Heterochromatic genes undergo epigenetic changes and escape silencing in immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome
Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) syndrome is a rare autosomal recessive disorder that is characterized by a marked immunodeficiency, severe hypomethylation of the classical satellites 2 and 3 associated with disruption of constitutive heterochromatin, and facial anom...
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description | Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) syndrome is a rare autosomal recessive disorder that is characterized by a marked immunodeficiency, severe hypomethylation of the classical satellites 2 and 3 associated with disruption of constitutive heterochromatin, and facial anomalies. Sixty percent of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In the present study, we have shown that, in ICF lymphoblasts and peripheral blood, juxtacentromeric heterochromatic genes undergo dramatic changes in DNA methylation, indicating that they are bona fide targets of the DNMT3B protein. DNA methylation in heterochromatic genes dropped from about 80% in normal cells to approximately 30% in ICF cells. Hypomethylation was observed in five ICF patients and was associated with activation of these silent genes. Although DNA hypomethylation occurred in all the analyzed heterochromatic genes and in all the ICF patients, gene expression was restricted to some genes, every patient having his own group of activated genes. Histone modifications were preserved in ICF patients. Heterochromatic genes were associated with histone modifications that are typical of inactive chromatin: they had low acetylation on H3 and H4 histones and were slightly enriched in H3K9Me(3), both in ICF and controls. This was also the case for those heterochromatic genes that escaped silencing. This finding suggests that gene activation was not generalized to all the cells, but rather was restricted to a clonal cell population that may contribute to the phenotypic variability observed in ICF syndrome. A slight increase in H3K27 monomethylation was observed both in heterochromatin and active euchromatin in ICF patients; however, no correlation between this modification and activation of heterochromatic genes was found. |
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Sixty percent of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In the present study, we have shown that, in ICF lymphoblasts and peripheral blood, juxtacentromeric heterochromatic genes undergo dramatic changes in DNA methylation, indicating that they are bona fide targets of the DNMT3B protein. DNA methylation in heterochromatic genes dropped from about 80% in normal cells to approximately 30% in ICF cells. Hypomethylation was observed in five ICF patients and was associated with activation of these silent genes. Although DNA hypomethylation occurred in all the analyzed heterochromatic genes and in all the ICF patients, gene expression was restricted to some genes, every patient having his own group of activated genes. Histone modifications were preserved in ICF patients. Heterochromatic genes were associated with histone modifications that are typical of inactive chromatin: they had low acetylation on H3 and H4 histones and were slightly enriched in H3K9Me(3), both in ICF and controls. This was also the case for those heterochromatic genes that escaped silencing. This finding suggests that gene activation was not generalized to all the cells, but rather was restricted to a clonal cell population that may contribute to the phenotypic variability observed in ICF syndrome. A slight increase in H3K27 monomethylation was observed both in heterochromatin and active euchromatin in ICF patients; however, no correlation between this modification and activation of heterochromatic genes was found.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0019464</identifier><identifier>PMID: 21559330</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetylation ; Adolescent ; Adult ; Anomalies ; B cells ; Biology ; Cancer ; Centromere - ultrastructure ; Child ; Child, Preschool ; Chromatin ; Deoxyribonucleic acid ; Disruption ; DNA ; DNA (Cytosine-5-)-Methyltransferases - genetics ; DNA (Cytosine-5-)-Methyltransferases - physiology ; DNA binding proteins ; DNA methylation ; DNA methyltransferase ; DNA Methyltransferase 3B ; Epigenesis, Genetic ; Epigenetic inheritance ; Euchromatin ; Euchromatin - metabolism ; Face - abnormalities ; Female ; Gene expression ; Gene silencing ; Genes ; Genetic variability ; Genetic Variation ; Genomes ; Hereditary