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Zerbib J, Bloomberg A, Ben-David U. Targeting vulnerabilities of aneuploid cells for cancer therapy. Trends Cancer 2025:S2405-8033(25)00097-4. [PMID: 40368673 DOI: 10.1016/j.trecan.2025.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/04/2025] [Accepted: 04/04/2025] [Indexed: 05/16/2025]
Abstract
Aneuploidy is a common feature of cancer that drives tumor evolution, but it also creates cellular vulnerabilities that might be exploited therapeutically. Recent advances in genomic technologies and experimental models have uncovered diverse cellular consequences of aneuploidy, revealing dependencies on mitotic regulation, DNA replication and repair, proteostasis, metabolism, and immune interactions. Harnessing aneuploidy for precision oncology requires the combination of genomic, functional, and clinical studies that will enable translation of our improved understanding of aneuploidy to targeted therapies. In this review we discuss approaches to targeting both highly aneuploid cells and cells with specific common aneuploidies, summarize the biological underpinning of these aneuploidy-induced vulnerabilities, and explore their therapeutic implications.
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Affiliation(s)
- Johanna Zerbib
- Department of Human Molecular Genetics and Biochemistry, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Amit Bloomberg
- Department of Human Molecular Genetics and Biochemistry, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Uri Ben-David
- Department of Human Molecular Genetics and Biochemistry, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel.
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2
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Zuo X. Mitochondrial Imbalance in Down Syndrome: A Driver of Accelerated Brain Aging? Aging Dis 2025:AD.2025.0189. [PMID: 40249934 DOI: 10.14336/ad.2025.0189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 04/06/2025] [Indexed: 04/20/2025] Open
Abstract
Down syndrome (DS), caused by trisomy of chromosome 21 (HSA21), is a complex condition associated with neurodevelopmental impairments and accelerated brain aging, often culminating in early-onset Alzheimer's disease (AD). Central to this accelerated aging is mitochondrial imbalance, characterized by disrupted energy metabolism, increased oxidative stress, impaired dynamics, and defective quality control mechanisms like mitophagy. These abnormalities exacerbate neuronal vulnerability, driving cognitive decline and neurodegeneration. This review examines the genetic and biochemical underpinnings of mitochondrial dysfunction in DS, with a focus on the role of HSA21-encoded genes. We also highlight how mitochondrial dysfunction, amplified by oxidative stress and HSA21 gene dosage effects, converges with cellular senescence and neuroinflammation to accelerate Alzheimer-like pathology and brain aging in DS. Finally, we discuss emerging therapeutic strategies targeting mitochondrial pathways, which hold promise for mitigating neurodegenerative phenotypes and improving outcomes in DS.
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Donovan MG, Eduthan NP, Smith KP, Britton EC, Lyford HR, Araya P, Granrath RE, Waugh KA, Enriquez Estrada B, Rachubinski AL, Sullivan KD, Galbraith MD, Espinosa JM. Variegated overexpression of chromosome 21 genes reveals molecular and immune subtypes of Down syndrome. Nat Commun 2024; 15:5473. [PMID: 38942750 PMCID: PMC11213896 DOI: 10.1038/s41467-024-49781-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 06/18/2024] [Indexed: 06/30/2024] Open
Abstract
Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and diagnosis of co-occurring conditions. The mechanisms underlying this variable developmental and clinical presentation await elucidation. We report an investigation of human chromosome 21 gene overexpression in hundreds of research participants with Down syndrome, which led to the identification of two major subsets of co-expressed genes. Using clustering analyses, we identified three main molecular subtypes of trisomy 21, based on differential overexpression patterns of chromosome 21 genes. We subsequently performed multiomics comparative analyses among subtypes using whole blood transcriptomes, plasma proteomes and metabolomes, and immune cell profiles. These efforts revealed strong heterogeneity in dysregulation of key pathophysiological processes across the three subtypes, underscored by differential multiomics signatures related to inflammation, immunity, cell growth and proliferation, and metabolism. We also observed distinct patterns of immune cell changes across subtypes. These findings provide insights into the molecular heterogeneity of trisomy 21 and lay the foundation for the development of personalized medicine approaches for the clinical management of Down syndrome.
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Affiliation(s)
- Micah G Donovan
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA
| | - Neetha P Eduthan
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA
| | - Keith P Smith
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA
| | - Eleanor C Britton
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA
| | - Hannah R Lyford
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA
| | - Paula Araya
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA
| | - Ross E Granrath
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA
| | - Katherine A Waugh
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, USA
| | - Belinda Enriquez Estrada
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA
| | - Angela L Rachubinski
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA
- Department of Pediatrics, Section of Developmental Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, USA
| | - Kelly D Sullivan
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA
- Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, USA
| | - Matthew D Galbraith
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA.
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, USA.
| | - Joaquin M Espinosa
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, USA.
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, USA.
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Glass TJ, Russell JA, Fisher EH, Ostadi M, Aori N, Yu YE, Connor NP. Altered tongue muscle contractile properties coincide with altered swallow function in the adult Ts65Dn mouse model of down syndrome. Front Neurol 2024; 15:1384572. [PMID: 38585362 PMCID: PMC10995394 DOI: 10.3389/fneur.2024.1384572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 03/08/2024] [Indexed: 04/09/2024] Open
Abstract
Purpose Down syndrome (DS) is a developmental disability associated with difficulties in deglutition. The adult Ts65Dn mouse model of DS has been previously shown to have differences in measures of swallowing compared with euploid controls. However, the putative mechanisms of these differences in swallowing function are unclear. This study tested the hypothesis that the Ts65Dn genotype is associated with atypical measures of tongue muscle contractile properties, coinciding with atypical swallow function. Methods Adult (5-month-old) Ts65Dn (n = 15 female, 14 male) and euploid sibling controls (n = 16 female, 14 male) were evaluated through videofluoroscopy swallow studies (VFSS) to quantify measures of swallowing performance including swallow rate and inter-swallow interval (ISI). After VFSS, retrusive tongue muscle contractile properties, including measures of muscle fatigue, were determined using bilateral hypoglossal nerve stimulation. Results The Ts65Dn group had significantly slower swallow rates, significantly greater ISI times, significantly slower rates of tongue force development, and significantly greater levels of tongue muscle fatigue, with lower retrusive tongue forces than controls in fatigue conditions. Conclusion Tongue muscle contractile properties are altered in adult Ts65Dn and coincide with altered swallow function.
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Affiliation(s)
- Tiffany J. Glass
- Department of Surgery, Division of Otolaryngology, University of Wisconsin-Madison, Madison, WI, United States
| | - John A. Russell
- Department of Surgery, Division of Otolaryngology, University of Wisconsin-Madison, Madison, WI, United States
| | - Erin H. Fisher
- Department of Surgery, Division of Otolaryngology, University of Wisconsin-Madison, Madison, WI, United States
| | - Marziyeh Ostadi
- Department of Surgery, Division of Otolaryngology, University of Wisconsin-Madison, Madison, WI, United States
- Department of Communication Sciences and Disorders, University of Wisconsin-Madison, Madison, WI, United States
| | - Nanyumuzi Aori
- Department of Surgery, Division of Otolaryngology, University of Wisconsin-Madison, Madison, WI, United States
| | - Y. Eugene Yu
- The Children’s Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
- Genetics, Genomics and Bioinformatics Program, State University of New York at Buffalo, Buffalo, NY, United States
| | - Nadine P. Connor
- Department of Surgery, Division of Otolaryngology, University of Wisconsin-Madison, Madison, WI, United States
- Department of Communication Sciences and Disorders, University of Wisconsin-Madison, Madison, WI, United States
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Llambrich S, Tielemans B, Saliën E, Atzori M, Wouters K, Van Bulck V, Platt M, Vanherp L, Gallego Fernandez N, Grau de la Fuente L, Poptani H, Verlinden L, Himmelreich U, Croitor A, Attanasio C, Callaerts-Vegh Z, Gsell W, Martínez-Abadías N, Vande Velde G. Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model. eLife 2024; 12:RP89763. [PMID: 38497812 PMCID: PMC10948151 DOI: 10.7554/elife.89763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2024] Open
Abstract
Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental conditions. We overcame these limitations by conducting the first longitudinal controlled experiment evaluating genotype and GTE-EGCG prenatal chronic treatment effects before and after treatment discontinuation. Our findings revealed that the Ts65Dn mouse model reflected the pleiotropic nature of DS, exhibiting brachycephalic skull, ventriculomegaly, neurodevelopmental delay, hyperactivity, and impaired memory robustness with altered hippocampal metabolite concentration and gene expression. GTE-EGCG treatment modulated most systems simultaneously but did not rescue DS phenotypes. On the contrary, the treatment exacerbated trisomic phenotypes including body weight, tibia microarchitecture, neurodevelopment, adult cognition, and metabolite concentration, not supporting the therapeutic use of GTE-EGCG as a prenatal chronic treatment. Our results highlight the importance of longitudinal experiments assessing the co-modulation of multiple systems throughout development when characterizing preclinical models in complex disorders and evaluating the pleiotropic effects and general safety of pharmacological treatments.
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Affiliation(s)
- Sergi Llambrich
- Biomedical MRI, Department of Imaging and Pathology, KU LeuvenLeuvenBelgium
| | - Birger Tielemans
- Biomedical MRI, Department of Imaging and Pathology, KU LeuvenLeuvenBelgium
| | - Ellen Saliën
- Biomedical MRI, Department of Imaging and Pathology, KU LeuvenLeuvenBelgium
| | - Marta Atzori
- Department of Human Genetics, KU LeuvenLeuvenBelgium
| | - Kaat Wouters
- Laboratory of Biological Psychology, KU LeuvenLeuvenBelgium
| | | | - Mark Platt
- Centre for Preclinical Imaging, Department of Molecular and Clinical Cancer Medicine, University of LiverpoolLiverpoolUnited Kingdom
| | - Laure Vanherp
- Biomedical MRI, Department of Imaging and Pathology, KU LeuvenLeuvenBelgium
| | - Nuria Gallego Fernandez
- Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals (BEECA), Facultat de Biologia, Universitat de BarcelonaBarcelonaSpain
| | - Laura Grau de la Fuente
- Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals (BEECA), Facultat de Biologia, Universitat de BarcelonaBarcelonaSpain
| | - Harish Poptani
- Centre for Preclinical Imaging, Department of Molecular and Clinical Cancer Medicine, University of LiverpoolLiverpoolUnited Kingdom
| | - Lieve Verlinden
- Clinical and Experimental Endocrinology, KU LeuvenLeuvenBelgium
| | - Uwe Himmelreich
- Biomedical MRI, Department of Imaging and Pathology, KU LeuvenLeuvenBelgium
| | - Anca Croitor
- Biomedical MRI, Department of Imaging and Pathology, KU LeuvenLeuvenBelgium
| | | | | | - Willy Gsell
- Biomedical MRI, Department of Imaging and Pathology, KU LeuvenLeuvenBelgium
| | - Neus Martínez-Abadías
- Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals (BEECA), Facultat de Biologia, Universitat de BarcelonaBarcelonaSpain
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Hawley LE, Stringer M, Deal AJ, Folz A, Goodlett CR, Roper RJ. Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model. Neurobiol Dis 2024; 190:106359. [PMID: 37992782 PMCID: PMC10843801 DOI: 10.1016/j.nbd.2023.106359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/02/2023] [Accepted: 11/18/2023] [Indexed: 11/24/2023] Open
Abstract
Aberrant neurodevelopment in Down syndrome (DS)-caused by triplication of human chromosome 21-is commonly attributed to gene dosage imbalance, linking overexpression of trisomic genes with disrupted developmental processes, with DYRK1A particularly implicated. We hypothesized that regional brain DYRK1A protein overexpression in trisomic mice varies over development in sex-specific patterns that may be distinct from Dyrk1a transcription, and reduction of Dyrk1a copy number from 3 to 2 in otherwise trisomic mice reduces DYRK1A, independent of other trisomic genes. DYRK1A overexpression varied with age, sex, and brain region, with peak overexpression on postnatal day (P) 6 in both sexes. Sex-dependent differences were also evident from P15-P24. Reducing Dyrk1a copy number confirmed that these differences depended on Dyrk1a gene dosage and not other trisomic genes. Trisomic Dyrk1a mRNA and protein expression were not highly correlated. Sex-specific patterns of DYRK1A overexpression during trisomic neurodevelopment may provide mechanistic targets for therapeutic intervention in DS.
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Affiliation(s)
- Laura E Hawley
- Department of Biology, Indiana University - Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN, 46202, USA
| | - Megan Stringer
- Department of Psychology, Indiana University - Purdue University Indianapolis, 402 N. Blackford Street, LD124, Indianapolis, IN, 46202, USA
| | - Abigail J Deal
- Department of Biology, Indiana University - Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN, 46202, USA
| | - Andrew Folz
- Department of Biology, Indiana University - Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN, 46202, USA
| | - Charles R Goodlett
- Department of Psychology, Indiana University - Purdue University Indianapolis, 402 N. Blackford Street, LD124, Indianapolis, IN, 46202, USA
| | - Randall J Roper
- Department of Biology, Indiana University - Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN, 46202, USA.
