Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA- PCG pairs involved in intermediary metabolism
Polybrominated diphenyl ethers (PBDEs) were formally used as flame-retardants and are chemically stable, lipophlic persistent organic pollutants which are known to bioaccumulate in humans. Although its toxicities are well characterized, little is known about the changes in transcriptional regulation...
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description | Polybrominated diphenyl ethers (PBDEs) were formally used as flame-retardants and are chemically stable, lipophlic persistent organic pollutants which are known to bioaccumulate in humans. Although its toxicities are well characterized, little is known about the changes in transcriptional regulation caused by PBDE exposure. Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of transcriptional and translational processes. It is hypothesized that lncRNAs can regulate nearby protein-coding genes (PCGs) and changes in the transcription of lncRNAs may act in cis to perturb gene expression of its neighboring PCGs. The goals of this study were to 1) characterize PCGs and lncRNAs that are differentially regulated from exposure to PBDEs; 2) identify PCG-lncRNA pairs through genome annotation and predictive binding tools; and 3) determine enriched canonical pathways caused by differentially expressed lncRNA-PCGs pairs. HepaRG cells, which are human-derived hepatic cells that accurately represent gene expression profiles of human liver tissue, were exposed to BDE-47 and BDE-99 at a dose of 25 μM for 24 hours. Differentially expressed lncRNA-PCG pairs were identified through DESeq2 and HOMER; significant canonical pathways were determined through Ingenuity Pathway Analysis (IPA). LncTar was used to predict the binding of 19 lncRNA-PCG pairs with known roles in drug-processing pathways. Genome annotation revealed that the majority of the differentially expressed lncRNAs map to PCG introns. PBDEs regulated overlapping pathways with PXR and CAR such as protein ubiqutination pathway and peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (PPARα-RXRα) activation but also regulate distinctive pathways involved in intermediary metabolism. PBDEs uniquely down-regulated GDP-L-fucose biosynthesis, suggesting its role in modifying important pathways involved in intermediary metabolism such as carbohydrate and lipid metabolism. In conclusion, we provide strong evidence that PBDEs regulate both PCGs and lncRNAs in a PXR/CAR ligand-dependent and independent manner. |
doi_str_mv | 10.1371/journal.pone.0224644 |
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Although its toxicities are well characterized, little is known about the changes in transcriptional regulation caused by PBDE exposure. Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of transcriptional and translational processes. It is hypothesized that lncRNAs can regulate nearby protein-coding genes (PCGs) and changes in the transcription of lncRNAs may act in cis to perturb gene expression of its neighboring PCGs. The goals of this study were to 1) characterize PCGs and lncRNAs that are differentially regulated from exposure to PBDEs; 2) identify PCG-lncRNA pairs through genome annotation and predictive binding tools; and 3) determine enriched canonical pathways caused by differentially expressed lncRNA-PCGs pairs. HepaRG cells, which are human-derived hepatic cells that accurately represent gene expression profiles of human liver tissue, were exposed to BDE-47 and BDE-99 at a dose of 25 μM for 24 hours. Differentially expressed lncRNA-PCG pairs were identified through DESeq2 and HOMER; significant canonical pathways were determined through Ingenuity Pathway Analysis (IPA). LncTar was used to predict the binding of 19 lncRNA-PCG pairs with known roles in drug-processing pathways. Genome annotation revealed that the majority of the differentially expressed lncRNAs map to PCG introns. PBDEs regulated overlapping pathways with PXR and CAR such as protein ubiqutination pathway and peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (PPARα-RXRα) activation but also regulate distinctive pathways involved in intermediary metabolism. PBDEs uniquely down-regulated GDP-L-fucose biosynthesis, suggesting its role in modifying important pathways involved in intermediary metabolism such as carbohydrate and lipid metabolism. In conclusion, we provide strong evidence that PBDEs regulate both PCGs and lncRNAs in a PXR/CAR ligand-dependent and independent manner.