diseases ; Heterochromatin ; Heterochromatin - genetics ; Heterochromatin - metabolism ; Histones ; Histones - metabolism ; Humans ; ICF syndrome ; Immunodeficiency ; Localization ; Lymphoblasts ; Male ; Methylation ; Methyltransferases ; Middle Aged ; Mutation ; Patients ; Peripheral blood ; Phenotype ; Stability ; Stem cells ; Syndrome ; Transcription activation</subject><ispartof>PloS one, 2011-04, Vol.6 (4), p.e19464-e19464</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Brun et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Brun et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c658t-5e22f703ab4427b4d56120c9720c15ca2b7677f055e4a32d411071a6ed45650d3</citedby><cites>FETCH-LOGICAL-c658t-5e22f703ab4427b4d56120c9720c15ca2b7677f055e4a32d411071a6ed45650d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084872/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084872/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21559330$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Chadwick, Brian P.</contributor><creatorcontrib>Brun, Marie-Elisabeth</creatorcontrib><creatorcontrib>Lana, Erica</creatorcontrib><creatorcontrib>Rivals, Isabelle</creatorcontrib><creatorcontrib>Lefranc, Gérard</creatorcontrib><creatorcontrib>Sarda, Pierre</creatorcontrib><creatorcontrib>Claustres, Mireille</creatorcontrib><creatorcontrib>Mégarbané, André</creatorcontrib><creatorcontrib>De Sario, Albertina</creatorcontrib><title>Heterochromatic genes undergo epigenetic changes and escape silencing in immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) syndrome is a rare autosomal recessive disorder that is characterized by a marked immunodeficiency, severe hypomethylation of the classical satellites 2 and 3 associated with disruption of constitutive heterochromatin, and facial anomalies. 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metabolism</subject><subject>Face - abnormalities</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene silencing</subject><subject>Genes</subject><subject>Genetic variability</subject><subject>Genetic Variation</subject><subject>Genomes</subject><subject>Hereditary diseases</subject><subject>Heterochromatin</subject><subject>Heterochromatin - genetics</subject><subject>Heterochromatin - metabolism</subject><subject>Histones</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>ICF syndrome</subject><subject>Immunodeficiency</subject><subject>Localization</subject><subject>Lymphoblasts</subject><subject>Male</subject><subject>Methylation</subject><subject>Methyltransferases</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Patients</subject><subject>Peripheral blood</subject><subject>Phenotype</subject><subject>Stability</subject><subject>Stem cells</subject><subject>Syndrome</subject><subject>Transcription activation</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNptUl1rFDEUHUSxtfoPRAd8UMFd852ZF6Es1i4UfNHnkEnuzGaZSdZkprC_wz9sprstXSmBJNx7zrk3N6co3mK0xFTir9swRa_75S54WCKEaybYs-Ic15QsBEH0-aP7WfEqpS1CnFZCvCzOCOa8phSdF3-vYYQYzCaGQY_OlB14SOXkLcQulLBzc2BOmI32XU5pb0tIRu-gTK4Hb5zvSudLNwyTDxZaZ1yO7r-UBvyYZSFmtvNp1I3r3ZgTrTZO91kp1-xd1vy0Xl19LtPe2xn_unjR6j7Bm-N5Ufy--v5rdb24-fljvbq8WRjBq3HBgZBWIqobxohsmOUCE2RqmTfMjSaNFFK2iHNgmhLLMEYSawGWccGRpRfF-4Purg9JHeeZFCa1FIRjyTNifUDYoLdqF92g414F7dRdIMRO6ZiH04MipqkIto2RpmYNqRvCkWgAsdyerYjOWt-O1aZmAHs3HN2fiJ5mvNuoLtwqiipWSZIFPh4FYvgzQRrV4JKBvtcewpRU_trcNaY0Iz_8h3z6cUdUp3P_zrchlzWzprpkUlQ1EURk1PIJVF4WBmey99psglMCOxBMDClFaB-eiJGanXvfjJqdq47OzbR3j8fzQLq3Kv0H0DjtLw</recordid><startdate>20110429</startdate><enddate>20110429</enddate><creator>Brun, Marie-Elisabeth</creator><creator>Lana, Erica</creator><creator>Rivals, Isabelle</creator><creator>Lefranc, Gérard</creator><creator>Sarda, Pierre</creator><creator>Claustres, Mireille</creator><creator>Mégarbané, André</creator><creator>De Sario, Albertina</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110429</creationdate><title>Heterochromatic genes undergo epigenetic changes and escape silencing in immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome</title><author>Brun, Marie-Elisabeth ; Lana, Erica ; Rivals, Isabelle ; Lefranc, Gérard ; Sarda, Pierre ; Claustres, Mireille ; Mégarbané, André ; De Sario, Albertina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c658t-5e22f703ab4427b4d56120c9720c15ca2b7677f055e4a32d411071a6ed45650d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Acetylation</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Anomalies</topic><topic>B cells</topic><topic>Biology</topic><topic>Cancer</topic><topic>Centromere - ultrastructure</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Chromatin</topic><topic>Deoxyribonucleic