Base editing in bovine embryos reveals a species-specific role of SOX2 in regulation of pluripotency
The emergence of the first three lineages during development is orchestrated by a network of transcription factors, which are best characterized in mice. However, the role and regulation of these factors are not completely conserved in other mammals, including human and cattle. Here, we establish a...
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description | The emergence of the first three lineages during development is orchestrated by a network of transcription factors, which are best characterized in mice. However, the role and regulation of these factors are not completely conserved in other mammals, including human and cattle. Here, we establish a gene inactivation system with a robust efficiency by introducing premature codon with cytosine base editors in bovine early embryos. By using this approach, we have determined the functional consequences of three critical lineage-specific genes (SOX2, OCT4 and CDX2) in bovine embryos. In particular, SOX2 knockout results in a failure of the establishment of pluripotency in blastocysts. Indeed, OCT4 level is significantly reduced and NANOG barely detectable. Furthermore, the formation of primitive endoderm is compromised with few SOX17 positive cells. RNA-seq analysis of single blastocysts (day 7.5) reveals dysregulation of 2074 genes, among which 90% are up-regulated in SOX2-null blastocysts. Intriguingly, more than a dozen lineage-specific genes, including OCT4 and NANOG, are down-regulated. Moreover, SOX2 level is sustained in the trophectoderm in absence of CDX2. However, OCT4 knockout does not affect the expression of SOX2. Overall, we propose that SOX2 is indispensable for OCT4 and NANOG expression and CDX2 represses the expression of SOX2 in the trophectoderm in cattle, which are all in sharp contrast with results in mice. |
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However, the role and regulation of these factors are not completely conserved in other mammals, including human and cattle. Here, we establish a gene inactivation system with a robust efficiency by introducing premature codon with cytosine base editors in bovine early embryos. By using this approach, we have determined the functional consequences of three critical lineage-specific genes (SOX2, OCT4 and CDX2) in bovine embryos. In particular, SOX2 knockout results in a failure of the establishment of pluripotency in blastocysts. Indeed, OCT4 level is significantly reduced and NANOG barely detectable. Furthermore, the formation of primitive endoderm is compromised with few SOX17 positive cells. RNA-seq analysis of single blastocysts (day 7.5) reveals dysregulation of 2074 genes, among which 90% are up-regulated in SOX2-null blastocysts. Intriguingly, more than a dozen lineage-specific genes, including OCT4 and NANOG, are down-regulated. Moreover, SOX2 level is sustained in the trophectoderm in absence of CDX2. However, OCT4 knockout does not affect the expression of SOX2. Overall, we propose that SOX2 is indispensable for OCT4 and NANOG expression and CDX2 represses the expression of SOX2 in the trophectoderm in cattle, which are all in sharp contrast with results in mice.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1010307</identifier><identifier>PMID: 35788719</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Biology and Life Sciences ; Blastocysts ; Cattle ; CDX2 protein ; Cell development (Biology) ; Cytosine ; Editors ; Efficiency ; Embryos ; Endoderm ; Gene expression ; Genes ; Genetic aspects ; Genetic research ; Genomes ; Mutation ; Observations ; Oct-4 protein ; Physical Sciences ; Pluripotency ; Properties ; Proteins ; Research and Analysis Methods ; Transcription factors ; Trophectoderm</subject><ispartof>PLoS genetics, 2022-07, Vol.18 (7), p.e1010307-e1010307</ispartof><rights>COPYRIGHT 2022 Public Library of Science</rights><rights>2022 Luo 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>2022 Luo et al 2022 Luo et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c769t-81503d90530de608406a56130706912673da70782c37073adfcabcef937a45503</citedby><cites>FETCH-LOGICAL-c769t-81503d90530de608406a56130706912673da70782c37073adfcabcef937a45503</cites><orcidid>0000-0002-5460-549X ; 0000-0001-5334-119X ; 0000-0002-2324-9381 ; 0000-0002-4336-0650 ; 0000-0003-4496-8016</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/PMC9286228/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9286228/$$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></links><search><contributor>Bartolomei, Marisa S.