Link between epigenomic alterations and genome-wide aberrant transcriptional response to allergen in dendritic cells conveying maternal asthma risk
We investigated the link between epigenome-wide methylation aberrations at birth and genomic transcriptional changes upon allergen sensitization that occur in the neonatal dendritic cells (DC) due to maternal asthma. We previously demonstrated that neonates of asthmatic mothers are born with a funct...
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| description | We investigated the link between epigenome-wide methylation aberrations at birth and genomic transcriptional changes upon allergen sensitization that occur in the neonatal dendritic cells (DC) due to maternal asthma. We previously demonstrated that neonates of asthmatic mothers are born with a functional skew in splenic DCs that can be seen even in allergen-naïve pups and can convey allergy responses to normal recipients. However, minimal-to-no transcriptional or phenotypic changes were found to explain this alteration. Here we provide in-depth analysis of genome-wide DNA methylation profiles and RNA transcriptional (microarray) profiles before and after allergen sensitization. We identified differentially methylated and differentially expressed loci and performed manually-curated matching of methylation status of the key regulatory sequences (promoters and CpG islands) to expression of their respective transcripts before and after sensitization. We found that while allergen-naive DCs from asthma-at-risk neonates have minimal transcriptional change compared to controls, the methylation changes are extensive. The substantial transcriptional change only becomes evident upon allergen sensitization, when it occurs in multiple genes with the pre-existing epigenetic alterations. We demonstrate that maternal asthma leads to both hyper- and hypomethylation in neonatal DCs, and that both types of events at various loci significantly overlap with transcriptional responses to allergen. Pathway analysis indicates that approximately 1/2 of differentially expressed and differentially methylated genes directly interact in known networks involved in allergy and asthma processes. We conclude that congenital epigenetic changes in DCs are strongly linked to altered transcriptional responses to allergen and to early-life asthma origin. The findings are consistent with the emerging paradigm that asthma is a disease with underlying epigenetic changes. |
| doi_str_mv | 10.1371/journal.pone.0070387 |
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We previously demonstrated that neonates of asthmatic mothers are born with a functional skew in splenic DCs that can be seen even in allergen-naïve pups and can convey allergy responses to normal recipients. However, minimal-to-no transcriptional or phenotypic changes were found to explain this alteration. Here we provide in-depth analysis of genome-wide DNA methylation profiles and RNA transcriptional (microarray) profiles before and after allergen sensitization. We identified differentially methylated and differentially expressed loci and performed manually-curated matching of methylation status of the key regulatory sequences (promoters and CpG islands) to expression of their respective transcripts before and after sensitization. We found that while allergen-naive DCs from asthma-at-risk neonates have minimal transcriptional change compared to controls, the methylation changes are extensive. The substantial transcriptional change only becomes evident upon allergen sensitization, when it occurs in multiple genes with the pre-existing epigenetic alterations. We demonstrate that maternal asthma leads to both hyper- and hypomethylation in neonatal DCs, and that both types of events at various loci significantly overlap with transcriptional responses to allergen. Pathway analysis indicates that approximately 1/2 of differentially expressed and differentially methylated genes directly interact in known networks involved in allergy and asthma processes. We conclude that congenital epigenetic changes in DCs are strongly linked to altered transcriptional responses to allergen and to early-life asthma origin. The findings are consistent with the emerging paradigm that asthma is a disease with underlying epigenetic changes.