acid</topic><topic>Disruption</topic><topic>DNA</topic><topic>DNA (Cytosine-5-)-Methyltransferases - genetics</topic><topic>DNA (Cytosine-5-)-Methyltransferases - physiology</topic><topic>DNA binding proteins</topic><topic>DNA methylation</topic><topic>DNA methyltransferase</topic><topic>DNA Methyltransferase 3B</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetic inheritance</topic><topic>Euchromatin</topic><topic>Euchromatin - metabolism</topic><topic>Face - abnormalities</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene silencing</topic><topic>Genes</topic><topic>Genetic variability</topic><topic>Genetic Variation</topic><topic>Genomes</topic><topic>Hereditary diseases</topic><topic>Heterochromatin</topic><topic>Heterochromatin - genetics</topic><topic>Heterochromatin - metabolism</topic><topic>Histones</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>ICF syndrome</topic><topic>Immunodeficiency</topic><topic>Localization</topic><topic>Lymphoblasts</topic><topic>Male</topic><topic>Methylation</topic><topic>Methyltransferases</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Patients</topic><topic>Peripheral blood</topic><topic>Phenotype</topic><topic>Stability</topic><topic>Stem cells</topic><topic>Syndrome</topic><topic>Transcription activation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brun, Marie-Elisabeth</creatorcontrib><creatorcontrib>Lana, Erica</creatorcontrib><creatorcontrib>Rivals, Isabelle</creatorcontrib><creatorcontrib>Lefranc, Gérard</creatorcontrib><creatorcontrib>Sarda, Pierre</creatorcontrib><creatorcontrib>Claustres, Mireille</creatorcontrib><creatorcontrib>Mégarbané, André</creatorcontrib><creatorcontrib>De Sario, Albertina</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Sixty percent of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In the present study, we have shown that, in ICF lymphoblasts and peripheral blood, juxtacentromeric heterochromatic genes undergo dramatic changes in DNA methylation, indicating that they are bona fide targets of the DNMT3B protein. DNA methylation in heterochromatic genes dropped from about 80% in normal cells to approximately 30% in ICF cells. Hypomethylation was observed in five ICF patients and was associated with activation of these silent genes. Although DNA hypomethylation occurred in all the analyzed heterochromatic genes and in all the ICF patients, gene expression was restricted to some genes, every patient having his own group of activated genes. Histone modifications were preserved in ICF patients. Heterochromatic genes were associated with histone modifications that are typical of inactive chromatin: they had low acetylation on H3 and H4 histones and were slightly enriched in H3K9Me(3), both in ICF and controls. This was also the case for those heterochromatic genes that escaped silencing. This finding suggests that gene activation was not generalized to all the cells, but rather was restricted to a clonal cell population that may contribute to the phenotypic variability observed in ICF syndrome. A slight increase in H3K27 monomethylation was observed both in heterochromatin and active euchromatin in ICF patients; however, no correlation between this modification and activation of heterochromatic genes was found.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21559330</pmid><doi>10.1371/journal.pone.0019464</doi><oa>free_for_read</oa></addata></record> |
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source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Acetylation Adolescent Adult Anomalies B cells Biology Cancer Centromere - ultrastructure Child Child, Preschool Chromatin Deoxyribonucleic acid Disruption DNA DNA (Cytosine-5-)-Methyltransferases - genetics DNA (Cytosine-5-)-Methyltransferases - physiology DNA binding proteins DNA methylation DNA methyltransferase DNA Methyltransferase 3B Epigenesis, Genetic Epigenetic inheritance Euchromatin Euchromatin - metabolism Face - abnormalities Female Gene expression Gene silencing Genes Genetic variability Genetic Variation Genomes Hereditary diseases Heterochromatin Heterochromatin - genetics Heterochromatin - metabolism Histones Histones - metabolism Humans ICF syndrome Immunodeficiency Localization Lymphoblasts Male Methylation Methyltransferases Middle Aged Mutation Patients Peripheral blood Phenotype Stability Stem cells Syndrome Transcription activation |
title | Heterochromatic genes undergo epigenetic changes and escape silencing in immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome |
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