REPORT Mutations in Cohesin Complex Members SMC3 and SMC1A Cause a Mild Variant of Cornelia De Lange Syndrome with Predominant Mental Retardation
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Redundant and Specific Roles of Cohesin STAG Subunits in Chromatin Looping and Transcriptional Control
Downloaded from genome.cshlp.org on October 10, 2021 - Published by Cold Spring Harbor Laboratory Press Research Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcriptional control Valentina Casa,1,6 Macarena Moronta Gines,1,6 Eduardo Gade Gusmao,2,3,6 Johan A. Slotman,4 Anne Zirkel,2 Natasa Josipovic,2,3 Edwin Oole,5 Wilfred F.J. van IJcken,1,5 Adriaan B. Houtsmuller,4 Argyris Papantonis,2,3 and Kerstin S. Wendt1 1Department of Cell Biology, Erasmus MC, 3015 GD Rotterdam, The Netherlands; 2Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; 3Institute of Pathology, University Medical Center, Georg-August University of Göttingen, 37075 Göttingen, Germany; 4Optical Imaging Centre, Erasmus MC, 3015 GD Rotterdam, The Netherlands; 5Center for Biomics, Erasmus MC, 3015 GD Rotterdam, The Netherlands Cohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and transcriptional regulation during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. Besides its core subunits SMC3, SMC1A, and RAD21, cohesin in somatic cells contains one of two orthologous STAG sub- units, STAG1 or STAG2. How these variable subunits affect the function of the cohesin complex is still unclear. STAG1- and STAG2-cohesin were initially proposed to organize cohesion at telomeres and centromeres, respectively. Here, we uncover redundant and specific roles of STAG1 and STAG2 in gene regulation and chromatin looping using HCT116 cells with an auxin-inducible degron (AID) tag fused to either STAG1 or STAG2. Following rapid depletion of either subunit, we perform high-resolution Hi-C, gene expression, and sequential ChIP studies to show that STAG1 and STAG2 do not co-occupy in- dividual binding sites and have distinct ways by which they affect looping and gene expression. -
Low Tolerance for Transcriptional Variation at Cohesin Genes Is Accompanied by Functional Links to Disease-Relevant Pathways
bioRxiv preprint doi: https://doi.org/10.1101/2020.04.11.037358; this version posted April 13, 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. Title Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways Authors William Schierdingǂ1, Julia Horsfieldǂ2,3, Justin O’Sullivan1,3,4 ǂTo whom correspondence should be addressed. 1 Liggins Institute, The University of Auckland, Auckland, New Zealand 2 Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand 3 The Maurice Wilkins Centre for Biodiscovery, The University of Auckland, Auckland, New Zealand 4 MRC Lifecourse Epidemiology Unit, University of Southampton Acknowledgements This work was supported by a Royal Society of New Zealand Marsden Grant to JH and JOS (16-UOO- 072), and WS was supported by the same grant. Contributions WS planned the study, performed analyses, and drafted the manuscript. JH and JOS revised the manuscript. Competing interests None declared. bioRxiv preprint doi: https://doi.org/10.1101/2020.04.11.037358; this version posted April 13, 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. Abstract Variants in DNA regulatory elements can alter the regulation of distant genes through spatial- regulatory connections. -
Glioblastoma Cells Containing Mutations in the Cohesin Component STAG2 Are Sensitive to PARP Inhibition
Published OnlineFirst December 19, 2013; DOI: 10.1158/1535-7163.MCT-13-0749 Molecular Cancer Cancer Biology and Signal Transduction Therapeutics Glioblastoma Cells Containing Mutations in the Cohesin Component STAG2 Are Sensitive to PARP Inhibition Melanie L. Bailey1, Nigel J. O'Neil1, Derek M. van Pel2, David A. Solomon3, Todd Waldman4, and Philip Hieter1 Abstract Recent data have identified STAG2, a core subunit of the multifunctional cohesin complex, as a highly recurrently mutated gene in several types of cancer. We sought to identify a therapeutic strategy to selectively target cancer cells harboring inactivating mutations of STAG2 using two independent pairs of isogenic glioblastoma cell lines containing either an endogenous mutant STAG2 allele or a wild-type STAG2 allele restored by homologous recombination. We find that mutations in STAG2 are associated with significantly increased sensitivity to inhibitors of the DNA repair enzyme PARP. STAG2-mutated, PARP-inhibited cells accumulated in G2 phase and had a higher percentage of micronuclei, fragmented nuclei, and chromatin bridges compared with wild-type STAG2 cells. We also observed more 53BP1 foci in STAG2-mutated glioblastoma cells, suggesting that these cells have defects in DNA repair. Furthermore, cells with mutations in STAG2 were more sensitive than cells with wild-type STAG2 when PARP inhibitors were used in combination with DNA-damaging agents. These data suggest that PARP is a potential target for tumors harboring inactivating mutations in STAG2, and strongly recommend that STAG2 status be determined and correlated with therapeutic response to PARP inhibitors, both prospectively and retrospectively, in clinical trials. Mol Cancer Ther; 13(3); 724–32. -
Gene Regulation by Cohesin in Cancer: Is the Ring an Unexpected Party to Proliferation?