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Bravo‐Estupiñan DM, Aguilar‐Guerrero K, Quirós S, Acón M, Marín‐Müller C, Ibáñez‐Hernández M, Mora‐Rodríguez RA. Gene dosage compensation: Origins, criteria to identify compensated genes, and mechanisms including sensor loops as an emerging systems-level property in cancer. Cancer Med 2023; 12:22130-22155. [PMID: 37987212 PMCID: PMC10757140 DOI: 10.1002/cam4.6719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 10/31/2023] [Accepted: 11/07/2023] [Indexed: 11/22/2023] Open
Abstract
The gene dosage compensation hypothesis presents a mechanism through which the expression of certain genes is modulated to compensate for differences in the dose of genes when additional chromosomes are present. It is one of the means through which cancer cells actively cope with the potential damaging effects of aneuploidy, a hallmark of most cancers. Dosage compensation arises through several processes, including downregulation or overexpression of specific genes and the relocation of dosage-sensitive genes. In cancer, a majority of compensated genes are generally thought to be regulated at the translational or post-translational level, and include the basic components of a compensation loop, including sensors of gene dosage and modulators of gene expression. Post-translational regulation is mostly undertaken by a general degradation or aggregation of remaining protein subunits of macromolecular complexes. An increasingly important role has also been observed for transcriptional level regulation. This article reviews the process of targeted gene dosage compensation in cancer and other biological conditions, along with the mechanisms by which cells regulate specific genes to restore cellular homeostasis. These mechanisms represent potential targets for the inhibition of dosage compensation of specific genes in aneuploid cancers. This article critically examines the process of targeted gene dosage compensation in cancer and other biological contexts, alongside the criteria for identifying genes subject to dosage compensation and the intricate mechanisms by which cells orchestrate the regulation of specific genes to reinstate cellular homeostasis. Ultimately, our aim is to gain a comprehensive understanding of the intricate nature of a systems-level property. This property hinges upon the kinetic parameters of regulatory motifs, which we have termed "gene dosage sensor loops." These loops have the potential to operate at both the transcriptional and translational levels, thus emerging as promising candidates for the inhibition of dosage compensation in specific genes. Additionally, they represent novel and highly specific therapeutic targets in the context of aneuploid cancer.
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Affiliation(s)
- Diana M. Bravo‐Estupiñan
- CICICA, Centro de Investigación en Cirugía y Cáncer Research Center on Surgery and CancerUniversidad de Costa RicaSan JoséCosta Rica
- Programa de Doctorado en Ciencias, Sistema de Estudios de Posgrado (SEP)Universidad de Costa RicaSan JoséCosta Rica
- Laboratorio de Terapia Génica, Departamento de BioquímicaEscuela Nacional de Ciencias Biológicas del Instituto Politécnico NacionalCiudad de MéxicoMexico
- Speratum Biopharma, Inc.Centro Nacional de Innovación Biotecnológica Nacional (CENIBiot)San JoséCosta Rica
| | - Karol Aguilar‐Guerrero
- CICICA, Centro de Investigación en Cirugía y Cáncer Research Center on Surgery and CancerUniversidad de Costa RicaSan JoséCosta Rica
- Maestría académica en Microbiología, Programa de Posgrado en Microbiología, Parasitología, Química Clínica e InmunologíaUniversidad de Costa RicaSan JoséCosta Rica
| | - Steve Quirós
- CICICA, Centro de Investigación en Cirugía y Cáncer Research Center on Surgery and CancerUniversidad de Costa RicaSan JoséCosta Rica
- Laboratorio de Quimiosensibilidad tumoral (LQT), Centro de Investigación en enfermedades Tropicales (CIET), Facultad de MicrobiologíaUniversidad de Costa RicaSan JoséCosta Rica
| | - Man‐Sai Acón
- CICICA, Centro de Investigación en Cirugía y Cáncer Research Center on Surgery and CancerUniversidad de Costa RicaSan JoséCosta Rica
| | - Christian Marín‐Müller
- Speratum Biopharma, Inc.Centro Nacional de Innovación Biotecnológica Nacional (CENIBiot)San JoséCosta Rica
| | - Miguel Ibáñez‐Hernández
- Laboratorio de Terapia Génica, Departamento de BioquímicaEscuela Nacional de Ciencias Biológicas del Instituto Politécnico NacionalCiudad de MéxicoMexico
| | - Rodrigo A. Mora‐Rodríguez
- CICICA, Centro de Investigación en Cirugía y Cáncer Research Center on Surgery and CancerUniversidad de Costa RicaSan JoséCosta Rica
- Laboratorio de Quimiosensibilidad tumoral (LQT), Centro de Investigación en enfermedades Tropicales (CIET), Facultad de MicrobiologíaUniversidad de Costa RicaSan JoséCosta Rica
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Thomazeau A, Lassalle O, Manzoni OJ. Glutamatergic synaptic deficits in the prefrontal cortex of the Ts65Dn mouse model for Down syndrome. Front Neurosci 2023; 17:1171797. [PMID: 37841687 PMCID: PMC10569174 DOI: 10.3389/fnins.2023.1171797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 09/11/2023] [Indexed: 10/17/2023] Open
Abstract
Down syndrome (DS), the most prevalent cause of intellectual disability, stems from a chromosomal anomaly resulting in an entire or partial extra copy of chromosome 21. This leads to intellectual disability and a range of associated symptoms. While there has been considerable research focused on the Ts65Dn mouse model of DS, particularly in the context of the hippocampus, the synaptic underpinnings of prefrontal cortex (PFC) dysfunction in DS, including deficits in working memory, remain largely uncharted territory. In a previous study featuring mBACtgDyrk1a mice, which manifest overexpression of the Dyrk1a gene, a known candidate gene linked to intellectual disability and microcephaly in DS, we documented adverse effects on spine density, alterations in the molecular composition of synapses, and the presence of synaptic plasticity deficits within the PFC. The current study aimed to enrich our understanding of the roles of different genes in DS by studying Ts65Dn mice, which overexpress several genes including Dyrk1a, to compare with our previous work on mBACtgDyrk1a mice. Through ex-vivo electrophysiological experiments, including patch-clamp and extracellular field potential recordings, we identified alterations in the intrinsic properties of PFC layer V/VI pyramidal neurons in Ts65Dn male mice. Additionally, we observed changes in the synaptic plasticity range. Notably, long-term depression was absent in Ts65Dn mice, while synaptic or pharmacological long-term potentiation remained fully expressed in these mice. These findings provide valuable insights into the intricate synaptic mechanisms contributing to PFC dysfunction in DS, shedding light on potential therapeutic avenues for addressing the neurocognitive symptoms associated with this condition.
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Affiliation(s)
- Aurore Thomazeau
- Côte d’Azur, CNRS UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France
- Université Aix-Marseille, Marseille, France
- INMED, INSERM U1249, Marseille, France
| | - Olivier Lassalle
- Université Aix-Marseille, Marseille, France
- INMED, INSERM U1249, Marseille, France
| | - Olivier J. Manzoni
- Université Aix-Marseille, Marseille, France
- INMED, INSERM U1249, Marseille, France
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9
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Mehdipour P, Fathi N, Nosratabadi M. Personalized clinical managements through exploring circulating neural cells and electroencephalography. World J Exp Med 2023; 13:75-94. [PMID: 37767542 PMCID: PMC10520756 DOI: 10.5493/wjem.v13.i4.75] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 05/22/2023] [Accepted: 07/11/2023] [Indexed: 09/15/2023] Open
Abstract
BACKGROUND Since an initial diagnosis of Alzheimer disease (AD) in 1907, early detection, was unavailable through 116 years. Up-regulation of V-Ets erythroblastosis virus E26 oncogene homolog 2 (Ets2) is capable to enhance neuronal susceptibility and degeneration. Protein expression (PE) of Ets2 has functional impact on AD and Down's syndrome, with diverse intensity. PE of Ets2 has an influential pathogenic impact on AD. Clinical aspects of neurological disorders directly interact with psychological maladies. However, deterioration requires an early management including programmed based protection. AIM To include cell biology in neuro-genetics; personalized, prognostics, predictive, preventive, predisposing (5xP) platform, accompanied by stratifying brain channels behavior pre- and post-intervention by light music in the AD-patients. METHODS Include exploration of PE assay and electroencephalography of brain channels. The processes are applied according to: (1) Triangle style, by application of cellular network; and (2) PE assay of Ets2 in the peripheral blood of the patients with AD, by Manual single cell based analysis, and Flow-cytometry. (1) Applying the Genetic counselling and pedigree analysis; (2) considering the psychological status of the referral cases; (3) considering the macro-and/or micro-environmental factors; (4) performing the required Genetics' analysis; and (5) applying the required complementary test(s). RESULTS PE of Ets2 has pathogenic role in AD. PE unmasked the nature of heterogeneity/diversity/course of evolution by exploring Ets2, D1853N polymorphism in Ataxia Telangiectasia mutated gene (ATM), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and course of evolution at the single cell level of the brain. Ets2 revealed different cellular behavior in the blood and suggested the strategy as 'Gene Product-Based Therapy' and the personalized managements for the patients. PE reflected weak expression of ATM, mosaic pattern of Ets2; remarkable expression of VEGF and EGF by highlighting an early detective platform, considering circulating neural cells (CNCs) and the required molecular investigation, for the target individual(s) predisposed to AD or other neural disease including brain neoplasia. Brain channels-cooperation with diverse/interactive-ratios lead to strategic balancing for improving the life-quality in AD. CONCLUSION We highlighted application of the single CNCs and correlated Ratio based between Brain channels by providing the 5xP personalized clinical management model for an early detection and therapy of the patients with AD and their targeted/predisposed relatives. Novel-evolutionary/hypothetic/heterogenic-results in brain-channels offer personalizd/constructive markers with unlimited cooperation in health and disease.
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Affiliation(s)
- Parvin Mehdipour
- Department of Medical Genetics, Tehran University of Medical Sciences, Tehran 14176-1315, Iran
| | - Nima Fathi
- Neuro-Science, Paarand Specialized Center for Human Enhancement, Tehran 157699304, Iran
| | - Masoud Nosratabadi
- Department of Research, Paarand Specialized Center for Human Enhancement, Tehran 157699304, Iran
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10
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Rusu B, Kukreja B, Wu T, Dan SJ, Feng MY, Kalish BT. Single-Nucleus Profiling Identifies Accelerated Oligodendrocyte Precursor Cell Senescence in a Mouse Model of Down Syndrome. eNeuro 2023; 10:ENEURO.0147-23.2023. [PMID: 37491366 PMCID: PMC10449487 DOI: 10.1523/eneuro.0147-23.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/06/2023] [Accepted: 07/10/2023] [Indexed: 07/27/2023] Open
Abstract
Down syndrome (DS), the most common genetic cause of intellectual disability, is associated with lifelong cognitive deficits. However, the mechanisms by which triplication of chromosome 21 genes drive neuroinflammation and cognitive dysfunction are poorly understood. Here, using the Ts65Dn mouse model of DS, we performed an integrated single-nucleus ATAC and RNA-sequencing (snATAC-seq and snRNA-seq) analysis of the adult cortex. We identified cell type-specific transcriptional and chromatin-associated changes in the Ts65Dn cortex, including regulators of neuroinflammation, transcription and translation, myelination, and mitochondrial function. We discovered enrichment of a senescence-associated transcriptional signature in Ts65Dn oligodendrocyte (OL) precursor cells (OPCs) and epigenetic changes consistent with a loss of heterochromatin. We found that senescence is restricted to a subset of OPCs concentrated in deep cortical layers. Treatment of Ts65Dn mice with a senescence-reducing flavonoid rescued cortical OPC proliferation, restored microglial homeostasis, and improved contextual fear memory. Together, these findings suggest that cortical OPC senescence may be an important driver of neuropathology in DS.
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Affiliation(s)
- Bianca Rusu
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1A8, Canada
- Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto, Ontario M5G 1L7, Canada
| | - Bharti Kukreja
- Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto, Ontario M5G 1L7, Canada
| | - Taiyi Wu
- Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto, Ontario M5G 1L7, Canada
| | - Sophie J Dan
- Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto, Ontario M5G 1L7, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario M5G 1A8, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario M5G 1A8, Canada
| | - Min Yi Feng
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1A8, Canada
- Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto, Ontario M5G 1L7, Canada
| | - Brian T Kalish
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1A8, Canada
- Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto, Ontario M5G 1L7, Canada
- Division of Neonatology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
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11
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Inguscio CR, Lacavalla MA, Cisterna B, Zancanaro C, Malatesta M. Physical Training Chronically Stimulates the Motor Neuron Cell Nucleus in the Ts65Dn Mouse, a Model of Down Syndrome. Cells 2023; 12:1488. [PMID: 37296609 PMCID: PMC10252427 DOI: 10.3390/cells12111488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/20/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Down syndrome (DS) is a genetically-based disease based on the trisomy of chromosome 21 (Hsa21). DS is characterized by intellectual disability in association with several pathological traits among which early aging and altered motor coordination are prominent. Physical training or passive exercise were found to be useful in counteracting motor impairment in DS subjects. In this study we used the Ts65Dn mouse, a widely accepted animal model of DS, to investigate the ultrastructural architecture of the medullary motor neuron cell nucleus taken as marker of the cell functional state. Using transmission electron microscopy, ultrastructural morphometry, and immunocytochemistry we carried out a detailed investigation of possible trisomy-related alteration(s) of nuclear constituents, which are known to vary their amount and distribution as a function of nuclear activity, as well as the effect of adapted physical training upon them. Results demonstrated that trisomy per se affects nuclear constituents to a limited extent; however, adapted physical training is able to chronically stimulate pre-mRNA transcription and processing activity in motor neuron nuclei of trisomic mice, although to a lesser extent than in their euploid mates. These findings are a step towards understanding the mechanisms underlying the positive effect of physical activity in DS.
