Long-Range Control of Renin Gene Expression in Tsukuba Hypertensive Mice
Renin, a rate-limiting enzyme in the renin-angiotensin system, is regulated to maintain blood pressure homeostasis: renin gene expression in the kidney is suppressed in a hypertensive environment. We found that expression of a 15-kb human RENIN (hREN) transgene was aberrantly upregulated (>4.2-fo...
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| description | Renin, a rate-limiting enzyme in the renin-angiotensin system, is regulated to maintain blood pressure homeostasis: renin gene expression in the kidney is suppressed in a hypertensive environment. We found that expression of a 15-kb human RENIN (hREN) transgene was aberrantly upregulated (>4.2-fold), while the endogenous mouse renin (mRen) gene was suppressed (>1.7-fold) in Tsukuba hypertensive mice (THM), a model for genetically induced hypertension. We then generated transgenic mice using a 13-kb mRen gene fragment that was homologous to the 15-kb hREN transgene and found that its expression was also upregulated (>3.1-fold) in THM, suggesting that putative silencing elements of the renin genes were distally located in the loci. We next examined the possible role of a previously identified mouse distal enhancer (mdE) located outside of the 13-kb mRen gene fragment. Deletion of the mdE in the context of a 156-kb mRen transgene did not affect its transcriptional repression in THM, implying that although the silencing element of the mRen gene is located within the 156-kb fragment tested, it is distinct from the mdE. Consistent with these results, deletion of the 63-kb region upstream of the mdE from the endogenous mRen gene locus abrogated its transcriptional repression in THM. We finally tested whether dysregulation of the short renin transgenes also occurred in the fetal or neonatal kidneys of THM and found that their expression was not aberrantly upregulated, demonstrating that aberrant regulation of short renin transgenes commences sometime between neonate and adult periods. |
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We found that expression of a 15-kb human RENIN (hREN) transgene was aberrantly upregulated (>4.2-fold), while the endogenous mouse renin (mRen) gene was suppressed (>1.7-fold) in Tsukuba hypertensive mice (THM), a model for genetically induced hypertension. We then generated transgenic mice using a 13-kb mRen gene fragment that was homologous to the 15-kb hREN transgene and found that its expression was also upregulated (>3.1-fold) in THM, suggesting that putative silencing elements of the renin genes were distally located in the loci. We next examined the possible role of a previously identified mouse distal enhancer (mdE) located outside of the 13-kb mRen gene fragment. Deletion of the mdE in the context of a 156-kb mRen transgene did not affect its transcriptional repression in THM, implying that although the silencing element of the mRen gene is located within the 156-kb fragment tested, it is distinct from the mdE. Consistent with these results, deletion of the 63-kb region upstream of the mdE from the endogenous mRen gene locus abrogated its transcriptional repression in THM. We finally tested whether dysregulation of the short renin transgenes also occurred in the fetal or neonatal kidneys of THM and found that their expression was not aberrantly upregulated, demonstrating that aberrant regulation of short renin transgenes commences sometime between neonate and adult periods.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0166974</identifier><identifier>PMID: 27861631</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alleles ; Analysis ; Angiotensin ; Angiotensins ; Animals ; Binding sites ; Biology and Life Sciences ; Blood pressure ; CRISPR ; Deoxyribonucleic acid ; Disease Models, Animal ; DNA ; Enhancer Elements, Genetic ; Environmental science ; Enzymes ; Fetuses ; Fragmentation ; Gene deletion ; Gene Editing ; Gene Expression ; Gene Expression Regulation ; Gene silencing ; Gene Targeting ; Genes ; Genetic engineering ; Genetic Loci ; Genetic Vectors - genetics ; Genomes ; Genomics ; Homeostasis ; Homology ; Humans ; Hypertension ; Hypertension - genetics ; Hypertension - physiopathology ; Kidney - metabolism ; Kidneys ; Life sciences ; Loci ; Medicine and Health Sciences ; Mice ; Mice, Transgenic ; Neonates ; Organ Specificity - genetics ; Physiology ; Renin ; Renin - genetics ; Research and Analysis Methods ; Rodents ; Sequence Deletion ; Transcription (Genetics) ; Transgenes ; Transgenic animals ; Transgenic mice</subject><ispartof>PloS one, 2016-11, Vol.11 (11), p.e0166974-e0166974</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Ushiki 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>2016 Ushiki et al 2016 Ushiki et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c835t-20434cea500570a2382a203325dbfe276920f97e7e6730baca7b944dde767b633</citedby><cites>FETCH-LOGICAL-c835t-20434cea500570a2382a203325dbfe276920f97e7e6730baca7b944dde767b633</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/PMC5115840/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115840/$$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/27861631$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Bader, Michael</contributor><creatorcontrib>Ushiki, Aki</creatorcontrib><creatorcontrib>Matsuzaki, Hitomi</creatorcontrib><creatorcontrib>Ishida, Junji</creatorcontrib><creatorcontrib>Fukamizu, Akiyoshi</creatorcontrib><creatorcontrib>Tanimoto, Keiji</creatorcontrib><title>Long-Range Control of Renin Gene Expression in Tsukuba Hypertensive Mice</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Renin, a rate-limiting enzyme in the renin-angiotensin system, is regulated to maintain blood pressure homeostasis: renin gene expression in the kidney is suppressed in a hypertensive environment. We found that expression of a 15-kb human RENIN (hREN) transgene was aberrantly upregulated (>4.2-fold), while the endogenous mouse renin (mRen) gene was suppressed (>1.7-fold) in Tsukuba hypertensive mice (THM), a model for genetically induced hypertension. We then generated transgenic mice using a 13-kb mRen gene fragment that was homologous to the 15-kb hREN transgene and found that its expression was also upregulated (>3.1-fold) in THM, suggesting that putative silencing elements of the renin genes were distally located in the loci. We next examined the possible role of a previously identified mouse distal enhancer (mdE) located outside of the 13-kb mRen gene fragment. Deletion of the mdE in the context of a 156-kb mRen transgene did not affect its transcriptional repression in THM, implying that although the silencing element of the mRen gene is located within the 156-kb fragment tested, it is distinct from the mdE. Consistent with these results, deletion of the 63-kb region upstream of the mdE from the endogenous mRen gene locus abrogated its transcriptional repression in THM. We finally tested whether dysregulation of the short renin transgenes also occurred in the fetal or neonatal kidneys of THM and found that their expression was not aberrantly upregulated, demonstrating that aberrant regulation of short renin transgenes commences sometime between neonate and adult periods.</description><subject>Alleles</subject><subject>Analysis</subject><subject>Angiotensin</subject><subject>Angiotensins</subject><subject>Animals</subject><subject>Binding sites</subject><subject>Biology and Life Sciences</subject><subject>Blood pressure</subject><subject>CRISPR</subject><subject>Deoxyribonucleic acid</subject><subject>Disease Models, Animal</subject><subject>DNA</subject><subject>Enhancer Elements, Genetic</subject><subject>Environmental science</subject><subject>Enzymes</subject><subject>Fetuses</subject><subject>Fragmentation</subject><subject>Gene deletion</subject><subject>Gene Editing</subject><subject>Gene Expression</subject><subject>Gene Expression Regulation</subject><subject>Gene silencing</subject><subject>Gene Targeting</subject><subject>Genes</subject><subject>Genetic engineering</subject><subject>Genetic Loci</subject><subject>Genetic Vectors - genetics</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Homeostasis</subject><subject>Homology</subject><subject>Humans</subject><subject>Hypertension</subject><subject>Hypertension - genetics</subject><subject>Hypertension - physiopathology</subject><subject>Kidney - metabolism</subject><subject>Kidneys</subject><subject>Life sciences</subject><subject>Loci</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Neonates</subject><subject>Organ Specificity - genetics</subject><subject>Physiology</subject><subject>Renin</subject><subject>Renin - genetics</subject><subject>Research and Analysis Methods</subject><subject>Rodents</subject><subject>Sequence Deletion</subject><subject>Transcription 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Control of Renin Gene Expression in Tsukuba Hypertensive Mice</title><author>Ushiki, Aki ; Matsuzaki, Hitomi ; Ishida, Junji ; Fukamizu, Akiyoshi ; Tanimoto, Keiji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c835t-20434cea500570a2382a203325dbfe276920f97e7e6730baca7b944dde767b633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Alleles</topic><topic>Analysis</topic><topic>Angiotensin</topic><topic>Angiotensins</topic><topic>Animals</topic><topic>Binding sites</topic><topic>Biology and Life Sciences</topic><topic>Blood pressure</topic><topic>CRISPR</topic><topic>Deoxyribonucleic acid</topic><topic>Disease Models, Animal</topic><topic>DNA</topic><topic>Enhancer Elements, Genetic</topic><topic>Environmental science</topic><topic>Enzymes</topic><topic>Fetuses</topic><topic>Fragmentation</topic><topic>Gene deletion</topic><topic>Gene Editing</topic><topic>Gene 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We found that expression of a 15-kb human RENIN (hREN) transgene was aberrantly upregulated (>4.2-fold), while the endogenous mouse renin (mRen) gene was suppressed (>1.7-fold) in Tsukuba hypertensive mice (THM), a model for genetically induced hypertension. We then generated transgenic mice using a 13-kb mRen gene fragment that was homologous to the 15-kb hREN transgene and found that its expression was also upregulated (>3.1-fold) in THM, suggesting that putative silencing elements of the renin genes were distally located in the loci. We next examined the possible role of a previously identified mouse distal enhancer (mdE) located outside of the 13-kb mRen gene fragment. Deletion of the mdE in the context of a 156-kb mRen transgene did not affect its transcriptional repression in THM, implying that although the silencing element of the mRen gene is located within the 156-kb fragment tested, it is distinct from the mdE. Consistent with these results, deletion of the 63-kb region upstream of the mdE from the endogenous mRen gene locus abrogated its transcriptional repression in THM. We finally tested whether dysregulation of the short renin transgenes also occurred in the fetal or neonatal kidneys of THM and found that their expression was not aberrantly upregulated, demonstrating that aberrant regulation of short renin transgenes commences sometime between neonate and adult periods.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27861631</pmid><doi>10.1371/journal.pone.0166974</doi><tpages>e0166974</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Alleles Analysis Angiotensin Angiotensins Animals Binding sites Biology and Life Sciences Blood pressure CRISPR Deoxyribonucleic acid Disease Models, Animal DNA Enhancer Elements, Genetic Environmental science Enzymes Fetuses Fragmentation Gene deletion Gene Editing Gene Expression Gene Expression Regulation Gene silencing Gene Targeting Genes Genetic engineering Genetic Loci Genetic Vectors - genetics Genomes Genomics Homeostasis Homology Humans Hypertension Hypertension - genetics Hypertension - physiopathology Kidney - metabolism Kidneys Life sciences Loci Medicine and Health Sciences Mice Mice, Transgenic Neonates Organ Specificity - genetics Physiology Renin Renin - genetics Research and Analysis Methods Rodents Sequence Deletion Transcription (Genetics) Transgenes Transgenic animals Transgenic mice |
| title | Long-Range Control of Renin Gene Expression in Tsukuba Hypertensive Mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T08%3A53%3A52IST&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=Long-Range%20Control%20of%20Renin%20Gene%20Expression%20in%20Tsukuba%20Hypertensive%20Mice&rft.jtitle=PloS%20one&rft.au=Ushiki,%20Aki&rft.date=2016-11-18&rft.volume=11&rft.issue=11&rft.spage=e0166974&rft.epage=e0166974&rft.pages=e0166974-e0166974&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0166974&rft_dat=%3Cgale_plos_%3EA471881540%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=1841403258&rft_id=info:pmid/27861631&rft_galeid=A471881540&rft_doaj_id=oai_doaj_org_article_6467ab6125644cd29092845589daa9ed&rfr_iscdi=true |