for correspondence Annapurna Poduri, Epilepsy Genetics Massachusetts Program, Division of Epilepsy and Clinical Electrophysiology, 2 Epilepsy Genetics Program, Division of Epilepsy and Clinical Department of Neurology, Fegan 9, Boston Children’s Hospital, 300 Electrophysiology, Department of Neurology, Boston Children’s Longwood Avenue, Boston, MA 02115 Hospital, Boston, Massachusetts (e-mail: [email protected]). Semin Neurol 2015;35:277–287. Abstract Megalencephaly is a developmental disorder characterized by brain overgrowth secondary to increased size and/or numbers of neurons and glia. These disorders can be divided into metabolic and developmental categories based on their molecular etiologies. Metabolic megalencephalies are mostly caused by genetic defects in cellular metabolism, whereas developmental megalencephalies have recently been shown to be caused by alterations in signaling pathways that regulate neuronal replication, growth, and migration. These disorders often lead to epilepsy, developmental disabilities, and Keywords behavioral problems; specific disorders have associations with overgrowth or abnor- ► megalencephaly malities in other tissues. The molecular underpinnings of many of these disorders are ► hemimegalencephaly now understood, providing insight into how dysregulation of critical pathways leads to ► -
Structural Basis of ALC1/CHD1L Autoinhibition and the Mechanism of Activation By
bioRxiv preprint doi: https://doi.org/10.1101/2021.06.24.449738; this version posted June 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome Li Wang,1,2,† Kangjing Chen,1,2,† and Zhucheng Chen1,2,3, * 1Key Laboratory for Protein Sciences of Ministry of Education, School of Life Science, Tsinghua University, Beijing, 100084, P.R. China 2Beijing Advanced Innovation Center for Structural Biology & Beijing Frontier Research Center for Biological Structure, School of Life Science, Tsinghua University, Beijing 100084, China 3Tsinghua-Peking Center for Life Sciences, Beijing 100084, China † These authors contributed equally: Li Wang, Kangjing Chen *Correspondence to: Zhucheng Chen Email: [email protected] Telephone: 86-10-62796096 Abstract Chromatin remodeler ALC1 (amplification in liver cancer 1) is crucial for repairing damaged DNA. It is autoinhibited and activated by nucleosomal epitopes. However, the mechanisms by which ALC1 is regulated remain unclear. Here we report the crystal structure of human ALC1 and the cryoEM structure bound to the nucleosome. The structure shows the macro domain of ALC1 binds to lobe 2 of the ATPase motor, sequestering two elements for nucleosome recognition, explaining the autoinhibition mechanism of the enzyme. The H4 tail competes with the macro domain for lobe 2- binding, explaining the requirement for this nucleosomal epitope for ALC1 activation. -
UNIVERSITY of CALIFORNIA Los Angeles
UNIVERSITY OF CALIFORNIA Los Angeles Identifying Novel Molecular Biomarkers and Therapeutic Targets for Prostate Cancer A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Molecular and Medical Pharmacology by Tanushree Ravi Shenoy 2017 © Copyright by Tanushree Ravi Shenoy 2017 ABSTRACT OF THE DISSERTATION Identifying Novel Molecular Biomarkers and Therapeutic Targets for Prostate Cancer by Tanushree Ravi Shenoy Doctor of Philosophy in Molecular and Medical Pharmacology University of California, Los Angeles, 2017 Professor Owen N Witte, Co-Chair Professor Hong Wu, Co-Chair Prostate cancer is the most common malignancy in males, and the third leading cause of male cancer-related death in the Western world. Although most prostate cancers are diagnosed at an early and treatable stages, predicting the outcome of prostate cancer progression and treatment has proven to be challenging because of the heterogeneous nature of the disease. Recent cancer genome studies have identified novel alterations as well as the potential actionable targets. Among these novel alterations is chromodomain helicase DNA-binding protein 1 (CHD1). CHD1 deletion occurs in as many as 20% of prostate cancers and may be associated with genomic instability. To validate the function of CHD1 in prostate cancer in vivo, we created the Pb-Cre+;Chd1L/L mouse model, whereby Chd1 is deleted in mouse prostate epithelial cells, and engineered CHD1-deleted prostate cancer cell lines. We found that while Chd1 deletion alone does not induce prostate cancer in vivo, it confers DNA damage sensitivity and homologous ii recombination impairment, making CHD1-deficient cells sensitive to PARP inhibitors and Platinum-based drugs. -
South Carolina Birth Defects Program Resource Guide