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Affiliation(s)
| | | | | | - Carlo Zancanaro
- Department of Neurosciences, Biomedicine and Movement Sciences, Anatomy and Histology Section, University of Verona, Strada Le Grazie 8, I-37134 Verona, Italy; (C.R.I.); (M.A.L.); (B.C.); (M.M.)
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12
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Li R, Song B, Xu L, Zheng J, Pan W, Cai F, Wang J, Wu Y, Song W. Regulation of USP25 by SP1 Associates with Amyloidogenesis. J Alzheimers Dis 2023; 92:1459-1472. [PMID: 36938736 DOI: 10.3233/jad-221184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/15/2023]
Abstract
BACKGROUND Trisomy 21, an extra copy of human chromosome 21 (HSA21), causes most Down's syndrome (DS) cases. Individuals with DS inevitably develop Alzheimer's disease (AD) neuropathological phenotypes after middle age including amyloid plaques and tau neurofibrillary tangles. Ubiquitin Specific Peptidase 25 (USP25), encoding by USP25 gene located on HSA21, is a deubiquitinating enzyme, which plays an important role in both DS and AD pathogenesis. However, the regulation of USP25 remains unclear. OBJECTIVE We aimed to determine the regulation of USP25 by specificity protein 1 (SP1) in neuronal cells and its potential role in amyloidogenesis. METHODS The transcription start site and promoter activity was identified by SMART-RACE and Dual-luciferase assay. Functional SP1-responsive elements were examined by EMSA. USP25 expression was examined by RT-PCR and immunoblotting. Student's t-test or one-way ANOVA were applied or statistical analysis. RESULTS The transcription start site of human USP25 gene was identified. Three functional SP1 responsive elements in human USP25 gene were revealed. SP1 promotes USP25 transcription and subsequent USP25 protein expression, while SP1 inhibition significantly reduces USP25 expression in both non-neuronal and neuronal cells. Moreover, SP1 inhibition dramatically reduces amyloidogenesis. CONCLUSION We demonstrates that transcription factor SP1 regulates USP25 gene expression, which associates with amyloidogenesis. It suggests that SP1 signaling may play an important role in USP25 regulation and contribute to USP25-mediated DS and AD pathogenesis.
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Affiliation(s)
- Ran Li
- The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province,Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Beibei Song
- Townsend Family Laboratories, Department of Psychiatry, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, BC, Canada
| | - Lu Xu
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province,Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jiali Zheng
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province,Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenhao Pan
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province,Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Fang Cai
- Townsend Family Laboratories, Department of Psychiatry, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, BC, Canada
| | - Juelu Wang
- Townsend Family Laboratories, Department of Psychiatry, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, BC, Canada
| | - Yili Wu
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province,Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Oujiang Laboratory Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China
| | - Weihong Song
- The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province,Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Oujiang Laboratory Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China
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13
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Brosens JJ, Bennett PR, Abrahams VM, Ramhorst R, Coomarasamy A, Quenby S, Lucas ES, McCoy RC. Maternal selection of human embryos in early gestation: Insights from recurrent miscarriage. Semin Cell Dev Biol 2022; 131:14-24. [PMID: 35094946 PMCID: PMC9325922 DOI: 10.1016/j.semcdb.2022.01.007] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/21/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023]
Abstract
Compared to most mammals, human pregnancy is unusual in that it involves chromosomally diverse embryos, cyclical breakdown and regeneration of the uterine mucosa, and intimate integration of fetal and maternal cells at the uteroplacental interface. Not surprisingly, pregnancy often falters in early gestation. Whether these losses result in clinical miscarriages depends on the origins and impacts of chromosomal errors on fetal development and the ability of the decidualizing endometrium to engage in embryo biosensing and selection. Aneuploidy originating in oocytes during meiosis drives the age-related risk of miscarriage. By contrast, the frequency of endometrial cycles with an impaired decidual response may account for the stepwise increase in miscarriage rates with each pregnancy loss independently of maternal age. Additional physiological mechanisms operate in early gestation to ensure that most failing pregnancies are lost before vascular maternal-fetal connections are established by the end of the first trimester. Here, we summarise how investigations into the mechanisms that cause miscarriage led to new insights into the processes that govern maternal selection of human embryos in early gestation.
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Affiliation(s)
- Jan J Brosens
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK; Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire NHS Trust, Coventry CV2 2DX, UK.
| | - Phillip R Bennett
- Tommy's National Centre for Miscarriage Research, Imperial College London, UK
| | - Vikki M Abrahams
- Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University, New Haven, CT, USA
| | - Rosanna Ramhorst
- CONICET, Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales IQUIBICEN, Buenos Aires, Argentina
| | - Arri Coomarasamy
- Tommy's National Centre for Miscarriage Research, Institute of Metabolism and Systems Research, University of Birmingham, UK
| | - Siobhan Quenby
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK; Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Emma S Lucas
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK
| | - Rajiv C McCoy
- Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, USA
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14
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Fulton SL, Wenderski W, Lepack AE, Eagle AL, Fanutza T, Bastle RM, Ramakrishnan A, Hays EC, Neal A, Bendl J, Farrelly LA, Al-Kachak A, Lyu Y, Cetin B, Chan JC, Tran TN, Neve RL, Roper RJ, Brennand KJ, Roussos P, Schimenti JC, Friedman AK, Shen L, Blitzer RD, Robison AJ, Crabtree GR, Maze I. Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome. Nat Commun 2022; 13:6384. [PMID: 36289231 PMCID: PMC9606253 DOI: 10.1038/s41467-022-34200-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 10/17/2022] [Indexed: 12/25/2022] Open
Abstract
With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.
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Affiliation(s)
- Sasha L Fulton
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Wendy Wenderski
- Department of Pathology, Stanford Medical School, Palo Alto, CA, 94305, USA
- Department of Genetics, Stanford Medical School, Palo Alto, CA, 94305, USA
- Department of Developmental Biology, Stanford Medical School, Palo Alto, CA, 94305, USA
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA, 94305, USA
| | - Ashley E Lepack
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Andrew L Eagle
- Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA
| | - Tomas Fanutza
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ryan M Bastle
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Aarthi Ramakrishnan
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Emma C Hays
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Arianna Neal
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jaroslav Bendl
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Center for Disease Neuroepigenomics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Lorna A Farrelly
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Amni Al-Kachak
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Yang Lyu
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Bulent Cetin
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jennifer C Chan
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Tina N Tran
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, 14853, USA
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA
| | - Rachael L Neve
- McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Randall J Roper
- Department of Biology, Indiana University-Purdue University, Indianapolis, IN, 46202, USA
| | - Kristen J Brennand
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Departments of Psychiatry and Genetics, Wu Tsai Institute, Yale School of Medicine, New Haven, CT, 065109, USA
| | - Panos Roussos
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Center for Disease Neuroepigenomics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- J.J. Peters Veterans Affairs Hospital, Bronx, NY, 10468, USA
| | - John C Schimenti
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, 14853, USA
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA
| | - Allyson K Friedman
- Department of Biological Sciences, City University of New York-Hunter College, New York, NY, 10065, USA
| | - Li Shen
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Robert D Blitzer
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Alfred J Robison
- Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA
| | - Gerald R Crabtree
- Department of Pathology, Stanford Medical School, Palo Alto, CA, 94305, USA
- Department of Genetics, Stanford Medical School, Palo Alto, CA, 94305, USA
- Department of Developmental Biology, Stanford Medical School, Palo Alto, CA, 94305, USA
- Howard Hughes Medical Institute, Stanford University, Palo Alto, CA, 94305, USA
| | - Ian Maze
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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15
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Alassaf A. Natal Teeth in an Infant With Down Syndrome: A Rare Presentation With a Genetic Evaluation and Review of the Literature. Cureus 2022; 14:e30101. [DOI: 10.7759/cureus.30101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2022] [Indexed: 11/05/2022] Open
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16
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Cannavo C, Cleverley K, Maduro C, Mumford P, Moulding D, Fisher EMC, Wiseman FK. Endosomal structure and APP biology are not altered in a preclinical mouse cellular model of Down syndrome. PLoS One 2022; 17:e0262558. [PMID: 35544526 PMCID: PMC9094519 DOI: 10.1371/journal.pone.0262558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 04/21/2022] [Indexed: 11/18/2022] Open
Abstract
Individuals who have Down syndrome (trisomy 21) are at greatly increased risk of developing Alzheimer's disease, characterised by the accumulation in the brain of amyloid-β plaques. Amyloid-β is a product of the processing of the amyloid precursor protein, encoded by the APP gene on chromosome 21. In Down syndrome the first site of amyloid-β accumulation is within endosomes, and changes to endosome biology occur early in Alzheimer's disease. Here, we determine if primary mouse embryonic fibroblasts isolated from a mouse model of Down syndrome can be used to study endosome and APP cell biology. We report that in this cellular model, endosome number, size and APP processing are not altered, likely because APP is not dosage sensitive in the model, despite three copies of App.
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Affiliation(s)
- Claudia Cannavo
- UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London, United Kingdom
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom
| | - Karen Cleverley
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom
| | - Cheryl Maduro
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom
| | - Paige Mumford
- UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London, United Kingdom
| | - Dale Moulding
- Light Microscopy Core Facility, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Elizabeth M. C. Fisher
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom
| | - Frances K. Wiseman
- UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London, United Kingdom
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17
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Venegas-Zamora L, Bravo-Acuña F, Sigcho F, Gomez W, Bustamante-Salazar J, Pedrozo Z, Parra V. New Molecular and Organelle Alterations Linked to Down Syndrome Heart Disease. Front Genet 2022; 12:792231. [PMID: 35126461 PMCID: PMC8808411 DOI: 10.3389/fgene.2021.792231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 12/13/2021] [Indexed: 12/13/2022] Open
Abstract
Down syndrome (DS) is a genetic disorder caused by a trisomy of the human chromosome 21 (Hsa21). Overexpression of Hsa21 genes that encode proteins and non-coding RNAs (ncRNAs) can disrupt several cellular functions and biological processes, especially in the heart. Congenital heart defects (CHDs) are present in 45–50% of individuals with DS. Here, we describe the genetic background of this condition (Hsa21 and non-Hsa21 genes), including the role of ncRNAs, and the relevance of these new players in the study of the pathophysiology of DS heart diseases. Additionally, we discuss several distinct pathways in cardiomyocytes which help maintain a functional heart, but that might trigger hypertrophy and oxidative stress when altered. Moreover, we highlight the importance of investigating how mitochondrial and lysosomal dysfunction could eventually contribute to understanding impaired heart function and development in subjects with the Hsa21 trisomy. Altogether, this review focuses on the newest insights about the gene expression, molecular pathways, and organelle alterations involved in the cardiac phenotype of DS.
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Affiliation(s)
- Leslye Venegas-Zamora
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Francisco Bravo-Acuña
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Francisco Sigcho
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Wileidy Gomez
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Laboratory of Neuroprotection and Autophagy, Center for Integrative Biology, Faculty of Science, Universidad Mayor, Santiago, Chile
| | - José Bustamante-Salazar
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Zully Pedrozo
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Red para El Estudio de Enfermedades Cardiopulmonares de Alta Letalidad (REECPAL), Universidad de Chile, Santiago, Chile
- *Correspondence: Zully Pedrozo, ; Valentina Parra,
| | - Valentina Parra
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
- Red para El Estudio de Enfermedades Cardiopulmonares de Alta Letalidad (REECPAL), Universidad de Chile, Santiago, Chile
- *Correspondence: Zully Pedrozo, ; Valentina Parra,
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18
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Acón M, Geiß C, Torres-Calvo J, Bravo-Estupiñan D, Oviedo G, Arias-Arias JL, Rojas-Matey LA, Edwin B, Vásquez-Vargas G, Oses-Vargas Y, Guevara-Coto J, Segura-Castillo A, Siles-Canales F, Quirós-Barrantes S, Régnier-Vigouroux A, Mendes P, Mora-Rodríguez R. MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer. iScience 2021; 24:103407. [PMID: 34877484 PMCID: PMC8627999 DOI: 10.1016/j.isci.2021.103407] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 10/01/2021] [Accepted: 11/03/2021] [Indexed: 12/11/2022] Open
Abstract
We hypothesize that dosage compensation of critical genes arises from systems-level properties for cancer cells to withstand the negative effects of aneuploidy. We identified several candidate genes in cancer multiomics data and developed a biocomputational platform to construct a mathematical model of their interaction network with micro-RNAs and transcription factors, where the property of dosage compensation emerged for MYC and was dependent on the kinetic parameters of its feedback interactions with three micro-RNAs. These circuits were experimentally validated using a genetic tug-of-war technique to overexpress an exogenous MYC, leading to overexpression of the three microRNAs involved and downregulation of endogenous MYC. In addition, MYC overexpression or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity in MYC-amplified colon cancer cells. Finally, we identified negative correlation of MYC dosage compensation with patient survival in TCGA breast cancer patients, highlighting the potential of this mechanism to prevent aneuploid cancer progression.