Published OnlineFirst September 22, 2011; DOI: 10.1158/1541-7786.MCR-11-0382 Molecular Cancer Review Research Gene Regulation by Cohesin in Cancer: Is the Ring an Unexpected Party to Proliferation? Jenny M. Rhodes, Miranda McEwan, and Julia A. Horsfield Abstract Cohesin is a multisubunit protein complex that plays an integral role in sister chromatid cohesion, DNA repair, and meiosis. Of significance, both over- and underexpression of cohesin are associated with cancer. It is generally believed that cohesin dysregulation contributes to cancer by leading to aneuploidy or chromosome instability. For cancers with loss of cohesin function, this idea seems plausible. However, overexpression of cohesin in cancer appears to be more significant for prognosis than its loss. Increased levels of cohesin subunits correlate with poor prognosis and resistance to drug, hormone, and radiation therapies. However, if there is sufficient cohesin for sister chromatid cohesion, overexpression of cohesin subunits should not obligatorily lead to aneuploidy. This raises the possibility that excess cohesin promotes cancer by alternative mechanisms. Over the last decade, it has emerged that cohesin regulates gene transcription. Recent studies have shown that gene regulation by cohesin contributes to stem cell pluripotency and cell differentiation. Of importance, cohesin positively regulates the transcription of genes known to be dysregulated in cancer, such as Runx1, Runx3, and Myc. Furthermore, cohesin binds with estrogen receptor a throughout the genome in breast cancer cells, suggesting that it may be involved in the transcription of estrogen-responsive genes. Here, we will review evidence supporting the idea that the gene regulation func- tion of cohesin represents a previously unrecognized mechanism for the development of cancer. -
High Constitutive Cytokine Release by Primary Human Acute Myeloid Leukemia Cells Is Associated with a Specific Intercellular Communication Phenotype
Supplementary Information High Constitutive Cytokine Release by Primary Human Acute Myeloid Leukemia Cells Is Associated with a Specific Intercellular Communication Phenotype Håkon Reikvam 1,2,*, Elise Aasebø 1, Annette K. Brenner 2, Sushma Bartaula-Brevik 1, Ida Sofie Grønningsæter 2, Rakel Brendsdal Forthun 2, Randi Hovland 3,4 and Øystein Bruserud 1,2 1 Department of Clinical Science, University of Bergen, 5020, Bergen, Norway 2 Department of Medicine, Haukeland University Hospital, 5021, Bergen, Norway 3 Department of Medical Genetics, Haukeland University Hospital, 5021, Bergen, Norway 4 Institute of Biomedicine, University of Bergen, 5020, Bergen, Norway * Correspondence: [email protected]; Tel.: +55-97-50-00 J. Clin. Med. 2019, 8, x 2 of 36 Figure S1. Mutational studies in a cohort of 71 AML patients. The figure shows the number of patients with the various mutations (upper), the number of mutations in for each patient (middle) and the number of main classes with mutation(s) in each patient (lower). 2 J. Clin. Med. 2019, 8, x; doi: www.mdpi.com/journal/jcm J. Clin. Med. 2019, 8, x 3 of 36 Figure S2. The immunophenotype of primary human AML cells derived from 62 unselected patients. The expression of the eight differentiation markers CD13, CD14, CD15, CD33, CD34, CD45, CD117 and HLA-DR was investigated for 62 of the 71 patients included in our present study. We performed an unsupervised hierarchical cluster analysis and identified four patient main clusters/patient subsets. The mutational profile for each f the 62 patients is also given (middle), no individual mutation of main class of mutations showed any significant association with any of the for differentiation marker clusters (middle). -
Cohesin Mutations in Cancer: Emerging Therapeutic Targets
International Journal of Molecular Sciences Review Cohesin Mutations in Cancer: Emerging Therapeutic Targets Jisha Antony 1,2,*, Chue Vin Chin 1 and Julia A. Horsfield 1,2,3,* 1 Department of Pathology, Otago Medical School, University of Otago, Dunedin 9016, New Zealand; [email protected] 2 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand 3 Genetics Otago Research Centre, University of Otago, Dunedin 9016, New Zealand * Correspondence: [email protected] (J.A.); julia.horsfi[email protected] (J.A.H.) Abstract: The cohesin complex is crucial for mediating sister chromatid cohesion and for hierarchal three-dimensional organization of the genome. Mutations in cohesin genes are present in a range of cancers. Extensive research over the last few years has shown that cohesin mutations are key