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0224644</identifier><identifier>PMID: 32101552</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Annotations ; Binding ; Bioaccumulation ; Biochemistry ; Biology and life sciences ; Biosynthesis ; Carbohydrate Metabolism ; Carbohydrates ; Cell cycle ; Cell Line ; Cyclin-dependent kinases ; Cytochrome ; Enzymes ; Ethers ; Exposure ; Flame retardants ; Flame Retardants - administration & dosage ; Flame Retardants - pharmacology ; Fucose ; GDP-fucose ; Gene expression ; Gene Expression Profiling - methods ; Gene Expression Regulation ; Gene regulation ; Genes ; Genomes ; Genomics ; Gross domestic product ; Guanosine diphosphate ; Halogenated Diphenyl Ethers - administration & dosage ; Halogenated Diphenyl Ethers - pharmacology ; Health maintenance organizations ; Health sciences ; Hepatocytes - drug effects ; Hepatocytes - metabolism ; Humans ; Introns ; Introns - genetics ; Kinases ; Lipid Metabolism ; Lipids ; Liver cancer ; Medicine and Health Sciences ; Metabolism ; Metabolites ; Non-coding RNA ; Occupational health ; Organic chemistry ; Oxidative stress ; Penicillin ; Persistent organic pollutants ; Pollutants ; Polybrominated diphenyl ethers ; PPAR alpha - metabolism ; Pregnane X Receptor - genetics ; Pregnane X Receptor - metabolism ; Proteins ; Receptors, Cytoplasmic and Nuclear - genetics ; Receptors, Cytoplasmic and Nuclear - metabolism ; Retardants ; Retinoid X Receptor alpha - metabolism ; Retinoid X receptor α ; RNA polymerase ; RNA, Long Noncoding - metabolism ; Toxicity ; Transcription ; Transcription (Genetics)</subject><ispartof>PloS one, 2020-02, Vol.15 (2), p.e0224644</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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>2020 Zhang et al 2020 Zhang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-a18095b19d407a9681a1ad43a1f69ccbddc8fff7a9d291f7215a37ea930f8dde3</citedby><cites>FETCH-LOGICAL-c692t-a18095b19d407a9681a1ad43a1f69ccbddc8fff7a9d291f7215a37ea930f8dde3</cites><orcidid>0000-0002-8564-1784</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043721/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043721/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,2098,2917,23853,27911,27912,53778,53780,79357,79358</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32101552$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Avila, Matias A.</contributor><creatorcontrib>Zhang, Angela</creatorcontrib><creatorcontrib>Li, Cindy Yanfei</creatorcontrib><creatorcontrib>Kelly, Edward J</creatorcontrib><creatorcontrib>Sheppard, Lianne</creatorcontrib><creatorcontrib>Cui, Julia Yue</creatorcontrib><title>Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA- PCG pairs involved in intermediary metabolism</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Polybrominated diphenyl ethers (PBDEs) were formally used as flame-retardants and are chemically stable, lipophlic persistent organic pollutants which are known to bioaccumulate in humans. Although its toxicities are well characterized, little is known about the changes in transcriptional regulation caused by PBDE exposure. Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of transcriptional and translational processes. It is hypothesized that lncRNAs can regulate nearby protein-coding genes (PCGs) and changes in the transcription of lncRNAs may act in cis to perturb gene expression of its neighboring PCGs. The goals of this study were to 1) characterize PCGs and lncRNAs that are differentially regulated from exposure to PBDEs; 2) identify PCG-lncRNA pairs through genome annotation and predictive binding tools; and 3) determine enriched canonical pathways caused by differentially expressed lncRNA-PCGs pairs. HepaRG cells, which are human-derived hepatic cells that accurately represent gene expression profiles of human liver tissue, were exposed to BDE-47 and BDE-99 at a dose of 25 μM for 24 hours. Differentially expressed lncRNA-PCG pairs were identified through DESeq2 and HOMER; significant canonical pathways were determined through Ingenuity Pathway Analysis (IPA). LncTar was used to predict the binding of 19 lncRNA-PCG pairs with known roles in drug-processing pathways. Genome annotation revealed that the majority of the differentially expressed lncRNAs map to PCG introns. PBDEs regulated overlapping pathways with PXR and CAR such as protein ubiqutination pathway and peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (PPARα-RXRα) activation but also regulate distinctive pathways involved in intermediary metabolism. PBDEs uniquely down-regulated GDP-L-fucose biosynthesis, suggesting its role in modifying important pathways involved in intermediary metabolism such as carbohydrate and lipid metabolism. In conclusion, we provide strong evidence that PBDEs regulate both PCGs and lncRNAs in a PXR/CAR ligand-dependent and independent manner.</description><subject>Annotations</subject><subject>Binding</subject><subject>Bioaccumulation</subject><subject>Biochemistry</subject><subject>Biology and life sciences</subject><subject>Biosynthesis</subject><subject>Carbohydrate Metabolism</subject><subject>Carbohydrates</subject><subject>Cell cycle</subject><subject>Cell Line</subject><subject>Cyclin-dependent kinases</subject><subject>Cytochrome</subject><subject>Enzymes</subject><subject>Ethers</subject><subject>Exposure</subject><subject>Flame retardants</subject><subject>Flame Retardants - administration & dosage</subject><subject>Flame Retardants - pharmacology</subject><subject>Fucose</subject><subject>GDP-fucose</subject><subject>Gene expression</subject><subject>Gene Expression Profiling - methods</subject><subject>Gene Expression Regulation</subject><subject>Gene regulation</subject><subject>Genes</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Gross domestic product</subject><subject>Guanosine diphosphate</subject><subject>Halogenated Diphenyl Ethers - administration & dosage</subject><subject>Halogenated Diphenyl Ethers - pharmacology</subject><subject>Health maintenance organizations</subject><subject>Health sciences</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>Introns</subject><subject>Introns - genetics</subject><subject>Kinases</subject><subject>Lipid Metabolism</subject><subject>Lipids</subject><subject>Liver cancer</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Non-coding RNA</subject><subject>Occupational health</subject><subject>Organic chemistry</subject><subject>Oxidative stress</subject><subject>Penicillin</subject><subject>Persistent organic pollutants</subject><subject>Pollutants</subject><subject>Polybrominated diphenyl ethers</subject><subject>PPAR alpha - metabolism</subject><subject>Pregnane X Receptor - genetics</subject><subject>Pregnane X Receptor - metabolism</subject><subject>Proteins</subject><subject>Receptors, Cytoplasmic and Nuclear - genetics</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Retardants</subject><subject>Retinoid X Receptor alpha - metabolism</subject><subject>Retinoid X receptor α</subject><subject>RNA polymerase</subject><subject>RNA, Long Noncoding - metabolism</subject><subject>Toxicity</subject><subject>Transcription</subject><subject>Transcription (Genetics)</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</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>eNqNkl1r2zAUhs3YWLts_2BshsFgF870Ycv2zSBLuzRQ1pJ1uxWKPhIFWfIkO7SwHz91cUsMGwwbZKznfXV0zpskryGYQlzCjzvXe8vMtHVWTgFCOcnzJ8kprDHKCAL46dH3SfIihB0ABa4IeZ6cYAQBLAp0mvy68cwG7nXbuUbztPVOaaPtJnUqvf58dp7J29YFKdIL2bLVIuXSmJD2di91XKOw05yZ1Fi--jrL0uv5Im2Z9iHVdu_MPgq1jW8nfSOFZv4ubWTH1s7o0LxMnilmgnw1rJPk-5fzm_lFdnm1WM5nlxknNeoyBitQF2tYixyUrCYVZJCJHDOoSM35WgheKaXilkA1VCWCBcOlZDUGqhJC4kny9uDbGhfo0LhAESYFJLAqy0gsD4RwbEdbr5tYKXVM0z8_nN9Q5uNNjaR1rQAEQpQFhDmpKoYrJHJFclisEYiHTpJPw2n9Ot6ZS9t5Zkam4x2rt3Tj9rQEOY7FR4N3g4F3P3sZun-UPFAbFqvSVrloxhsdOJ0RWGBQ1HHek2T6Fyo-QsZxx-jEacux4MNIEJlO3nYb1odAl99W_89e_Riz74_YrWSm2wZn-k47G8ZgfgC5dyF4qR47BwG9T_5DN-h98umQ_Ch7c9z1R9FD1PFvdWX-1Q</recordid><startdate>20200226</startdate><enddate>20200226</enddate><creator>Zhang, Angela</creator><creator>Li, Cindy