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Affiliation(s)
- ManSai Acón
- Lab of Tumor Chemosensitivity (LQT), Research Center for Tropical Diseases (CIET), Faculty of Microbiology, University of Costa Rica, 11501-2060 San José, Costa Rica
- Master Program on Bioinformatics and Systems Biology, Postgraduate Program SEP, University of Costa Rica, 11501-2060 San José, Costa Rica
| | - Carsten Geiß
- Institute for Developmental Biology and Neurobiology, Johannes Gutenberg University, 55128 Mainz, Germany
| | - Jorge Torres-Calvo
- Lab of Tumor Chemosensitivity (LQT), Research Center for Tropical Diseases (CIET), Faculty of Microbiology, University of Costa Rica, 11501-2060 San José, Costa Rica
- Master Program on Bioinformatics and Systems Biology, Postgraduate Program SEP, University of Costa Rica, 11501-2060 San José, Costa Rica
| | - Diana Bravo-Estupiñan
- Lab of Tumor Chemosensitivity (LQT), Research Center for Tropical Diseases (CIET), Faculty of Microbiology, University of Costa Rica, 11501-2060 San José, Costa Rica
- Ph.D. Program in Sciences, Postgraduate Program SEP, University of Costa Rica, 11501-2060 San José, Costa Rica
| | - Guillermo Oviedo
- Lab of Tumor Chemosensitivity (LQT), Research Center for Tropical Diseases (CIET), Faculty of Microbiology, University of Costa Rica, 11501-2060 San José, Costa Rica
- Master Program on Bioinformatics and Systems Biology, Postgraduate Program SEP, University of Costa Rica, 11501-2060 San José, Costa Rica
| | - Jorge L Arias-Arias
- Lab of Tumor Chemosensitivity (LQT), Research Center for Tropical Diseases (CIET), Faculty of Microbiology, University of Costa Rica, 11501-2060 San José, Costa Rica
| | - Luis A Rojas-Matey
- Master Program on Bioinformatics and Systems Biology, Postgraduate Program SEP, University of Costa Rica, 11501-2060 San José, Costa Rica
| | - Baez Edwin
- Lab of Tumor Chemosensitivity (LQT), Research Center for Tropical Diseases (CIET), Faculty of Microbiology, University of Costa Rica, 11501-2060 San José, Costa Rica
- Master Program on Bioinformatics and Systems Biology, Postgraduate Program SEP, University of Costa Rica, 11501-2060 San José, Costa Rica
| | - Gloriana Vásquez-Vargas
- Lab of Tumor Chemosensitivity (LQT), Research Center for Tropical Diseases (CIET), Faculty of Microbiology, University of Costa Rica, 11501-2060 San José, Costa Rica
| | - Yendry Oses-Vargas
- Lab of Tumor Chemosensitivity (LQT), Research Center for Tropical Diseases (CIET), Faculty of Microbiology, University of Costa Rica, 11501-2060 San José, Costa Rica
| | - José Guevara-Coto
- School of Computer Sciences and Informatics (ECCI), University of Costa Rica, San Jose Costa Rica, 11501-2060 San José, Costa Rica
| | - Andrés Segura-Castillo
- Laboratorio de Investigación e Innovación Tecnológica, Universidad Estatal a Distancia (UNED), 474-2050 San José, Costa Rica
| | - Francisco Siles-Canales
- Pattern Recognition and Intelligent Systems Laboratory, Department of Electrical Engineering, Universidad de Costa Rica, 11501-2060 San José, Costa Rica
- DC Lab, Lab of Surgery and Cancer, University of Costa Rica, 11501-2060 San José, Costa Rica
| | - Steve Quirós-Barrantes
- Lab of Tumor Chemosensitivity (LQT), Research Center for Tropical Diseases (CIET), Faculty of Microbiology, University of Costa Rica, 11501-2060 San José, Costa Rica
- DC Lab, Lab of Surgery and Cancer, University of Costa Rica, 11501-2060 San José, Costa Rica
| | - Anne Régnier-Vigouroux
- Institute for Developmental Biology and Neurobiology, Johannes Gutenberg University, 55128 Mainz, Germany
| | - Pedro Mendes
- Center for Cell Analysis and Modeling and Department of Cell Biology, University of Connecticut School of Medicine, Farmington, 06030 CT, USA
| | - Rodrigo Mora-Rodríguez
- Lab of Tumor Chemosensitivity (LQT), Research Center for Tropical Diseases (CIET), Faculty of Microbiology, University of Costa Rica, 11501-2060 San José, Costa Rica
- Master Program on Bioinformatics and Systems Biology, Postgraduate Program SEP, University of Costa Rica, 11501-2060 San José, Costa Rica
- DC Lab, Lab of Surgery and Cancer, University of Costa Rica, 11501-2060 San José, Costa Rica
- Institute for Developmental Biology and Neurobiology, Johannes Gutenberg University, 55128 Mainz, Germany
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19
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Pors J, Philipp T, Terry J. Placental Expression of the Forelimb Patterning Transcription Factor MEIS2 in Trisomy 15. Fetal Pediatr Pathol 2021; 40:597-604. [PMID: 32138576 DOI: 10.1080/15513815.2020.1732509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
BackgroundObservations of first trimester human trisomy 15 (T15) embryos have identified meromelic changes in the upper limbs. These changes are similar to those observed in animal studies investigating the effects of overexpression of Meis2, a signaling transcription factor expressed during forelimb development. Although it would be exceedingly difficult to assess MEIS2 expression in the human embryonic arm, MEIS2 has been reported as consistently expressed in first trimester placental villus stroma. Methods: This study addresses whether gene dosage effect might underlie meromelia in T15 by comparing MEIS2 expression in placentas from T15 and euploid spontaneous abortions employing manual and automated assessment of MEIS2 immunohistochemical scoring. Results: Average MEIS2 expression is increased in T15 first trimester placental tissue compared to euploid controls but that the difference is marginal. Manual and automated scoring showed moderately strong correlation. Conclusion: Extrapolation of these results suggests MEIS2 overexpression may not be required for meromelia in T15.
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Affiliation(s)
- Jennifer Pors
- Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Tom Philipp
- Department of Gynecology and Obstetrics, Danube Hospital, Vienna, Austria
| | - Jefferson Terry
- Pathology, BC Children's Hospital, Vancouver, British Columbia, Canada
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20
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Calcagni G, Pugnaloni F, Digilio MC, Unolt M, Putotto C, Niceta M, Baban A, Piceci Sparascio F, Drago F, De Luca A, Tartaglia M, Marino B, Versacci P. Cardiac Defects and Genetic Syndromes: Old Uncertainties and New Insights. Genes (Basel) 2021; 12:genes12071047. [PMID: 34356063 PMCID: PMC8307133 DOI: 10.3390/genes12071047] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/29/2021] [Accepted: 07/05/2021] [Indexed: 02/02/2023] Open
Abstract
Recent advances in understanding the genetic causes and anatomic subtypes of cardiac defects have revealed new links between genetic etiology, pathogenetic mechanisms and cardiac phenotypes. Although the same genetic background can result in different cardiac phenotypes, and similar phenotypes can be caused by different genetic causes, researchers’ effort to identify specific genotype–phenotype correlations remains crucial. In this review, we report on recent advances in the cardiac pathogenesis of three genetic diseases: Down syndrome, del22q11.2 deletion syndrome and Ellis–Van Creveld syndrome. In these conditions, the frequent and specific association with congenital heart defects and the recent characterization of the underlying molecular events contributing to pathogenesis provide significant examples of genotype–phenotype correlations. Defining these correlations is expected to improve diagnosis and patient stratification, and it has relevant implications for patient management and potential therapeutic options.
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Affiliation(s)
- Giulio Calcagni
- Department of Pediatric Cardiology and Cardiac Surgery, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.U.); (A.B.); (F.D.)
- Correspondence: ; Tel.: +39-06-68594096
| | - Flaminia Pugnaloni
- Department of Pediatrics, Obstetrics and Gynecology, “Sapienza” University, 00161 Rome, Italy; (F.P.); (C.P.); (B.M.); (P.V.)
| | - Maria Cristina Digilio
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.C.D.); (M.N.); (M.T.)
| | - Marta Unolt
- Department of Pediatric Cardiology and Cardiac Surgery, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.U.); (A.B.); (F.D.)
| | - Carolina Putotto
- Department of Pediatrics, Obstetrics and Gynecology, “Sapienza” University, 00161 Rome, Italy; (F.P.); (C.P.); (B.M.); (P.V.)
| | - Marcello Niceta
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.C.D.); (M.N.); (M.T.)
| | - Anwar Baban
- Department of Pediatric Cardiology and Cardiac Surgery, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.U.); (A.B.); (F.D.)
| | - Francesca Piceci Sparascio
- Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (F.P.S.); (A.D.L.)
| | - Fabrizio Drago
- Department of Pediatric Cardiology and Cardiac Surgery, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.U.); (A.B.); (F.D.)
| | - Alessandro De Luca
- Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (F.P.S.); (A.D.L.)
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.C.D.); (M.N.); (M.T.)
| | - Bruno Marino
- Department of Pediatrics, Obstetrics and Gynecology, “Sapienza” University, 00161 Rome, Italy; (F.P.); (C.P.); (B.M.); (P.V.)
| | - Paolo Versacci
- Department of Pediatrics, Obstetrics and Gynecology, “Sapienza” University, 00161 Rome, Italy; (F.P.); (C.P.); (B.M.); (P.V.)
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21
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Shi W, Yang F, Dai R, Sun Y, Chu Y, Liao S, Hao B. METTL3-Mediated N6-Methyladenosine Modification Is Involved in the Dysregulation of NRIP1 Expression in Down Syndrome. Front Cell Dev Biol 2021; 9:621374. [PMID: 33869171 PMCID: PMC8047211 DOI: 10.3389/fcell.2021.621374] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 03/08/2021] [Indexed: 11/13/2022] Open
Abstract
Down syndrome (DS) is a common genetic condition in which a person is born with an extra copy of chromosome 21. Intellectual disability is the most common characteristic of DS. N6-methyladenosine (m6A) is a common RNA modification that is implicated in many biological processes. It is highly enriched within the brain and plays an essential role in human brain development. However, the mRNA m6A modification in the fetal brain of DS has not been explored. Here, we report m6A mRNA profiles and mRNA expression profiles of fetal brain cortex tissue from DSs and controls. We observed that the m6A modification in DS brain tissues was reduced genome-wide, which may be due to decreased the m6A methyltransferase like 3 (METTL3) protein expression. The nuclear receptor-interacting protein 1 (NRIP1/RIP140) is coded by a highly conserved chromosome 21 (Hsa21) gene. Overexpression of NRIP1 is associated with mitochondrial dysfunction in DS. The NRIP1 mRNA increased in fetal brain tissues of DS, whereas the m6A modification of the NRIP1 mRNA significantly decreased. METTL3 knockdown reduced the m6A modification of NRIP1 mRNA and increased its expression, and an increase in NRIP1 m6A modification and a decrease in its expression were observed in METTL3-overexpressed cells. The Luciferase reporter assay confirmed that METTL3 regulates NRIP1 expression in an m6A-dependent manner. The decay rate of NRIP1 mRNA was significantly reduced in METTL3-knockdown cells but increased in METTL3-overexpressed cells. We proposed that the m6A modification of NRIP1 mRNA in DS fetal brain tissue is reduced, reducing its transcript degradation rate, resulting in abnormally increased expression of NRIP1, at least partially, in the DS brain. It provides a new mechanism for the molecular pathology of DS and leads to a new insight that may become therapeutically relevant.
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Affiliation(s)
- Weili Shi
- Henan Provincial People's Hospital, Medical Genetics Institute of Henan Province, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, People's Hospital of Zhengzhou University, Zhengzhou, China.,National Health Commission Key Laboratory of Birth Defect Prevention, Henan Key Laboratory of Population Defects Prevention, Zhengzhou, China
| | - Fan Yang
- Zhengzhou Central Hospital, Department of Neurology, Zhengzhou, China
| | - Ranran Dai
- Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yafei Sun
- National Health Commission Key Laboratory of Birth Defect Prevention, Henan Key Laboratory of Population Defects Prevention, Zhengzhou, China
| | - Yan Chu
- Henan Provincial People's Hospital, Medical Genetics Institute of Henan Province, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Shixiu Liao
- Henan Provincial People's Hospital, Medical Genetics Institute of Henan Province, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, People's Hospital of Zhengzhou University, Zhengzhou, China.,National Health Commission Key Laboratory of Birth Defect Prevention, Henan Key Laboratory of Population Defects Prevention, Zhengzhou, China
| | - Bingtao Hao
- Henan Provincial People's Hospital, Medical Genetics Institute of Henan Province, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, People's Hospital of Zhengzhou University, Zhengzhou, China.,National Health Commission Key Laboratory of Birth Defect Prevention, Henan Key Laboratory of Population Defects Prevention, Zhengzhou, China.,Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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22
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Saber MM, Karimiavargani M, Uzawa T, Hettiarachchi N, Hamada M, Ito Y, Saitou N. Possible roles for the hominoid-specific DSCR4 gene in human cells. Genes Genet Syst 2021; 96:1-11. [PMID: 33762515 DOI: 10.1266/ggs.20-00012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Down syndrome in humans is caused by trisomy of chromosome 21. DSCR4 (Down syndrome critical region 4) is a de novo-originated protein-coding gene present only in human chromosome 21 and its homologous chromosomes in apes. Despite being located in a medically critical genomic region and an abundance of evidence indicating its functionality, the roles of DSCR4 in human cells are unknown. We used a bioinformatic approach to infer the biological importance and cellular roles of this gene. Our analysis indicates that DSCR4 is likely involved in the regulation of interconnected biological pathways related to cell migration, coagulation and the immune system. We also showed that these predicted biological functions are consistent with tissue-specific expression of DSCR4 in migratory immune system leukocyte cells and neural crest cells (NCCs) that shape facial morphology in the human embryo. The immune system and NCCs are known to be affected in Down syndrome individuals, who suffer from DSCR4 misregulation, which further supports our findings. Providing evidence for the critical roles of DSCR4 in human cells, our findings establish the basis for further experimental investigations that will be necessary to confirm the roles of DSCR4 in the etiology of Down syndrome.