events that contribute to neoplastic transformation. Cohesin is involved in a range of cellular processes; therefore, the impact of cohesin mutations in cancer is complex and can be cell context dependent. Candidate targets with therapeutic potential in cohesin mutant cells are emerging from functional studies. Here, we review emerging targets and pharmacological agents that have therapeutic potential in cohesin mutant cells. Keywords: cohesin; cancer; therapeutics; transcription; synthetic lethal 1. Introduction Citation: Antony, J.; Chin, C.V.; Genome sequencing of cancers has revealed mutations in new causative genes, includ- Horsfield, J.A. Cohesin Mutations in ing those in genes encoding subunits of the cohesin complex. Defects in cohesin function Cancer: Emerging Therapeutic from mutation or amplifications has opened up a new area of cancer research to which Targets. -
The Genetic Program of Pancreatic Beta-Cell Replication in Vivo
Page 1 of 65 Diabetes The genetic program of pancreatic beta-cell replication in vivo Agnes Klochendler1, Inbal Caspi2, Noa Corem1, Maya Moran3, Oriel Friedlich1, Sharona Elgavish4, Yuval Nevo4, Aharon Helman1, Benjamin Glaser5, Amir Eden3, Shalev Itzkovitz2, Yuval Dor1,* 1Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel 2Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. 3Department of Cell and Developmental Biology, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel 4Info-CORE, Bioinformatics Unit of the I-CORE Computation Center, The Hebrew University and Hadassah, The Institute for Medical Research Israel- Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel 5Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel *Correspondence: [email protected] Running title: The genetic program of pancreatic β-cell replication 1 Diabetes Publish Ahead of Print, published online March 18, 2016 Diabetes Page 2 of 65 Abstract The molecular program underlying infrequent replication of pancreatic beta- cells remains largely inaccessible. Using transgenic mice expressing GFP in cycling cells we sorted live, replicating beta-cells and determined their transcriptome. Replicating beta-cells upregulate hundreds of proliferation- related genes, along with many novel putative cell cycle components. Strikingly, genes involved in beta-cell functions, namely glucose sensing and insulin secretion were repressed. Further studies using single molecule RNA in situ hybridization revealed that in fact, replicating beta-cells double the amount of RNA for most genes, but this upregulation excludes genes involved in beta-cell function. -
Novel STAG1 Frameshift Mutation in a Patient Affected by a Syndromic Form of Neurodevelopmental Disorder
G C A T T A C G G C A T genes Case Report Novel STAG1 Frameshift Mutation in a Patient Affected by a Syndromic Form of Neurodevelopmental Disorder Ester Di Muro 1 , Pietro Palumbo 1 , Mario Benvenuto 1, Maria Accadia 2, Marilena Carmela Di Giacomo 3, Sergio Manieri 4, Rosaria Abate 4, Maria Tagliente 4, Stefano Castellana 5, Tommaso Mazza 5 , Massimo Carella 1 and Orazio Palumbo 1,* 1 Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (Foggia), Italy; [email protected] (E.D.M.); [email protected] (P.P.); [email protected] (M.B.); [email protected] (M.C.) 2 Medical Genetics Service, Hospital “Cardinale G. Panico”, 73039 Tricase (Lecce), Italy; [email protected] 3 U.O.C di Anatomia Patologica, AOR Ospedale “San Carlo”, 85100 Potenza, Italy; [email protected] 4 U.O.C di Pediatria, AOR Ospedale “San Carlo”, 85100 Potenza, Italy; [email protected] (S.M.); [email protected] (R.A.); [email protected] (M.T.) 5 Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (Foggia), Italy; [email protected] (S.C.); [email protected] (T.M.) * Correspondence: [email protected]; Tel.: +39-0882416345 Abstract: The cohesin complex is a large evolutionary conserved functional unit which plays an Citation: Di Muro, E.; Palumbo, P.; essential role in DNA repair and replication, chromosome segregation and gene expression. It Benvenuto, M.; Accadia, M.; Di consists of four core proteins, SMC1A, SMC3, RAD21, and STAG1/2, and by proteins regulating Giacomo, M.C.; Manieri, S.; Abate, R.; the interaction between the complex and the chromosomes. -
Protein List
Protein Accession Protein Id Protein Name P11171 41 Protein 4. -
Low Tolerance for Transcriptional Variation at Cohesin Genes Is