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0070387</identifier><identifier>PMID: 23950928</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aberration ; Allergens ; Allergens - immunology ; Allergies ; Animals ; Asthma ; Asthma - genetics ; Asthma - immunology ; Biology ; CpG Islands ; Dendritic cells ; Dendritic Cells - immunology ; Dendritic Cells - metabolism ; Deoxyribonucleic acid ; DNA ; DNA Methylation ; DNA microarrays ; Epigenesis, Genetic ; Epigenetic inheritance ; Epigenetics ; Epigenomics ; Female ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Regulatory Networks ; Genes ; Genetic aspects ; Genetic research ; Genome-Wide Association Study ; Genomes ; Genomics ; Health risks ; Humans ; Hypersensitivity ; Infant, Newborn ; Kinases ; Loci ; Male ; Medicine ; Methylation ; Mice ; Neonates ; Newborn babies ; Pregnancy ; Prenatal Exposure Delayed Effects - genetics ; Prenatal Exposure Delayed Effects - immunology ; Promoter Regions, Genetic ; Regulatory sequences ; Ribonucleic acid ; Risk ; Risk factors ; RNA ; Rodents ; Spleen ; Transcription (Genetics) ; Transcription, Genetic ; Womens health</subject><ispartof>PloS one, 2013-08, Vol.8 (8), p.e70387-e70387</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Mikhaylova et al. 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Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Mikhaylova et al 2013 Mikhaylova et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-b6f587dc2c02f50ef18293c30078b8fb90985e17abb694f402bda6a3fff223fe3</citedby><cites>FETCH-LOGICAL-c692t-b6f587dc2c02f50ef18293c30078b8fb90985e17abb694f402bda6a3fff223fe3</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/PMC3741290/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741290/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23950928$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mikhaylova, Lyudmila</creatorcontrib><creatorcontrib>Zhang, Yiming</creatorcontrib><creatorcontrib>Kobzik, Lester</creatorcontrib><creatorcontrib>Fedulov, Alexey V</creatorcontrib><title>Link between epigenomic alterations and genome-wide aberrant transcriptional response to allergen in dendritic cells conveying maternal asthma risk</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>We investigated the link between epigenome-wide methylation aberrations at birth and genomic transcriptional changes upon allergen sensitization that occur in the neonatal dendritic cells (DC) due to maternal asthma. We previously demonstrated that neonates of asthmatic mothers are born with a functional skew in splenic DCs that can be seen even in allergen-naïve pups and can convey allergy responses to normal recipients. However, minimal-to-no transcriptional or phenotypic changes were found to explain this alteration. Here we provide in-depth analysis of genome-wide DNA methylation profiles and RNA transcriptional (microarray) profiles before and after allergen sensitization. We identified differentially methylated and differentially expressed loci and performed manually-curated matching of methylation status of the key regulatory sequences (promoters and CpG islands) to expression of their respective transcripts before and after sensitization. We found that while allergen-naive DCs from asthma-at-risk neonates have minimal transcriptional change compared to controls, the methylation changes are extensive. The substantial transcriptional change only becomes evident upon allergen sensitization, when it occurs in multiple genes with the pre-existing epigenetic alterations. We demonstrate that maternal asthma leads to both hyper- and hypomethylation in neonatal DCs, and that both types of events at various loci significantly overlap with transcriptional responses to allergen. Pathway analysis indicates that approximately 1/2 of differentially expressed and differentially methylated genes directly interact in known networks involved in allergy and asthma processes. We conclude that congenital epigenetic changes in DCs are strongly linked to altered transcriptional responses to allergen and to early-life asthma origin. The findings are consistent with the emerging paradigm that asthma is a disease with underlying epigenetic changes.