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Affiliation(s)
- Morteza M Saber
- Population Genetics Laboratory, National Institute of Genetics.,Department of Biological Sciences, Graduate School of Science, University of Tokyo.,Nano Medical Engineering Laboratory, RIKEN.,Department of Electrical Engineering and Bioscience, Faculty of Science and Engineering, Waseda University
| | - Marziyeh Karimiavargani
- Nano Medical Engineering Laboratory, RIKEN.,Graduate School of Science and Engineering, Saitama University
| | | | | | - Michiaki Hamada
- Department of Electrical Engineering and Bioscience, Faculty of Science and Engineering, Waseda University.,Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology (AIST)
| | | | - Naruya Saitou
- Population Genetics Laboratory, National Institute of Genetics.,Department of Biological Sciences, Graduate School of Science, University of Tokyo.,Department of Genetics, School of Life Science, Graduate University for Advanced Studies.,Faculty of Medicine, University of the Ryukyus
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23
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Jilderda LJ, Zhou L, Foijer F. Understanding How Genetic Mutations Collaborate with Genomic Instability in Cancer. Cells 2021; 10:342. [PMID: 33562057 PMCID: PMC7914657 DOI: 10.3390/cells10020342] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/25/2021] [Accepted: 02/03/2021] [Indexed: 01/23/2023] Open
Abstract
Chromosomal instability is the process of mis-segregation for ongoing chromosomes, which leads to cells with an abnormal number of chromosomes, also known as an aneuploid state. Induced aneuploidy is detrimental during development and in primary cells but aneuploidy is also a hallmark of cancer cells. It is therefore believed that premalignant cells need to overcome aneuploidy-imposed stresses to become tumorigenic. Over the past decade, some aneuploidy-tolerating pathways have been identified through small-scale screens, which suggest that aneuploidy tolerance pathways can potentially be therapeutically exploited. However, to better understand the processes that lead to aneuploidy tolerance in cancer cells, large-scale and unbiased genetic screens are needed, both in euploid and aneuploid cancer models. In this review, we describe some of the currently known aneuploidy-tolerating hits, how large-scale genome-wide screens can broaden our knowledge on aneuploidy specific cancer driver genes, and how we can exploit the outcomes of these screens to improve future cancer therapy.
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Affiliation(s)
| | | | - Floris Foijer
- European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Centre Groningen, 9713 AV Groningen, The Netherlands; (L.J.J.); (L.Z.)
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24
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Puente-Bedia A, Berciano MT, Tapia O, Martínez-Cué C, Lafarga M, Rueda N. Nuclear Reorganization in Hippocampal Granule Cell Neurons from a Mouse Model of Down Syndrome: Changes in Chromatin Configuration, Nucleoli and Cajal Bodies. Int J Mol Sci 2021; 22:ijms22031259. [PMID: 33514010 PMCID: PMC7865916 DOI: 10.3390/ijms22031259] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 01/16/2021] [Accepted: 01/22/2021] [Indexed: 01/05/2023] Open
Abstract
Down syndrome (DS) or trisomy of chromosome 21 (Hsa21) is characterized by impaired hippocampal-dependent learning and memory. These alterations are due to defective neurogenesis and to neuromorphological and functional anomalies of numerous neuronal populations, including hippocampal granular cells (GCs). It has been proposed that the additional gene dose in trisomic cells induces modifications in nuclear compartments and on the chromatin landscape, which could contribute to some DS phenotypes. The Ts65Dn (TS) mouse model of DS carries a triplication of 92 genes orthologous to those found in Hsa21, and shares many phenotypes with DS individuals, including cognitive and neuromorphological alterations. Considering its essential role in hippocampal memory formation, we investigated whether the triplication of this set of Hsa21 orthologous genes in TS mice modifies the nuclear architecture of their GCs. Our results show that the TS mouse presents alterations in the nuclear architecture of its GCs, affecting nuclear compartments involved in transcription and pre-rRNA and pre-mRNA processing. In particular, the GCs of the TS mouse show alterations in the nucleolar fusion pattern and the molecular assembly of Cajal bodies (CBs). Furthermore, hippocampal GCs of TS mice present an epigenetic dysregulation of chromatin that results in an increased heterochromatinization and reduced global transcriptional activity. These nuclear alterations could play an important role in the neuromorphological and/or functional alterations of the hippocampal GCs implicated in the cognitive dysfunction characteristic of TS mice.
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Affiliation(s)
- Alba Puente-Bedia
- Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, 39011 Santander, Spain; (A.P.-B.); (C.M.-C.)
| | - María T. Berciano
- Department of Molecular Biology, “Red sobre Enfermedades Neurodegenerativas (CIBERNED)” and University of Cantabria-IDIVAL, 39011 Santander, Spain;
| | - Olga Tapia
- Instituto de Investigación Sanitaria Valdecilla (IDIVAL), “Red sobre Enfermedades Neurodegenerativas (CIBERNED)” and Universidad Europea del Atlántico, 39011 Santander, Spain;
| | - Carmen Martínez-Cué
- Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, 39011 Santander, Spain; (A.P.-B.); (C.M.-C.)
| | - Miguel Lafarga
- Department of Anatomy and Cell Biology, “Red sobre Enfermedades Neurodegenerativas (CIBERNED)” and University of Cantabria-IDIVAL, 39011 Santander, Spain
- Correspondence: (M.L.); (N.R.); Tel.: +34-942201966 (N.R.); Fax: +34-942201903 (N.R.)
| | - Noemí Rueda
- Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, 39011 Santander, Spain; (A.P.-B.); (C.M.-C.)
- Correspondence: (M.L.); (N.R.); Tel.: +34-942201966 (N.R.); Fax: +34-942201903 (N.R.)
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25
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Lim JH, Kang YJ, Lee BY, Han YJ, Chung JH, Kim MY, Kim MH, Kim JW, Cho YH, Ryu HM. Epigenome-wide base-resolution profiling of DNA methylation in chorionic villi of fetuses with Down syndrome by methyl-capture sequencing. Clin Epigenetics 2019; 11:180. [PMID: 31801612 PMCID: PMC6894197 DOI: 10.1186/s13148-019-0756-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 10/06/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Epigenetic mechanisms provide an interface between environmental factors and the genome and are influential in various diseases. These mechanisms, including DNA methylation, influence the regulation of development, differentiation, and establishment of cellular identity. Here, we performed high-throughput methylome profiling to determine whether differential patterns of DNA methylation correlate with Down syndrome (DS). MATERIALS AND METHODS We extracted DNA from the chorionic villi cells of five normal and five DS fetuses at the early developmental stage (12-13 weeks of gestation). Methyl-capture sequencing (MC-Seq) was used to investigate the methylation levels of CpG sites distributed across the whole genome to identify differentially methylated CpG sites (DMCs) and regions (DMRs) in DS. New functional annotations of DMR genes using bioinformatics tools were predicted. RESULTS DNA hypermethylation was observed in DS fetal chorionic villi cells. Significant differences were evident for 4,439 DMCs, including hypermethylation (n = 4,261) and hypomethylation (n = 178). Among them, 140 hypermethylated DMRs and only 1 hypomethylated DMR were located on 121 genes and 1 gene, respectively. One hundred twenty-two genes, including 141 DMRs, were associated with heart morphogenesis and development of the ear, thyroid gland, and nervous systems. The genes were significantly associated with DS and various diseases, including hepatopulmonary syndrome, conductive hearing loss, holoprosencephaly, heart diseases, glaucoma, and musculoskeletal abnormalities. CONCLUSIONS This is the first study to compare the whole-epigenome DNA methylation pattern of the chorionic villi cells from normal and DS fetuses at the early developmental-stage using MC-seq. Overall, our results indicate that the chorionic villi cells of DS fetuses are hypermethylated in all autosomes and suggested that altered DNA methylation may be a recurrent and functionally relevant downstream response to DS in human cells. This study provides basic information for future research focused on the pathophysiology of the DS and its potential effects, as well as the role DNA methylation plays in the early developmental stage of DS fetuses.
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Affiliation(s)
- Ji Hyae Lim
- Center for Biomarker Research and Precision Medicine, CHA Advanced Research Institute, Gyeonggi-do, Republic of Korea.,Department of Medical Genetics, College of Medicine, Hanyang University, 222, Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
| | - Yu-Jung Kang
- Center for Biomarker Research and Precision Medicine, CHA Advanced Research Institute, Gyeonggi-do, Republic of Korea
| | - Bom Yi Lee
- SD Genomics Co., Ltd., Seoul, Republic of Korea
| | - You Jung Han
- Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea
| | - Jin Hoon Chung
- Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea
| | - Moon Young Kim
- Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea
| | - Min Hyoung Kim
- Department of Obstetrics Gynecology, Mizmedi Hospital, Seoul, Republic of Korea
| | - Jin Woo Kim
- Laboratory of Medical Genetics, Medical Research Institute, Cheil General Hospital and Women's Healthcare Center, Seoul, Republic of Korea
| | - Youl-Hee Cho
- Department of Medical Genetics, College of Medicine, Hanyang University, 222, Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea.
| | - Hyun Mee Ryu
- Center for Biomarker Research and Precision Medicine, CHA Advanced Research Institute, Gyeonggi-do, Republic of Korea. .,Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea.
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26
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Abstract
Aneuploidy (i.e., abnormal chromosome number) is the leading cause of miscarriage and congenital defects in humans. Moreover, aneuploidy is ubiquitous in cancer. The deleterious phenotypes associated with aneuploidy are likely a result of the imbalance in the levels of gene products derived from the additional chromosome(s). Here, we summarize the current knowledge on how the presence of extra chromosomes impacts gene expression. We describe studies that have found a strict correlation between gene dosage and transcript levels as wells as studies that have found a less stringent correlation, hinting at the possible existence of dosage compensation mechanisms. We conclude by peering into the epigenetic changes found in aneuploid cells and outlining current knowledge gaps and potential areas of future investigation.
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Affiliation(s)
- Shihoko Kojima
- Department of Biological Sciences & Fralin Life Sciences Institute, Virginia Tech, Blacksburg, VA 24061, USA
| | - Daniela Cimini
- Department of Biological Sciences & Fralin Life Sciences Institute, Virginia Tech, Blacksburg, VA 24061, USA
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27
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Yu YE, Xing Z, Do C, Pao A, Lee EJ, Krinsky-McHale S, Silverman W, Schupf N, Tycko B. Genetic and epigenetic pathways in Down syndrome: Insights to the brain and immune system from humans and mouse models. PROGRESS IN BRAIN RESEARCH 2019; 251:1-28. [PMID: 32057305 PMCID: PMC7286740 DOI: 10.1016/bs.pbr.2019.09.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The presence of an extra copy of human chromosome 21 (Hsa21) leads to a constellation of phenotypic manifestations in Down syndrome (DS), including prominent effects on the brain and immune system. Intensive efforts to unravel the molecular mechanisms underlying these phenotypes may help developing effective therapies, both in DS and in the general population. Here we review recent progress in genetic and epigenetic analysis of trisomy 21 (Ts21). New mouse models of DS based on syntenic conservation of segments of the mouse and human chromosomes are starting to clarify the contributions of chromosomal subregions and orthologous genes to specific phenotypes in DS. The expression of genes on Hsa21 is regulated by epigenetic mechanisms, and with recent findings of highly recurrent gene-specific changes in DNA methylation patterns in brain and immune system cells with Ts21, the epigenomics of DS has become an active research area. Here we highlight the value of combining human studies with mouse models for defining DS critical genes and understanding the trans-acting effects of a simple chromosomal aneuploidy on genome-wide epigenetic patterning. These genetic and epigenetic studies are starting to uncover fundamental biological mechanisms, leading to insights that may soon become therapeutically relevant.
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Affiliation(s)
- Y Eugene Yu
- The Children's Guild Foundation Down Syndrome Research Program, Genetics and Genomics Program and Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States; Genetics, Genomics and Bioinformatics Program, State University of New York at Buffalo, Buffalo, NY, United States.
| | - Zhuo Xing
- The Children's Guild Foundation Down Syndrome Research Program, Genetics and Genomics Program and Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Catherine Do
- Department of Biomedical Research, Division of Genetics & Epigenetics, Hackensack-Meridian Health Center for Discovery and Innovation and Hackensack-Meridian Health School of Medicine at Seton Hall University, Nutley, NJ, United States
| | - Annie Pao
- The Children's Guild Foundation Down Syndrome Research Program, Genetics and Genomics Program and Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Eun Joon Lee
- Department of Biomedical Research, Division of Genetics & Epigenetics, Hackensack-Meridian Health Center for Discovery and Innovation and Hackensack-Meridian Health School of Medicine at Seton Hall University, Nutley, NJ, United States
| | - Sharon Krinsky-McHale
- New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, United States
| | - Wayne Silverman
- Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Pediatrics, University of California at Irvine, Irvine, CA, United States
| | - Nicole Schupf
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, United States
| | - Benjamin Tycko
- Department of Biomedical Research, Division of Genetics & Epigenetics, Hackensack-Meridian Health Center for Discovery and Innovation and Hackensack-Meridian Health School of Medicine at Seton Hall University, Nutley, NJ, United States.