Functional genomics J Med Genet: first published as 10.1136/jmedgenet-2020-107095 on 11 September 2020. Downloaded from ORIGINAL RESEARCH Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease- relevant pathways William Schierding ,1 Julia A Horsfield,2,3 Justin M O’Sullivan 1,3,4 ► Additional material is ABSTRACT of functional cohesin without eliminating it alto- published online only. To view Background: The cohesin complex plays an essential gether. Complete loss of cohesin is not tolerated please visit the journal online in healthy individuals.2 Thus, cohesin is haplo- (http:// dx. doi. org/ 10. 1136/ role in genome organisation and cell division. A full jmedgenet- 2020- 107095). complement of the cohesin complex and its regulators is insufficient such that normal tissue development important for normal development, since heterozygous and homeostasis requires that the concentrations 1Liggins Institute, The University mutations in genes encoding these components can of cohesin and its regulatory factors remain tightly of Auckland, Auckland, New be sufficient to produce a disease phenotype. The regulated. Zealand 2Department of Pathology, implication that genes encoding the cohesin subunits The human mitotic cohesin ring contains four Dunedin School of Medicine, or cohesin regulators must be tightly controlled and integral subunits: two structural maintenance University of Otago, Dunedin, resistant to variability in expression has not yet been proteins (SMC1A, SMC3), one stromalin HEAT- New Zealand 3 formally tested. repeat domain subunit (STAG1 or STAG2) and one Maurice Wilkins Centre 6 for Molecular Biodiscovery, Methods: Here, we identify spatial- regulatory kleisin subunit (RAD21). Genes encoding cohesin The University of Auckland, connections with potential to regulate expression of subunits are mutated in a wide range of cancers. -
Cohesin Complex-Associated Holoprosencephaly
This is a repository copy of Cohesin complex-associated holoprosencephaly. White Rose Research Online URL for this paper: https://eprints.whiterose.ac.uk/175395/ Version: Accepted Version Article: Kruszka, P., Berger, S.I., Casa, V. et al. (32 more authors) (2019) Cohesin complex- associated holoprosencephaly. Brain, 142 (9). pp. 2631-2643. ISSN 0006-8950 https://doi.org/10.1093/brain/awz210 This is a pre-copyedited, author-produced version of an article accepted for publication in Brain following peer review. The version of record Paul Kruszka, Seth I Berger, Valentina Casa, Mike R Dekker, Jenna Gaesser, Karin Weiss, Ariel F Martinez, David R Murdock, Raymond J Louie, Eloise J Prijoles, Angie W Lichty, Oebele F Brouwer, Evelien Zonneveld-Huijssoon, Mark J Stephan, Jacob Hogue, Ping Hu, Momoko Tanima-Nagai, Joshua L Everson, Chitra Prasad, Anna Cereda, Maria Iascone, Allison Schreiber, Vickie Zurcher, Nicole Corsten-Janssen, Luis Escobar, Nancy J Clegg, Mauricio R Delgado, Omkar Hajirnis, Meena Balasubramanian, Hülya Kayserili, Matthew Deardorff, Raymond A Poot, Kerstin S Wendt, Robert J Lipinski, Maximilian Muenke, Cohesin complex- associated holoprosencephaly, Brain, Volume 142, Issue 9, September 2019, Pages 2631–2643 is available online at: https://doi.org/10.1093/brain/awz210 Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. -
The Cohesin-Associated Protein Wapal Is Required for Proper Polycomb-Mediated Gene Silencing
The cohesin-associated protein Wapal is required for proper Polycomb-mediated gene silencing The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Stelloh, C., M. H. Reimer, K. Pulakanti, S. Blinka, J. Peterson, L. Pinello, S. Jia, et al. 2016. “The cohesin-associated protein Wapal is required for proper Polycomb-mediated gene silencing.” Epigenetics & Chromatin 9 (1): 14. doi:10.1186/s13072-016-0063-7. http:// dx.doi.org/10.1186/s13072-016-0063-7. Published Version doi:10.1186/s13072-016-0063-7 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:26860332 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Stelloh et al. Epigenetics & Chromatin (2016) 9:14 DOI 10.1186/s13072-016-0063-7 Epigenetics & Chromatin RESEARCH Open Access The cohesin‑associated protein Wapal is required for proper Polycomb‑mediated gene silencing Cary Stelloh1†, Michael H. Reimer1,2†, Kirthi Pulakanti1, Steven Blinka1,2, Jonathan Peterson1, Luca Pinello3, Shuang Jia4, Sergei Roumiantsev5, Martin J. Hessner4, Samuel Milanovich6, Guo‑Cheng Yuan3 and Sridhar Rao1,2,4* Abstract Background: The cohesin complex consists of multiple core subunits that play critical roles in mitosis and transcrip‑ tional regulation. The cohesin-associated protein Wapal plays a central role in off-loading cohesin to facilitate sister chromatid separation, but its role in regulating mammalian gene expression is not understood.