</description><subject>Aberration</subject><subject>Allergens</subject><subject>Allergens - immunology</subject><subject>Allergies</subject><subject>Animals</subject><subject>Asthma</subject><subject>Asthma - genetics</subject><subject>Asthma - immunology</subject><subject>Biology</subject><subject>CpG Islands</subject><subject>Dendritic cells</subject><subject>Dendritic Cells - immunology</subject><subject>Dendritic Cells - metabolism</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>DNA microarrays</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Epigenomics</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation</subject><subject>Gene Regulatory Networks</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic research</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Health risks</subject><subject>Humans</subject><subject>Hypersensitivity</subject><subject>Infant, Newborn</subject><subject>Kinases</subject><subject>Loci</subject><subject>Male</subject><subject>Medicine</subject><subject>Methylation</subject><subject>Mice</subject><subject>Neonates</subject><subject>Newborn babies</subject><subject>Pregnancy</subject><subject>Prenatal Exposure Delayed Effects - genetics</subject><subject>Prenatal Exposure Delayed Effects - immunology</subject><subject>Promoter Regions, Genetic</subject><subject>Regulatory sequences</subject><subject>Ribonucleic acid</subject><subject>Risk</subject><subject>Risk factors</subject><subject>RNA</subject><subject>Rodents</subject><subject>Spleen</subject><subject>Transcription (Genetics)</subject><subject>Transcription, Genetic</subject><subject>Womens health</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9tq3DAQhk1padK0b1BaQaG0F7uVJduybgoh9LCwEOjpVsjyyKvEljaSnTTP0ReuvOuEdclFMdhm_P3_aMYzSfIyxcuUsvTDhRu8le1y6ywsMWaYluxRcpxyShYFwfTxwftR8iyEC4xzWhbF0-SIUJ5jTsrj5M_a2EtUQX8DYBFsTQPWdUYh2fbgZW-cDUjaGu3isLgxNSBZgffS9qiP96C82Y6cbJGHEI8TAPUuGrTgowoZi2qwtTd9tFXQtgEpZ6_h1tgGdTKmGaUy9JtOIm_C5fPkiZZtgBfT8yT5-fnTj7Ovi_X5l9XZ6XqhCk76RVXovGS1IgoTnWPQaUk4VTT2oqxKXXHMyxxSJquq4JnOMKlqWUiqtSaEaqAnyeu977Z1QUz9DCLNKM54himLxGpP1E5eiK03nfS3wkkjdgHnGyF9LKsFoajMJC-4qhTLMsIqWuSsYrQotaQ5Hr0-TtmGqoNagY3da2em8y_WbETjrgVlWUo4jgbvJgPvrgYIvehMGPspLbhhPDcpcMpIOeZ68w_6cHUT1chYgLHaxbxqNBWnGStpikueRWr5ABWvGuKcxOHTJsZngvczQWR6-N03cghBrL5_-3_2_NecfXvAbiBO6Ca4dtjN6BzM9qDyLgQP-r7JKRbj7tx1Q4y7I6bdibJXhz_oXnS3LPQvJy0XgQ</recordid><startdate>20130812</startdate><enddate>20130812</enddate><creator>Mikhaylova, Lyudmila</creator><creator>Zhang, Yiming</creator><creator>Kobzik, Lester</creator><creator>Fedulov, Alexey V</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>IOV</scope><scope>ISR</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>AEUYN</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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130812</creationdate><title>Link between epigenomic alterations and genome-wide aberrant transcriptional response to allergen in dendritic cells conveying maternal asthma risk</title><author>Mikhaylova, Lyudmila ; Zhang, Yiming ; Kobzik, Lester ; Fedulov, Alexey V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-b6f587dc2c02f50ef18293c30078b8fb90985e17abb694f402bda6a3fff223fe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Aberration</topic><topic>Allergens</topic><topic>Allergens - immunology</topic><topic>Allergies</topic><topic>Animals</topic><topic>Asthma</topic><topic>Asthma - genetics</topic><topic>Asthma - immunology</topic><topic>Biology</topic><topic>CpG Islands</topic><topic>Dendritic cells</topic><topic>Dendritic Cells - immunology</topic><topic>Dendritic Cells - metabolism</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA Methylation</topic><topic>DNA microarrays</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetic inheritance</topic><topic>Epigenetics</topic><topic>Epigenomics</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation</topic><topic>Gene Regulatory Networks</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic research</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Health risks</topic><topic>Humans</topic><topic>Hypersensitivity</topic><topic>Infant, Newborn</topic><topic>Kinases</topic><topic>Loci</topic><topic>Male</topic><topic>Medicine</topic><topic>Methylation</topic><topic>Mice</topic><topic>Neonates</topic><topic>Newborn babies</topic><topic>Pregnancy</topic><topic>Prenatal Exposure Delayed Effects - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mikhaylova, Lyudmila</au><au>Zhang, Yiming</au><au>Kobzik, Lester</au><au>Fedulov, Alexey