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28
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Alhajraf F, Ness D, Hye A, Strydom A. Plasma amyloid and tau as dementia biomarkers in Down syndrome: Systematic review and meta-analyses. Dev Neurobiol 2019; 79:684-698. [PMID: 31389176 PMCID: PMC6790908 DOI: 10.1002/dneu.22715] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 08/02/2019] [Accepted: 08/02/2019] [Indexed: 12/18/2022]
Abstract
Individuals with Down syndrome (DS) are at high risk of developing Alzheimer's disease (AD). Discovering reliable biomarkers which could facilitate early AD diagnosis and be used to predict/monitor disease course would be extremely valuable. To examine if analytes in blood related to amyloid plaques may constitute such biomarkers, we conducted meta‐analyses of studies comparing plasma amyloid beta (Aβ) levels between DS individuals and controls, and between DS individuals with and without dementia. PubMed, Embase, and Google Scholar were searched for studies investigating the relationship between Aβ plasma concentrations and dementia in DS and 10 studies collectively comprising >1,600 adults, including >1,400 individuals with DS, were included. RevMan 5.3 was used to perform meta‐analyses. Meta‐analyses showed higher plasma Aβ40 (SMD = 1.79, 95% CI [1.14, 2.44], Z = 5.40, p < .00001) and plasma Aβ42 levels (SMD = 1.41, 95% CI [1.15, 1.68], Z = 10.46, p < .00001) in DS individuals than controls, and revealed that DS individuals with dementia had higher plasma Aβ40 levels (SMD = 0.23, 95% CI [0.05, 0.41], Z = 2.54, p = .01) and lower Aβ42/Aβ40 ratios (SMD = −0.33, 95% CI [−0.63, −0.03], Z = 2.15, p = .03) than DS individuals without dementia. Our results indicate that plasma Aβ40 levels may constitute a promising biomarker for predicting dementia status in individuals with DS. Further investigations using new ultra‐sensitive assays are required to obtain more reliable results and to investigate to what extent these results may be generalizable beyond the DS population.
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Affiliation(s)
- Falah Alhajraf
- UCL Queen Square Institute of Neurology, University College London, London, UK.,Al Amiri Hospital, Kuwait City, State of Kuwait
| | - Deborah Ness
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.,The LonDownS Consortium (London Down Syndrome Consortium), London, UK
| | - Abdul Hye
- The Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Andre Strydom
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.,The LonDownS Consortium (London Down Syndrome Consortium), London, UK
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29
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Farrelly LA, Maze I. An emerging perspective on 'histone code' mediated regulation of neural plasticity and disease. Curr Opin Neurobiol 2019; 59:157-163. [PMID: 31382083 PMCID: PMC6889037 DOI: 10.1016/j.conb.2019.07.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 07/07/2019] [Indexed: 12/19/2022]
Abstract
The last two decades have witnessed explosive advances in our understanding as to how the organization of chromatin, the association of DNA with histones and vast numbers of non-histone regulatory proteins, controls the expression of specific genes in brain. Prominent among such regulatory mechanisms are modifications of histones, along with the 'writers,' 'erasers,' and 'readers' of these modifications. Much of the work delineating these mechanisms has contributed to the idea that a 'histone code' may be a central determinant of a gene's activity and its potential to be activated or repressed in response to environmental perturbations (both beneficial and aberrant). Indeed, increasing evidence has demonstrated the significance of histone regulation in neurological plasticity and disease, although we are still at the earliest stages of examining all of the many potential chromatin changes involved. In this short review, we provide an emerging perspective on putative roles for histones, and their combinatorial readouts, in the context of neural plasticity, and we provide a conceptual framework for future mechanistic studies aimed at uncovering causal links between the neural 'histone code' and brain function/disease.
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Affiliation(s)
- Lorna A Farrelly
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Ian Maze
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
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30
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Farroni C, Marasco E, Marcellini V, Giorda E, Valentini D, Petrini S, D'Oria V, Pezzullo M, Cascioli S, Scarsella M, Ugazio AG, De Vincentiis GC, Grimsholm O, Carsetti R. Dysregulated miR-155 and miR-125b Are Related to Impaired B-cell Responses in Down Syndrome. Front Immunol 2018; 9:2683. [PMID: 30515165 PMCID: PMC6255899 DOI: 10.3389/fimmu.2018.02683] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 10/30/2018] [Indexed: 12/21/2022] Open
Abstract
Children with Down Syndrome (DS) suffer from immune deficiency with a severe reduction in switched memory B cells (MBCs) and poor response to vaccination. Chromosome 21 (HSA21) encodes two microRNAs (miRs), miR-125b, and miR-155, that regulate B-cell responses. We studied B- and T- cell subpopulations in tonsils of DS and age-matched healthy donors (HD) and found that the germinal center (GC) reaction was impaired in DS. GC size, numbers of GC B cells and Follicular Helper T cells (TFH) expressing BCL6 cells were severely reduced. The expression of miR-155 and miR-125b was increased in tonsillar memory B cells and miR-125b was also higher than expected in plasma cells (PCs). Activation-induced cytidine deaminase (AID) protein, a miR-155 target, was significantly reduced in MBCs of DS patients. Increased expression of miR-155 was also observed in vitro. MiR-155 was significantly overexpressed in PBMCs activated with CpG, whereas miR-125b was constitutively higher than normal. The increase of miR-155 and its functional consequences were blocked by antagomiRs in vitro. Our data show that the expression of HSA21-encoded miR-155 and miR-125b is altered in B cells of DS individuals both in vivo and in vitro. Because of HSA21-encoded miRs may play a role also in DS-associated dementia and leukemia, our study suggests that antagomiRs may represent pharmacological tools useful for the treatment of DS.
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Affiliation(s)
- Chiara Farroni
- B cell Pathophysiology Unit, Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Emiliano Marasco
- Division of Rheumatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | | | - Ezio Giorda
- Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Diletta Valentini
- Pediatric and Infectious Disease Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Stefania Petrini
- Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Valentina D'Oria
- Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Marco Pezzullo
- Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Simona Cascioli
- B cell Pathophysiology Unit, Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Marco Scarsella
- Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Alberto G Ugazio
- Institute of Child and Adolescent Health, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | | | - Ola Grimsholm
- B cell Pathophysiology Unit, Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.,Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden
| | - Rita Carsetti
- B cell Pathophysiology Unit, Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.,Unit of Diagnostic Immunology, Department of Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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31
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Aziz NM, Guedj F, Pennings JLA, Olmos-Serrano JL, Siegel A, Haydar TF, Bianchi DW. Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome. Dis Model Mech 2018; 11:dmm031013. [PMID: 29716957 PMCID: PMC6031353 DOI: 10.1242/dmm.031013] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 04/23/2018] [Indexed: 12/26/2022] Open
Abstract
Down syndrome (DS) results from triplication of human chromosome 21. Neuropathological hallmarks of DS include atypical central nervous system development that manifests prenatally and extends throughout life. As a result, individuals with DS exhibit cognitive and motor deficits, and have delays in achieving developmental milestones. To determine whether different mouse models of DS recapitulate the human prenatal and postnatal phenotypes, here, we directly compared brain histogenesis, gene expression and behavior over the lifespan of three cytogenetically distinct mouse models of DS: Ts1Cje, Ts65Dn and Dp(16)1/Yey. Histological data indicated that Ts65Dn mice were the most consistently affected with respect to somatic growth, neurogenesis and brain morphogenesis. Embryonic and adult gene expression results showed that Ts1Cje and Ts65Dn brains had considerably more differentially expressed (DEX) genes compared with Dp(16)1/Yey mice, despite the larger number of triplicated genes in the latter model. In addition, DEX genes showed little overlap in identity and chromosomal distribution in the three models, leading to dissimilarities in affected functional pathways. Perinatal and adult behavioral testing also highlighted differences among the models in their abilities to achieve various developmental milestones and perform hippocampal- and motor-based tasks. Interestingly, Dp(16)1/Yey mice showed no abnormalities in prenatal brain phenotypes, yet they manifested behavioral deficits starting at postnatal day 15 that continued through adulthood. In contrast, Ts1Cje mice showed mildly abnormal embryonic brain phenotypes, but only select behavioral deficits as neonates and adults. Altogether, our data showed widespread and unexpected fundamental differences in behavioral, gene expression and brain development phenotypes between these three mouse models. Our findings illustrate unique limitations of each model when studying aspects of brain development and function in DS. This work helps to inform model selection in future studies investigating how observed neurodevelopmental abnormalities arise, how they contribute to cognitive impairment, and when testing therapeutic molecules to ameliorate the intellectual disability associated with DS.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Nadine M Aziz
- Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA
| | - Faycal Guedj
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jeroen L A Pennings
- Center for Health Protection, National Institute for Public Health and the Environment, 3720 BA Bilthoven, The Netherlands
| | - Jose Luis Olmos-Serrano
- Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA
| | - Ashley Siegel
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Tarik F Haydar
- Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA
| | - Diana W Bianchi
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
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32
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Viganó C, von Schubert C, Ahrné E, Schmidt A, Lorber T, Bubendorf L, De Vetter JRF, Zaman GJR, Storchova Z, Nigg EA. Quantitative proteomic and phosphoproteomic comparison of human colon cancer DLD-1 cells differing in ploidy and chromosome stability. Mol Biol Cell 2018; 29:1031-1047. [PMID: 29496963 PMCID: PMC5921571 DOI: 10.1091/mbc.e17-10-0577] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 02/15/2018] [Accepted: 02/21/2018] [Indexed: 11/11/2022] Open
Abstract
Although aneuploidy is poorly tolerated during embryogenesis, aneuploidy and whole chromosomal instability (CIN) are common hallmarks of cancer, raising the question of how cancer cells can thrive in spite of chromosome aberrations. Here we present a comprehensive and quantitative proteomics analysis of isogenic DLD-1 colorectal adenocarcinoma cells lines, aimed at identifying cellular responses to changes in ploidy and/or CIN. Specifically, we compared diploid (2N) and tetraploid (4N) cells with posttetraploid aneuploid (PTA) clones and engineered trisomic clones. Our study provides a comparative data set on the proteomes and phosphoproteomes of the above cell lines, comprising several thousand proteins and phosphopeptides. In comparison to the parental 2N line, we observed changes in proteins associated with stress responses and with interferon signaling. Although we did not detect a conspicuous protein signature associated with CIN, we observed many changes in phosphopeptides that relate to fundamental cellular processes, including mitotic progression and spindle function. Most importantly, we found that most changes detectable in PTA cells were already present in the 4N progenitor line. This suggests that activation of mitotic pathways through hyper-phosphorylation likely constitutes an important response to chromosomal burden. In line with this conclusion, cells with extensive chromosome gains showed differential sensitivity toward a number of inhibitors targeting cell cycle kinases, suggesting that the efficacy of anti-mitotic drugs may depend on the karyotype of cancer cells.
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Affiliation(s)
| | | | - Erik Ahrné
- Biozentrum, University of Basel, 4056 Basel, Switzerland
| | | | - Thomas Lorber
- Institute of Pathology, University Hospital Basel, University of Basel, 4056 Basel, Switzerland
| | - Lukas Bubendorf
- Institute of Pathology, University Hospital Basel, University of Basel, 4056 Basel, Switzerland
| | | | - Guido J. R. Zaman
- Netherlands Translational Research Center B.V., 5340 Oss, The Netherlands
| | | | - Erich A. Nigg
- Biozentrum, University of Basel, 4056 Basel, Switzerland
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33
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Philipp T, Terry J, Feichtinger M, Grillenberger S, Hartmann B, Jirecek S. Morphology of early intrauterine deaths with full trisomy 15. Prenat Diagn 2018; 38:267-272. [DOI: 10.1002/pd.5230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 01/22/2018] [Accepted: 01/30/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Tom Philipp
- Department of Gynecology and Obstetrics; Danube Hospital; Vienna Austria
| | - Jefferson Terry
- Department of Pathology; BC Children's Hospital; Vancouver Canada
| | - Michael Feichtinger
- Department of Obstetrics and Gynecology, Division of Gynecologic Endocrinology and Reproductive Medicine; Medical University of Vienna; Vienna Austria
| | - Sandra Grillenberger
- Department of Pathology, Cytogenetic Laboratory; Danube Hospital; Vienna Austria
| | - Beda Hartmann
- Department of Gynecology and Obstetrics; Danube Hospital; Vienna Austria
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34
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Liamina D, Sibirnyj W, Khokhlova A, Saenko V, Rastorgueva E, Fomin A, Saenko Y. Radiation-Induced Changes of microRNA Expression Profiles in Radiosensitive and Radioresistant Leukemia Cell Lines with Different Levels of Chromosome Abnormalities. Cancers (Basel) 2017; 9:cancers9100136. [PMID: 29027959 PMCID: PMC5664075 DOI: 10.3390/cancers9100136] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 10/07/2017] [Accepted: 10/10/2017] [Indexed: 12/15/2022] Open
Abstract
In our study, we estimate an effect from chromosome aberrations and genome mutations on changes in microRNA expression profiles in cancer cell lines demonstrating different radiosensitivity. Here, cell viability and microRNA spectrum have been estimated 1, 4, and 24 h after irradiation. MiSeq high-throughput sequencing system (Illumina, San Diego, CA, USA) is employed to perform microRNA spectrum estimation. In the K562 cell line, the number of expressed microRNAs in chromosomes demonstrates a more pronounced variation. An analysis of microRNA effects on signaling pathway activity demonstrates differences in post-transcriptional regulation of the expression of genes included into 40 signaling pathways. In the K562 cell line, microRNA dynamics analyzed for their dependence on chromosome localization show a wider scattering of microRNA expression values for a pair of chromosomes compared to the HL-60 cell line. An analysis of microRNAs expression in the K562 and HL-60 cell lines after irradiation has shown that chromosome abnormalities can affect microRNA expression changes. A study of radiation-induced changes of microRNA expression profiles in the K562 and HL-60 cell lines has revealed a dependence of microRNA expression changes on the number of chromosome aberrations and genome mutations.