Yanfei</creator><creator>Kelly, Edward J</creator><creator>Sheppard, Lianne</creator><creator>Cui, Julia Yue</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>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-8564-1784</orcidid></search><sort><creationdate>20200226</creationdate><title>Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA- PCG pairs involved in intermediary metabolism</title><author>Zhang, Angela ; Li, Cindy Yanfei ; Kelly, Edward J ; Sheppard, Lianne ; Cui, Julia Yue</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-a18095b19d407a9681a1ad43a1f69ccbddc8fff7a9d291f7215a37ea930f8dde3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Annotations</topic><topic>Binding</topic><topic>Bioaccumulation</topic><topic>Biochemistry</topic><topic>Biology and life sciences</topic><topic>Biosynthesis</topic><topic>Carbohydrate Metabolism</topic><topic>Carbohydrates</topic><topic>Cell cycle</topic><topic>Cell Line</topic><topic>Cyclin-dependent kinases</topic><topic>Cytochrome</topic><topic>Enzymes</topic><topic>Ethers</topic><topic>Exposure</topic><topic>Flame retardants</topic><topic>Flame Retardants - administration & dosage</topic><topic>Flame Retardants - pharmacology</topic><topic>Fucose</topic><topic>GDP-fucose</topic><topic>Gene expression</topic><topic>Gene Expression Profiling - methods</topic><topic>Gene Expression Regulation</topic><topic>Gene regulation</topic><topic>Genes</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Gross domestic product</topic><topic>Guanosine diphosphate</topic><topic>Halogenated Diphenyl Ethers - administration & dosage</topic><topic>Halogenated Diphenyl Ethers - pharmacology</topic><topic>Health maintenance organizations</topic><topic>Health sciences</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - metabolism</topic><topic>Humans</topic><topic>Introns</topic><topic>Introns - genetics</topic><topic>Kinases</topic><topic>Lipid Metabolism</topic><topic>Lipids</topic><topic>Liver cancer</topic><topic>Medicine and Health Sciences</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Non-coding RNA</topic><topic>Occupational health</topic><topic>Organic chemistry</topic><topic>Oxidative stress</topic><topic>Penicillin</topic><topic>Persistent organic pollutants</topic><topic>Pollutants</topic><topic>Polybrominated diphenyl ethers</topic><topic>PPAR alpha - metabolism</topic><topic>Pregnane X Receptor - genetics</topic><topic>Pregnane X Receptor - metabolism</topic><topic>Proteins</topic><topic>Receptors, Cytoplasmic and Nuclear - genetics</topic><topic>Receptors, Cytoplasmic and Nuclear - metabolism</topic><topic>Retardants</topic><topic>Retinoid X Receptor alpha - metabolism</topic><topic>Retinoid X receptor α</topic><topic>RNA polymerase</topic><topic>RNA, Long Noncoding - metabolism</topic><topic>Toxicity</topic><topic>Transcription</topic><topic>Transcription (Genetics)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Angela</creatorcontrib><creatorcontrib>Li, Cindy Yanfei</creatorcontrib><creatorcontrib>Kelly, Edward J</creatorcontrib><creatorcontrib>Sheppard, Lianne</creatorcontrib><creatorcontrib>Cui, Julia Yue</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</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 One Sustainability</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 (ProQuest)</collection><collection>Natural Science Collection (ProQuest)</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 - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</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>Zhang, Angela</au><au>Li, Cindy Yanfei</au><au>Kelly, Edward J</au><au>Sheppard, Lianne</au><au>Cui, Julia Yue</au><au>Avila, Matias A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA- PCG pairs involved in intermediary metabolism</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2020-02-26</date><risdate>2020</risdate><volume>15</volume><issue>2</issue><spage>e0224644</spage><pages>e0224644-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Polybrominated diphenyl ethers (PBDEs) were formally used as flame-retardants and are chemically stable, lipophlic persistent organic pollutants which are known to bioaccumulate in humans. Although its toxicities are well characterized, little is known about the changes in transcriptional regulation caused by PBDE exposure. Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of transcriptional and translational processes. It is hypothesized that lncRNAs can regulate nearby protein-coding genes (PCGs) and changes in the transcription of lncRNAs may act in cis to perturb gene expression of its neighboring PCGs. The goals of this study were to 1) characterize PCGs and lncRNAs that are differentially regulated from exposure to PBDEs; 2) identify PCG-lncRNA pairs through genome annotation and predictive binding tools; and 3) determine enriched canonical pathways caused by differentially expressed lncRNA-PCGs pairs. HepaRG cells, which are human-derived hepatic cells that accurately represent gene expression profiles of human liver tissue, were exposed to BDE-47 and BDE-99 at a dose of 25 μM for 24 hours. Differentially expressed lncRNA-PCG pairs were identified through DESeq2 and HOMER; significant canonical pathways were determined through Ingenuity Pathway Analysis (IPA). LncTar was used to predict the binding of 19 lncRNA-PCG pairs with known roles in drug-processing pathways. Genome annotation revealed that the majority of the differentially expressed lncRNAs map to PCG introns. PBDEs regulated overlapping pathways with PXR and CAR such as protein ubiqutination pathway and peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (PPARα-RXRα) activation but also regulate distinctive pathways involved in intermediary metabolism. PBDEs uniquely down-regulated GDP-L-fucose biosynthesis, suggesting its role in modifying important pathways involved in intermediary metabolism such as carbohydrate and lipid metabolism. In conclusion, we provide strong evidence that PBDEs regulate both PCGs and lncRNAs in a PXR/CAR ligand-dependent and independent manner.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32101552</pmid><doi>10.1371/journal.pone.0224644</doi><tpages>e0224644</tpages><orcidid>https://orcid.org/0000-0002-8564-1784</orcidid><oa>free_for_read</oa></addata></record> |
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identifier | ISSN: 1932-6203 |
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issn | 1932-6203 1932-6203 |
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subjects | Annotations Binding Bioaccumulation Biochemistry Biology and life sciences Biosynthesis Carbohydrate Metabolism Carbohydrates Cell cycle Cell Line Cyclin-dependent kinases Cytochrome Enzymes Ethers Exposure Flame retardants Flame Retardants - administration & dosage Flame Retardants - pharmacology Fucose GDP-fucose Gene expression Gene Expression Profiling - methods Gene Expression Regulation Gene regulation Genes Genomes Genomics Gross domestic product Guanosine diphosphate Halogenated Diphenyl Ethers - administration & dosage Halogenated Diphenyl Ethers - pharmacology Health maintenance organizations Health sciences Hepatocytes - drug effects Hepatocytes - metabolism Humans Introns Introns - genetics Kinases Lipid Metabolism Lipids Liver cancer Medicine and Health Sciences Metabolism Metabolites Non-coding RNA Occupational health Organic chemistry Oxidative stress Penicillin Persistent organic pollutants Pollutants Polybrominated diphenyl ethers PPAR alpha - metabolism Pregnane X Receptor - genetics Pregnane X Receptor - metabolism Proteins Receptors, Cytoplasmic and Nuclear - genetics Receptors, Cytoplasmic and Nuclear - metabolism Retardants Retinoid X Receptor alpha - metabolism Retinoid X receptor α RNA polymerase RNA, Long Noncoding - metabolism Toxicity Transcription Transcription (Genetics) |
title | Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA- PCG pairs involved in intermediary metabolism |
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