V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Link between epigenomic alterations and genome-wide aberrant transcriptional response to allergen in dendritic cells conveying maternal asthma risk</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-08-12</date><risdate>2013</risdate><volume>8</volume><issue>8</issue><spage>e70387</spage><epage>e70387</epage><pages>e70387-e70387</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>We investigated the link between epigenome-wide methylation aberrations at birth and genomic transcriptional changes upon allergen sensitization that occur in the neonatal dendritic cells (DC) due to maternal asthma. We previously demonstrated that neonates of asthmatic mothers are born with a functional skew in splenic DCs that can be seen even in allergen-naïve pups and can convey allergy responses to normal recipients. However, minimal-to-no transcriptional or phenotypic changes were found to explain this alteration. Here we provide in-depth analysis of genome-wide DNA methylation profiles and RNA transcriptional (microarray) profiles before and after allergen sensitization. We identified differentially methylated and differentially expressed loci and performed manually-curated matching of methylation status of the key regulatory sequences (promoters and CpG islands) to expression of their respective transcripts before and after sensitization. We found that while allergen-naive DCs from asthma-at-risk neonates have minimal transcriptional change compared to controls, the methylation changes are extensive. The substantial transcriptional change only becomes evident upon allergen sensitization, when it occurs in multiple genes with the pre-existing epigenetic alterations. We demonstrate that maternal asthma leads to both hyper- and hypomethylation in neonatal DCs, and that both types of events at various loci significantly overlap with transcriptional responses to allergen. Pathway analysis indicates that approximately 1/2 of differentially expressed and differentially methylated genes directly interact in known networks involved in allergy and asthma processes. We conclude that congenital epigenetic changes in DCs are strongly linked to altered transcriptional responses to allergen and to early-life asthma origin. The findings are consistent with the emerging paradigm that asthma is a disease with underlying epigenetic changes.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23950928</pmid><doi>10.1371/journal.pone.0070387</doi><tpages>e70387</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aberration Allergens Allergens - immunology Allergies Animals Asthma Asthma - genetics Asthma - immunology Biology CpG Islands Dendritic cells Dendritic Cells - immunology Dendritic Cells - metabolism Deoxyribonucleic acid DNA DNA Methylation DNA microarrays Epigenesis, Genetic Epigenetic inheritance Epigenetics Epigenomics Female Gene Expression Profiling Gene Expression Regulation Gene Regulatory Networks Genes Genetic aspects Genetic research Genome-Wide Association Study Genomes Genomics Health risks Humans Hypersensitivity Infant, Newborn Kinases Loci Male Medicine Methylation Mice Neonates Newborn babies Pregnancy Prenatal Exposure Delayed Effects - genetics Prenatal Exposure Delayed Effects - immunology Promoter Regions, Genetic Regulatory sequences Ribonucleic acid Risk Risk factors RNA Rodents Spleen Transcription (Genetics) Transcription, Genetic Womens health |
| title | Link between epigenomic alterations and genome-wide aberrant transcriptional response to allergen in dendritic cells conveying maternal asthma risk |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T15%3A02%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Link%20between%20epigenomic%20alterations%20and%20genome-wide%20aberrant%20transcriptional%20response%20to%20allergen%20in%20dendritic%20cells%20conveying%20maternal%20asthma%20risk&rft.jtitle=PloS%20one&rft.au=Mikhaylova,%20Lyudmila&rft.date=2013-08-12&rft.volume=8&rft.issue=8&rft.spage=e70387&rft.epage=e70387&rft.pages=e70387-e70387&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0070387&rft_dat=%3Cgale_plos_%3EA478310894%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1430494037&rft_id=info:pmid/23950928&rft_galeid=A478310894&rft_doaj_id=oai_doaj_org_article_c3a4a969cbc74427b3657b7368fa3507&rfr_iscdi=true |