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Affiliation(s)
- Daria Liamina
- Laboratory of Molecular and Cell Biology, S.P. Kapitsa Research Institute of Technology, Ulyanovsk State University, 42 Lva Tolstogo St., Ulyanovsk 432017, Russia.
| | - Wladimir Sibirnyj
- Department of Bioenergetics and Food Analysis, Faculty of Biology and Agriculture, University of Rzeszow, Ćwiklińskiej St., 35-601 Rzeszów, Poland.
| | - Anna Khokhlova
- Laboratory of Molecular and Cell Biology, S.P. Kapitsa Research Institute of Technology, Ulyanovsk State University, 42 Lva Tolstogo St., Ulyanovsk 432017, Russia.
| | - Viacheslav Saenko
- Laboratory of Molecular and Cell Biology, S.P. Kapitsa Research Institute of Technology, Ulyanovsk State University, 42 Lva Tolstogo St., Ulyanovsk 432017, Russia.
| | - Eugenia Rastorgueva
- Department of General and Clinical Pharmacology and Microbiology, Faculty of Medicine, Ulyanovsk State University, 42 Lva Tolstogo St., Ulyanovsk 432017, Russia.
| | - Aleksandr Fomin
- S.P. Kapitsa Research Institute of Technology, Ulyanovsk State University, 42 Lva Tolstogo St., Ulyanovsk 432017, Russia.
| | - Yury Saenko
- Laboratory of Molecular and Cell Biology, S.P. Kapitsa Research Institute of Technology, Ulyanovsk State University, 42 Lva Tolstogo St., Ulyanovsk 432017, Russia.
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35
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Stringer M, Goodlett CR, Roper RJ. Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits. Mol Genet Genomic Med 2017; 5:451-465. [PMID: 28944229 PMCID: PMC5606891 DOI: 10.1002/mgg3.334] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 08/21/2017] [Accepted: 08/24/2017] [Indexed: 12/11/2022] Open
Abstract
Overexpression of Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS-associated phenotypes have been largely unsuccessful. Epigallocatechin-3-gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS-associated phenotypes that have been reported in preclinical studies and clinical trials. However, the beneficial effects of EGCG are inconsistent and there is no direct evidence that any observed improvement actually occurs through Dyrk1a inhibition. Inconclusive outcomes likely reflect a lack of knowledge about the tissue-specific patterns of spatial and temporal overexpression and elevated activity of Dyrk1a that may contribute to emerging DS traits during development. Emerging evidence indicates that Dyrk1a expression varies over the life span in DS mouse models, yet preclinical therapeutic treatments targeting Dyrk1a have largely not considered these developmental changes. Therapies intended to improve DS phenotypes through normalizing trisomic Dyrk1a need to optimize the timing and dose of treatment to match the spatiotemporal patterning of excessive Dyrk1a activity in relevant tissues. This will require more precise identification of developmental periods of vulnerability to enduring adverse effects of elevated Dyrk1a, representing the concurrence of increased Dyrk1a expression together with hypothesized tissue-specific-sensitive periods when Dyrk1a regulates cellular processes that shape the long-term functional properties of the tissue. Future efforts targeting inhibition of trisomic Dyrk1a should identify these putative spatiotemporally specific developmental sensitive periods and determine whether normalizing Dyrk1a activity then can lead to improved outcomes in DS phenotypes.
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Affiliation(s)
- Megan Stringer
- Department of PsychologyIUPUI402 North Blackford Street, LD 124IndianapolisIndiana46202-3275
| | - Charles R Goodlett
- Department of PsychologyIUPUI402 North Blackford Street, LD 124IndianapolisIndiana46202-3275
| | - Randall J Roper
- Department of BiologyIUPUI723 West Michigan Street SL 306IndianapolisIndiana46202-3275
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36
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Lee JH, Lee AJ, Dang LH, Pang D, Kisselev S, Krinsky-McHale SJ, Zigman WB, Luchsinger JA, Silverman W, Tycko B, Clark LN, Schupf N. Candidate gene analysis for Alzheimer's disease in adults with Down syndrome. Neurobiol Aging 2017; 56:150-158. [PMID: 28554490 DOI: 10.1016/j.neurobiolaging.2017.04.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 03/17/2017] [Accepted: 04/21/2017] [Indexed: 11/16/2022]
Abstract
Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer's disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g., age at onset of AD, amyloid β levels) among adults with DS, suggesting the importance of factors that modify risk within this particularly vulnerable population, including genotypic variability. Previous genetic studies in the general population have identified multiple genes that are associated with AD. This study examined the contribution of polymorphisms in these genes to the risk of AD in adults with DS ranging from 30 to 78 years of age at study entry (N = 320). We used multiple logistic regressions to estimate the likelihood of AD using single-nucleotide polymorphisms (SNPs) in candidate genes, adjusting for age, sex, race/ethnicity, level of intellectual disability and APOE genotype. This study identified multiple SNPs in APP and CST3 that were associated with AD at a gene-wise level empirical p-value of 0.05, with odds ratios in the range of 1.5-2. SNPs in MARK4 were marginally associated with AD. CST3 and MARK4 may contribute to our understanding of potential mechanisms where CST3 may contribute to the amyloid pathway by inhibiting plaque formation, and MARK4 may contribute to the regulation of the transition between stable and dynamic microtubules.
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Affiliation(s)
- Joseph H Lee
- Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Taub Institute, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA.
| | - Annie J Lee
- Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Lam-Ha Dang
- Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA
| | - Deborah Pang
- Department of Psychology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
| | - Sergey Kisselev
- Department of Pathology & Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Sharon J Krinsky-McHale
- Department of Psychology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
| | - Warren B Zigman
- Department of Psychology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
| | - José A Luchsinger
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Wayne Silverman
- Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Benjamin Tycko
- Department of Pathology & Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Lorraine N Clark
- Taub Institute, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Pathology & Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Nicole Schupf
- Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Taub Institute, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA
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37
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Do C, Xing Z, Yu YE, Tycko B. Trans-acting epigenetic effects of chromosomal aneuploidies: lessons from Down syndrome and mouse models. Epigenomics 2016; 9:189-207. [PMID: 27911079 PMCID: PMC5549717 DOI: 10.2217/epi-2016-0138] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
An important line of postgenomic research seeks to understand how genetic factors can influence epigenetic patterning. Here we review epigenetic effects of chromosomal aneuploidies, focusing on findings in Down syndrome (DS, trisomy 21). Recent work in human DS and mouse models has shown that the extra chromosome 21 acts in trans to produce epigenetic changes, including differential CpG methylation (DS-DM), in specific sets of downstream target genes, mostly on other chromosomes. Mechanistic hypotheses emerging from these data include roles of chromosome 21-linked methylation pathway genes (DNMT3L and others) and transcription factor genes (RUNX1, OLIG2, GABPA, ERG and ETS2) in shaping the patterns of DS-DM. The findings may have broader implications for trans-acting epigenetic effects of chromosomal and subchromosomal aneuploidies in other human developmental and neuropsychiatric disorders, and in cancers.
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Affiliation(s)
- Catherine Do
- Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
| | - Zhuo Xing
- The Children's Guild Foundation Down Syndrome Research Program, Genetics Program & Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Y Eugene Yu
- The Children's Guild Foundation Down Syndrome Research Program, Genetics Program & Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Benjamin Tycko
- Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.,Taub Institute for Research on Alzheimer's disease & the Aging Brain, Columbia University, New York, NY 10032, USA.,Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.,Department of Pathology & Cell Biology, Columbia University, New York, NY 10032, USA
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38
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Créau N, Cabet E, Daubigney F, Souchet B, Bennaï S, Delabar J. Specific age-related molecular alterations in the cerebellum of Down syndrome mouse models. Brain Res 2016; 1646:342-353. [PMID: 27297494 DOI: 10.1016/j.brainres.2016.06.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 05/07/2016] [Accepted: 06/02/2016] [Indexed: 12/27/2022]
Abstract
Down syndrome, or trisomy 21, has been modeled with various trisomic and transgenic mice to help understand the consequences of an altered gene dosage in brain development and function. Though Down syndrome has been associated with premature aging, little is known about the molecular and cellular alterations that target brain function. To help identify alterations at specific ages, we analyzed the cerebellum of Ts1Cje mice, trisomic for 77 HSA21 orthologs, at three ages-young (4 months), middle-age (12 months), and old (17 months)-compared to age-matched controls. Quantification of neuronal and glial markers (n=11) revealed increases in GFAP, with an age effect, and S100B, with age and genotype effects. The genotype effect on S100B with age was unexpected as Ts1Cje has only two copies of the S100b gene. Interestingly, the different increase in GFAP observed between Ts1Cje (trisomic segment includes Pcp4 gene) and controls was magnified in TgPCP4 mice (1 extra copy of the human PCP4 gene) at the same age. S100B increase was not found in the TgPCP4 confirming a difference of regulation with aging for GFAP and S100B and excluding the calcium signaling regulator, Pcp4, as a potential candidate for increase of S100B in the Ts1Cje. To understand these differences, comparison of GFAP and S100B immunostainings at young and middle-age were performed. Immunohistochemical detection of differences in GFAP and S100B localization with aging implicate S100B+ oligodendrocytes as a new phenotypic target in this specific aging process.
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Affiliation(s)
- Nicole Créau
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, UMR8251, CNRS, Paris, France.
| | - Eva Cabet
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, UMR8251, CNRS, Paris, France
| | - Fabrice Daubigney
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, UMR8251, CNRS, Paris, France
| | - Benoit Souchet
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, UMR8251, CNRS, Paris, France
| | - Soumia Bennaï
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, UMR8251, CNRS, Paris, France
| | - Jean Delabar
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, UMR8251, CNRS, Paris, France
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El Hajj N, Dittrich M, Böck J, Kraus TFJ, Nanda I, Müller T, Seidmann L, Tralau T, Galetzka D, Schneider E, Haaf T. Epigenetic dysregulation in the developing Down syndrome cortex. Epigenetics 2016; 11:563-78. [PMID: 27245352 PMCID: PMC4990229 DOI: 10.1080/15592294.2016.1192736] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 05/12/2016] [Accepted: 05/17/2016] [Indexed: 12/18/2022] Open
Abstract
Using Illumina 450K arrays, 1.85% of all analyzed CpG sites were significantly hypermethylated and 0.31% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The methylation changes on chromosome 21 appeared to be balanced between hypo- and hyper-methylation, whereas, consistent with prior reports, all other chromosomes showed 3-11 times more hyper- than hypo-methylated sites. Reduced NRSF/REST expression due to upregulation of DYRK1A (on chromosome 21q22.13) and methylation of REST binding sites during early developmental stages may contribute to this genome-wide excess of hypermethylated sites. Upregulation of DNMT3L (on chromosome 21q22.4) could lead to de novo methylation in neuroprogenitors, which then persists in the fetal DS brain where DNMT3A and DNMT3B become downregulated. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the protocadherin gamma (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHG subfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHG expression is expected to reduce dendrite arborization and growth in cortical neurons. Since constitutive hypermethylation of PCDHG and other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions.
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Affiliation(s)
- Nady El Hajj
- Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany
| | - Marcus Dittrich
- Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany
- Department of Bioinformatics, Julius Maximilians University, Würzburg, Germany
| | - Julia Böck
- Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany
| | - Theo F. J. Kraus
- Center for Neuropathology and Prion Research, Ludwig Maximilians University, Munich, Germany
| | - Indrajit Nanda
- Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany
| | - Tobias Müller
- Department of Bioinformatics, Julius Maximilians University, Würzburg, Germany
| | - Larissa Seidmann
- Department of Pathology, University Medical Center, Mainz, Germany
| | - Tim Tralau
- Rehabilitation Clinic for Children and Adolescents, Westerland/Sylt, Germany
| | - Danuta Galetzka
- Department of Radiation Oncology and Radiotherapy, University Medical Center, Mainz, Germany
| | - Eberhard Schneider
- Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany
| | - Thomas Haaf
- Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany
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40
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Lu S, Yin X. Overexpression of Dyrk1A regulates cardiac troponin T splicing in cells and mice. Biochem Biophys Res Commun 2016; 473:993-998. [PMID: 27049307 DOI: 10.1016/j.bbrc.2016.04.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 04/01/2016] [Indexed: 11/15/2022]
Abstract
The human heart expresses four isoforms of cardiac troponin T (cTnT) through alternative splicing of exons 4 and 5 of the cTnT gene. Alternative splicing of cTnT exon 5 is developmentally regulated. cTnT isoforms containing exon 5 are expressed in the fetal and neonatal heart but not in the mature heart. SRp55 is an essential splicing factor involved in cTnT exon 5 splicing and it is phosphorylated by Dyrk1A (dual specificity tyrosine phosphorylation regulated kinase 1A). In the present study, we found Dyrk1A interacted with SRp55 and enhanced its promotion of cTnT exon 5 inclusion. The shift from cTnT exon 5 inclusion to exclusion during development was delayed in the heart of Ts65Dn mice due to Dyrk1A overexpression. These results provide new insight into the role of Dyrk1A in the neonatal cardiac development.