South Carolina Birth Defects Program Resource Guide A South Carolina where healthy births are promoted, every birth defect matters, and families impacted by birth defects are supported. Table Of Contents Introduction Introduction 1 Thousands of families in South Carolina have been impacted by a birth defect. Birth defects are structural changes which are already there when a baby is born that can affect any part of the body (e.g., heart, brain, South Carolina Birth Defects Program Mission and Vision 2 foot). They may affect how the body looks, works, or both. Birth defects can vary from mild to severe. The well-being of each child affected with a birth defect depends mostly on which organ or body part is involved, General Information on Birth Defects in South Carolina 4 how much it is affected, early detection, and timely entry into Early Intervention services. Cardiovascular (Heart) Birth Defects in South Carolina 5 Learning that a child has a birth defect can be difficult for a family. Families often feel alone when they find out about a birth defect. They are not alone. According to the Centers for Disease Control and Prevention, birth Interview with a Parent of a Child with a Critical Congenital Heart Birth Defect 7 defects affect 1 in 33 babies born every year and cause 1 in 5 infant deaths. In 2004, South Carolina government officials created a way to track these important conditions through a law called “The South Carolina Birth Orofacial Birth Defects 11 Defects Act.” The South Carolina Birth Defects Program (SCBDP) was created through this law. -
Understanding Nucleotide Excision Repair and Its Roles in Cancer and Ageing
REVIEWS DNA DAMAGE Understanding nucleotide excision repair and its roles in cancer and ageing Jurgen A. Marteijn*, Hannes Lans*, Wim Vermeulen, Jan H. J. Hoeijmakers Abstract | Nucleotide excision repair (NER) eliminates various structurally unrelated DNA lesions by a multiwise ‘cut and patch’-type reaction. The global genome NER (GG‑NER) subpathway prevents mutagenesis by probing the genome for helix-distorting lesions, whereas transcription-coupled NER (TC‑NER) removes transcription-blocking lesions to permit unperturbed gene expression, thereby preventing cell death. Consequently, defects in GG‑NER result in cancer predisposition, whereas defects in TC‑NER cause a variety of diseases ranging from ultraviolet radiation‑sensitive syndrome to severe premature ageing conditions such as Cockayne syndrome. Recent studies have uncovered new aspects of DNA-damage detection by NER, how NER is regulated by extensive post-translational modifications, and the dynamic chromatin interactions that control its efficiency. Based on these findings, a mechanistic model is proposed that explains the complex genotype–phenotype correlations of transcription-coupled repair disorders. The integrity of DNA is constantly threatened by endo of an intricate DNA-damage response (DDR), which genously formed metabolic products and by-products, comprises sophisticated repair and damage signalling such as reactive oxygen species (ROS) and alkylating processes. The DDR involves DNA-damage sensors and agents, and by its intrinsic chemical instability (for exam signalling kinases that regulate a range of downstream ple, by its ability to spontaneously undergo hydrolytic mediator and effector molecules that control repair, cell deamination and depurination). Environmental chemi cycle progression and cell fate4. The core of this DDR is cals and radiation also affect the physical constitution of formed by a network of complementary DNA repair sys DNA1. -
Endosomal Trafficking Defects Alter Neural Progenitor Proliferation And
bioRxiv preprint doi: https://doi.org/10.1101/2020.08.17.254037; this version posted August 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 2 Endosomal trafficking defects alter neural progenitor proliferation 3 and cause microcephaly 4 5 Jacopo A. Carpentieri1, Amandine Di Cicco1, David Andreau1, Laurence Del Maestro2, Fatima 6 El Marjou1, Laure Coquand1, Jean-Baptiste Brault1, Nadia Bahi-Buisson3, Alexandre D. 7 Baffet1,4,# 8 9 1- Institut Curie, PSL Research University, CNRS UMR144, 75005 Paris, France 10 2- Centre Épigénétique et destin cellulaire, Université Paris Diderot, CNRS UMR 7216, 75013 Paris, 11 France 12 3- INSERM U1163, Institut Imagine, Necker Hospital, 75015 Paris, France 13 4- Institut national de la santé et de la recherche médicale (Inserm) 14 # Corresponding author: [email protected] 15 16 Abstract 17 Primary microcephaly and megalencephaly are severe brain malformations defined by reduced 18 and increased brain size, respectively. Whether these two pathologies arise from related alterations at 19 the molecular level is unclear. Microcephaly has been largely associated with centrosomal defects, 20 leading to cell death. Here, we investigated the consequences of WDR81 loss of function, which cause 21 severe microcephaly in patients. We show that WDR81 regulates endosomal trafficking of EGFR, 22 and that loss of function leads to reduced MAP kinase pathway activation. Mouse radial glial 23 progenitor cells knocked-out for WDR81 display reduced proliferation rates, leading to reduced brain 24 size. -
CHD1L Promotes Hepatocellular Carcinoma Progression and Metastasis in Mice and Is Associated with These Processes in Human Patients
CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients Leilei Chen, … , Yan Li, Xin-Yuan Guan J Clin Invest. 2010;120(4):1178-1191. https://doi.org/10.1172/JCI40665. Research Article Chromodomain helicase/ATPase DNA binding protein 1–like gene (CHD1L) is a recently identified oncogene localized at 1q21, a frequently amplified region in hepatocellular carcinoma (HCC). To explore its oncogenic mechanisms, we set out to identify CHD1L-regulated genes using a chromatin immunoprecipitation–based (ChIP-based) cloning strategy in a human HCC cell line. We then further characterized 1 identified gene, ARHGEF9, which encodes a specific guanine nucleotide exchange factor (GEF) for the Rho small GTPase Cdc42. Overexpression of ARHGEF9 was detected in approximately half the human HCC samples analyzed and positively correlated with CHD1L overexpression. In vitro and in vivo functional studies in mice showed that CHD1L contributed to tumor cell migration, invasion, and metastasis by increasing cell motility and inducing filopodia formation and epithelial-mesenchymal transition (EMT) via ARHGEF9- mediated Cdc42 activation. Silencing ARHGEF9 expression by RNAi effectively abolished the invasive and metastatic abilities of CHD1L in mice. Furthermore, investigation of clinical HCC specimens showed that CHD1L and ARHGEF9 were markedly overexpressed in metastatic HCC tissue compared with healthy tissue. Increased expression of CHD1L was often observed at the invasive front of HCC tumors and correlated with venous infiltration, microsatellite tumor nodule formation, and poor disease-free survival. These findings suggest that CHD1L-ARHGEF9-Cdc42-EMT might be a novel pathway involved in HCC progression and metastasis. -
Proximal Microdeletions and Microduplications of 1Q21.1 Contribute to Variable Abnormal Phenotypes
European Journal of Human Genetics (2012) 20, 754–761 & 2012 Macmillan Publishers Limited All rights reserved 1018-4813/12 www.nature.com/ejhg ARTICLE Proximal microdeletions and microduplications of 1q21.1 contribute to variable abnormal phenotypes Jill A Rosenfeld1, Ryan N Traylor1, G Bradley Schaefer2, Elizabeth W McPherson3, Blake C Ballif1, Eva Klopocki4, Stefan Mundlos4, Lisa G Shaffer*,1 and Arthur S Aylsworth5, 1q21.1 Study Group6 Chromosomal band 1q21.1 can be divided into two distinct regions, proximal and distal, based on segmental duplications that mediate recurrent rearrangements. Microdeletions and microduplications of the distal region within 1q21.1, which are susceptibility factors for a variety of neurodevelopmental phenotypes, have been more extensively studied than proximal microdeletions and microduplications. Proximal microdeletions are known as a susceptibility factor for thrombocytopenia-absent radius (TAR) syndrome, but it is unclear if these proximal microdeletions have other phenotypic consequences. Therefore, to elucidate the clinical significance of rearrangements of the proximal 1q21.1 region, we evaluated the phenotypes in patients identified with 1q21.1 rearrangements after referral for clinical microarray testing. We report clinical information for 55 probands with copy number variations (CNVs) involving proximal 1q21.1: 22 microdeletions and 20 reciprocal microduplications limited to proximal 1q21.1 and 13 microdeletions that include both the proximal and distal regions. Six individuals with proximal microdeletions have TAR syndrome. Three individuals with proximal microdeletions and two individuals with larger microdeletions of proximal and distal 1q21.1 have a ‘partial’ TAR phenotype. Furthermore, one subject with TAR syndrome has a smaller, atypical deletion, narrowing the critical deletion region for the syndrome. -
Miller–Dieker Syndrome, Type 1 Lissencephaly
Journal of Perinatology (2008) 28, 313–315 r 2008 Nature Publishing Group All rights reserved. 0743-8346/08 $30 www.nature.com/jp IMAGING CASE BOOK Miller–Dieker syndrome, type 1 lissencephaly TE Herman and MJ Siegel Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA Journal of Perinatology (2008) 28, 313–315; doi:10.1038/sj.jp.7211920 bitemporal shallowness. The ears were low set. Retromicrognathia, and microphthalmia, more marked on the left, were also present. Case presentation The child had a cranial sonogram (Figure 1) and cranial magnetic A 1910 g infant was born at 41-weeks gestation to a 19-year-old resonance imaging (Figure 2). gravida 1 mother after a pregnancy complicated by hydramnios and poor fetal movement. The child was delivered by a cesarean section because of fetal decelerations with labor. Severe intrauterine Denouement and discussion growth retardation was present with the infant’s weight, length and The cranial sonogram demonstrated an abnormally smooth brain head circumference all less than the tenth percentile for gestational with no gyration or sulcation with a wide, shallow sylvian fissure age. The patient’s head demonstrated a wasted appearance with creating a figure-of-8 appearance. The absence of all gyri is Figure 1 (a) Coronal cranial sonogram at the level of the third ventricle demonstrating a figure-of-8 appearance of the brain with wide sylvian fissure and with no sulci or gyri. (b) Sagittal right lateral cranial sonogram demonstrating absence of gyri over the ipsilateral hemisphere. (c) Right sagittal sonogram demonstrating echogenic linear thalamostriate vessels (arrow).