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Affiliation(s)
- Shu Lu
- Department of Intensive Care Unit, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, PR China
| | - Xiaomin Yin
- Department of Biochemistry, Medical School, Nantong University, Nantong, Jiangsu, 226001, PR China; Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Beijing 100053, PR China.
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41
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Differential Expression of Inflammation-Related Genes in Children with Down Syndrome. Mediators Inflamm 2016; 2016:6985903. [PMID: 27293319 PMCID: PMC4879265 DOI: 10.1155/2016/6985903] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 04/05/2016] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE The aim of the study was to investigate the expression patterns of a specific set of genes involved in the inflammation process in children with Down Syndrome (DS) and children without the syndrome (control group) to identify differences that may be related to the immune abnormalities observed in DS individuals. METHOD RNA samples were obtained from peripheral blood, and gene expression was quantified using the TaqMan® Array Plate Human Inflammation Kit, which facilitated the investigation into 92 inflammation-related genes and four reference genes using real-time polymerase chain reaction (qPCR). RESULTS Twenty genes showed differential expression in children with DS; 12 were overexpressed (PLA2G2D, CACNA1D, ALOX12, VCAM1, ICAM1, PLCD1, ADRB1, HTR3A, PDE4C, CASP1, PLA2G5, and PLCB4), and eight were underexpressed (LTA4H, BDKRB1, ADRB2, CD40LG, ITGAM, TNFRSF1B, ITGB1, and TBXAS1). After statistically correcting for the false discovery rate, only the genes BDKRB1 and LTA4H showed differential expression, and both were underexpressed within the DS group. CONCLUSION DS children showed differential expression of inflammation-related genes that were not located on chromosome 21 compared with children without DS. The BDKRB1 and LTA4H genes may differentiate the case and control groups based on the inflammatory response, which plays an important role in DS pathogenesis.
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42
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Saadeldin IM, Khoirinaya C, Kim SJ, Moon JH, Almadaly E, Lee BC. Blastocysts derivation from somatic cell fusion with premature oocytes (prematuration somatic cell fusion). Dev Growth Differ 2016; 58:157-66. [PMID: 26857553 DOI: 10.1111/dgd.12264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Revised: 01/03/2016] [Accepted: 01/04/2016] [Indexed: 11/28/2022]
Abstract
This study was undertaken to investigate the development of immature oocytes after their fusion with male somatic cells expressing red fluorescence protein (RFP). RFP-expressing cells were fused with immature oocytes, matured in vitro and then parthenogenetically activated. Somatic nuclei showed spindle formation, 1st polar body extrusion after in vitro maturation and protruded the 2nd polar body after parthenogenetic activation. RFP was expressed in the resultant embryos; two-cell stage and blastocysts. Chromosomal analysis showed aneuploidy in 81.82% of the resulting blastocysts while 18.18% of the resulting blastocysts were diploid. Among eight RFP-expressing blastocysts, Xist mRNAs was detected in six while Sry mRNA was detected in only one blastocyst. We propose "prematuration somatic cell fusion" as an approach to generate embryos using somatic cells instead of spermatozoa. The current approach, if improved, would assist production of embryos for couples where the male partner is sterile, however, genetic and chromosomal analysis of the resultant embryos are required before transfer to the mothers.
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Affiliation(s)
- Islam M Saadeldin
- Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Candrani Khoirinaya
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and the Research Institute for Veterinary Science, Seoul National University, Seoul, 151-742, Korea
| | - Su Jin Kim
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and the Research Institute for Veterinary Science, Seoul National University, Seoul, 151-742, Korea
| | - Joon Ho Moon
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and the Research Institute for Veterinary Science, Seoul National University, Seoul, 151-742, Korea
| | - Essam Almadaly
- Department of Theriogenology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt
| | - Byeong Chun Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and the Research Institute for Veterinary Science, Seoul National University, Seoul, 151-742, Korea.,Designed Animal and Transplantation, Institute of Green Bio Science Technology, Seoul National University, Seoul, 232-916, Pyeongchang, Korea
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Abstract
Adaptation is the process in which organisms improve their fitness by changing their phenotype using genetic or non-genetic mechanisms. The adaptation toolbox consists of varied molecular and genetic means that we posit span an almost continuous "adaptation spectrum." Different adaptations are characterized by the time needed for organisms to attain them and by their duration. We suggest that organisms often adapt by progressing the adaptation spectrum, starting with rapidly attained physiological and epigenetic adaptations and culminating with slower long-lasting genetic ones. A tantalizing possibility is that earlier adaptations facilitate realization of later ones.
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44
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Abstract
Dividing cells that experience chromosome mis-segregation generate aneuploid daughter cells, which contain an incorrect number of chromosomes. Although aneuploidy interferes with the proliferation of untransformed cells, it is also, paradoxically, a hallmark of cancer, a disease defined by increased proliferative potential. These contradictory effects are also observed in mouse models of chromosome instability (CIN). CIN can inhibit and promote tumorigenesis. Recent work has provided insights into the cellular consequences of CIN and aneuploidy. Chromosome mis-segregation per se can alter the genome in many more ways than just causing the gain or loss of chromosomes. The short- and long-term effects of aneuploidy are caused by gene-specific effects and a stereotypic aneuploidy stress response. Importantly, these recent findings provide insights into the role of aneuploidy in tumorigenesis.
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45
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Jiang X, Liu C, Yu T, Zhang L, Meng K, Xing Z, Belichenko PV, Kleschevnikov AM, Pao A, Peresie J, Wie S, Mobley WC, Yu YE. Genetic dissection of the Down syndrome critical region. Hum Mol Genet 2015; 24:6540-51. [PMID: 26374847 DOI: 10.1093/hmg/ddv364] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 09/02/2015] [Indexed: 01/11/2023] Open
Abstract
Down syndrome (DS), caused by trisomy 21, is the most common chromosomal disorder associated with developmental cognitive deficits. Despite intensive efforts, the genetic mechanisms underlying developmental cognitive deficits remain poorly understood, and no treatment has been proven effective. The previous mouse-based experiments suggest that the so-called Down syndrome critical region of human chromosome 21 is an important region for this phenotype, which is demarcated by Setd4/Cbr1 and Fam3b/Mx2. We first confirmed the importance of the Cbr1-Fam3b region using compound mutant mice, which carry a duplication spanning the entire human chromosome 21 orthologous region on mouse chromosome 16 [Dp(16)1Yey] and Ms1Rhr. By dividing the Setd4-Mx2 region into complementary Setd4-Kcnj6 and Kcnj15-Mx2 intervals, we started an unbiased dissection through generating and analyzing Dp(16)1Yey/Df(16Setd4-Kcnj6)Yey and Dp(16)1Yey/Df(16Kcnj15-Mx2)Yey mice. Surprisingly, the Dp(16)1Yey-associated cognitive phenotypes were not rescued by either deletion in the compound mutants, suggesting the possible presence of at least one causative gene in each of the two regions. The partial rescue by a Dyrk1a mutation in a compound mutant carrying Dp(16)1Yey and the Dyrk1a mutation confirmed the causative role of Dyrk1a, whereas the absence of a similar rescue by Df(16Dyrk1a-Kcnj6)Yey in Dp(16)1Yey/Df(16Dyrk1a-Kcnj6)Yey mice demonstrated the importance of Kcnj6. Our results revealed the high levels of complexities of gene actions and interactions associated with the Setd4/Cbr1-Fam3b/Mx2 region as well as their relationship with developmental cognitive deficits in DS.
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Affiliation(s)
- Xiaoling Jiang
- The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Chunhong Liu
- The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Tao Yu
- The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA, Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Li Zhang
- The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA, Department of Physiology and Pathophysiology, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Kai Meng
- The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA, Department of Physiology and Pathophysiology, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Zhuo Xing
- The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Pavel V Belichenko
- Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA and
| | - Alexander M Kleschevnikov
- Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA and
| | - Annie Pao
- The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Jennifer Peresie
- The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Sarah Wie
- The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - William C Mobley
- Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA and
| | - Y Eugene Yu
- The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA, Genetics, Genomics and Bioinformatics Program, Department of Cellular and Molecular Biology, Roswell Park Division of Graduate School,State University of New York at Buffalo, Buffalo, NY 14263, USA
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46
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Long-term effects of neonatal treatment with fluoxetine on cognitive performance in Ts65Dn mice. Neurobiol Dis 2015; 74:204-18. [DOI: 10.1016/j.nbd.2014.12.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Revised: 11/18/2014] [Accepted: 12/01/2014] [Indexed: 11/23/2022] Open
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Abstract
In many animals, males have one X and females have two X chromosomes. The difference in X chromosome dosage between the two sexes is compensated by mechanisms that regulate X chromosome transcription. Recent advances in genomic techniques have provided new insights into the molecular mechanisms of X chromosome dosage compensation. In this review, I summarize our current understanding of dosage imbalance in general, and then review the molecular mechanisms of X chromosome dosage compensation with an emphasis on the parallels and differences between the three well-studied model systems, M. musculus, D. melanogaster and C. elegans.
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Affiliation(s)
- Sevinç Ercan
- Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY 10003, USA
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48
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Trivedi DK, Iles RK. Shotgun metabolomic profiles in maternal urine identify potential mass spectral markers of abnormal fetal biochemistry - dihydrouracil and progesterone in the metabolism of Down syndrome. Biomed Chromatogr 2014; 29:1173-83. [PMID: 25545476 DOI: 10.1002/bmc.3404] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 10/23/2014] [Accepted: 11/04/2014] [Indexed: 12/15/2022]
Abstract
In Down syndrome (DS) in particular, the precise cellular mechanisms linking genotype to phenotype is not straightforward despite a clear mapping of the genetic cause. Metabolomic profiling might be more revealing in understanding molecular-cellular mechanisms of inborn errors of metabolism/syndromes than genomics alone and also result in new prenatal screening approaches. The urinary metabolome of 122 maternal urine from women with and without an aneuploid pregnancy (predominantly Down syndrome) were compared by both zwitterionic hydrophilic interaction chromatography (ZIC-HILIC) and reversed-phase liquid chromatography (RPLC) coupled to hybrid ion trap time of flight mass spectral analysis. ZIC-HILIC mass spectrometry resolved 10-fold more unique molecular ions than RPLC mass spectrometry, of which molecules corresponding to ions of m/z 114.07 and m/z 314.20 showed maternal urinary level changes that significantly coincided with the presence of a DS fetus. The ion of m/z 314.20 was identified as progesterone and m/z 114.07 as dihydrouracil. A metabolomics profiling-based maternal urinary screening test modelled from this separation data would detect approximately 87 and 60.87% (using HILIC-MS and RPLC-MS, respectively) of all DS pregnancies between 9 and 23 weeks of gestation with no false positives.
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Affiliation(s)
- Drupad K Trivedi
- Eric Leonard Kruse Foundation for Health Research, UK.,Biomedical Sciences, Middlesex University, Hendon, NW4 4BT, UK.,University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK
| | - Ray K Iles
- Eric Leonard Kruse Foundation for Health Research, UK.,MAP Diagnostics, Ely, UK
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49
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Dekker AD, De Deyn PP, Rots MG. Epigenetics: The neglected key to minimize learning and memory deficits in Down syndrome. Neurosci Biobehav Rev 2014; 45:72-84. [DOI: 10.1016/j.neubiorev.2014.05.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 05/04/2014] [Accepted: 05/13/2014] [Indexed: 10/25/2022]
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50
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Jansa P, Homolka D, Blatny R, Mistrik M, Bartek J, Forejt J. Dosage compensation of an aneuploid genome in mouse spermatogenic cells. Biol Reprod 2014; 90:124. [PMID: 24790161 DOI: 10.1095/biolreprod.114.118497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Autosomal trisomies and monosomies bring serious threats to embryonic development through transcriptional disarray caused primarily by the dosage effect of the aneuploid part of the genome. The present study compared the effect of a mouse-viable 30-Mb segmental trisomy on the genome-wide transcriptional profile of somatic (liver) cells and male germ cells. Although the 1.6-fold change in expression of triplicated genes reflected the gene dosage in liver cells, the extra copy genes were compensated in early pachytene spermatocytes, showing 1.18-fold increase. Although more pronounced, the dosage compensation of trisomic genes was concordant with the incidence of HORMAD2 protein and histone gammaH2AX markers of unsynapsed chromatin. A possible explanation for this includes insufficient sensitivity to detect the meiotic silencing of unsynapsed chromatin markers in the 30-Mb region of the chromosome or an earlier silencing effect of another epigenetic factor. Taken together, our results indicate that the meiotic silencing of unsynapsed chromatin is the major, but most likely not the only, factor driving the dosage compensation of triplicated genes in primary spermatocytes.
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Affiliation(s)
- Petr Jansa
- Laboratory of Mouse Molecular Genetics Division BIOCEV, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | - David Homolka
- Laboratory of Mouse Molecular Genetics Division BIOCEV, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Radek Blatny
- Laboratory of Mouse Molecular Genetics Division BIOCEV, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Martin Mistrik
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Czech Republic
| | - Jiri Bartek
- Laboratory of Genome Integrity, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Czech Republic Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Jiri Forejt
- Laboratory of Mouse Molecular Genetics Division BIOCEV, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
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