</contributor><creatorcontrib>Luo, Lei</creatorcontrib><creatorcontrib>Shi, Yan</creatorcontrib><creatorcontrib>Wang, Huanan</creatorcontrib><creatorcontrib>Wang, Zizengchen</creatorcontrib><creatorcontrib>Dang, Yanna</creatorcontrib><creatorcontrib>Li, Shuang</creatorcontrib><creatorcontrib>Wang, Shaohua</creatorcontrib><creatorcontrib>Zhang, Kun</creatorcontrib><title>Base editing in bovine embryos reveals a species-specific role of SOX2 in regulation of pluripotency</title><title>PLoS genetics</title><description>The emergence of the first three lineages during development is orchestrated by a network of transcription factors, which are best characterized in mice. However, the role and regulation of these factors are not completely conserved in other mammals, including human and cattle. Here, we establish a gene inactivation system with a robust efficiency by introducing premature codon with cytosine base editors in bovine early embryos. By using this approach, we have determined the functional consequences of three critical lineage-specific genes (SOX2, OCT4 and CDX2) in bovine embryos. In particular, SOX2 knockout results in a failure of the establishment of pluripotency in blastocysts. Indeed, OCT4 level is significantly reduced and NANOG barely detectable. Furthermore, the formation of primitive endoderm is compromised with few SOX17 positive cells. RNA-seq analysis of single blastocysts (day 7.5) reveals dysregulation of 2074 genes, among which 90% are up-regulated in SOX2-null blastocysts. Intriguingly, more than a dozen lineage-specific genes, including OCT4 and NANOG, are down-regulated. Moreover, SOX2 level is sustained in the trophectoderm in absence of CDX2. However, OCT4 knockout does not affect the expression of SOX2. Overall, we propose that SOX2 is indispensable for OCT4 and NANOG expression and CDX2 represses the expression of SOX2 in the trophectoderm in cattle, which are all in sharp contrast with results in mice.</description><subject>Biology and Life Sciences</subject><subject>Blastocysts</subject><subject>Cattle</subject><subject>CDX2 protein</subject><subject>Cell development (Biology)</subject><subject>Cytosine</subject><subject>Editors</subject><subject>Efficiency</subject><subject>Embryos</subject><subject>Endoderm</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic research</subject><subject>Genomes</subject><subject>Mutation</subject><subject>Observations</subject><subject>Oct-4 protein</subject><subject>Physical Sciences</subject><subject>Pluripotency</subject><subject>Properties</subject><subject>Proteins</subject><subject>Research and Analysis Methods</subject><subject>Transcription 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editing in bovine embryos reveals a species-specific role of SOX2 in regulation of pluripotency</title><author>Luo, Lei ; Shi, Yan ; Wang, Huanan ; Wang, Zizengchen ; Dang, Yanna ; Li, Shuang ; Wang, Shaohua ; Zhang, Kun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c769t-81503d90530de608406a56130706912673da70782c37073adfcabcef937a45503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Biology and Life Sciences</topic><topic>Blastocysts</topic><topic>Cattle</topic><topic>CDX2 protein</topic><topic>Cell development (Biology)</topic><topic>Cytosine</topic><topic>Editors</topic><topic>Efficiency</topic><topic>Embryos</topic><topic>Endoderm</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic research</topic><topic>Genomes</topic><topic>Mutation</topic><topic>Observations</topic><topic>Oct-4 protein</topic><topic>Physical 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genetics</jtitle><date>2022-07-05</date><risdate>2022</risdate><volume>18</volume><issue>7</issue><spage>e1010307</spage><epage>e1010307</epage><pages>e1010307-e1010307</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>The emergence of the first three lineages during development is orchestrated by a network of transcription factors, which are best characterized in mice. However, the role and regulation of these factors are not completely conserved in other mammals, including human and cattle. Here, we establish a gene inactivation system with a robust efficiency by introducing premature codon with cytosine base editors in bovine early embryos. By using this approach, we have determined the functional consequences of three critical lineage-specific genes (SOX2, OCT4 and CDX2) in bovine embryos. In particular, SOX2 knockout results in a failure of the establishment of pluripotency in blastocysts. Indeed, OCT4 level is significantly reduced and NANOG barely detectable. Furthermore, the formation of primitive endoderm is compromised with few SOX17 positive cells. RNA-seq analysis of single blastocysts (day 7.5) reveals dysregulation of 2074 genes, among which 90% are up-regulated in SOX2-null blastocysts. Intriguingly, more than a dozen lineage-specific genes, including OCT4 and NANOG, are down-regulated. Moreover, SOX2 level is sustained in the trophectoderm in absence of CDX2. However, OCT4 knockout does not affect the expression of SOX2. Overall, we propose that SOX2 is indispensable for OCT4 and NANOG expression and CDX2 represses the expression of SOX2 in the trophectoderm in cattle, which are all in sharp contrast with results in mice.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>35788719</pmid><doi>10.1371/journal.pgen.1010307</doi><tpages>e1010307</tpages><orcidid>https://orcid.org/0000-0002-5460-549X</orcidid><orcidid>https://orcid.org/0000-0001-5334-119X</orcidid><orcidid>https://orcid.org/0000-0002-2324-9381</orcidid><orcidid>https://orcid.org/0000-0002-4336-0650</orcidid><orcidid>https://orcid.org/0000-0003-4496-8016</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Biology and Life Sciences Blastocysts Cattle CDX2 protein Cell development (Biology) Cytosine Editors Efficiency Embryos Endoderm Gene expression Genes Genetic aspects Genetic research Genomes Mutation Observations Oct-4 protein Physical Sciences Pluripotency Properties Proteins Research and Analysis Methods Transcription factors Trophectoderm |
title | Base editing in bovine embryos reveals a species-specific role of SOX2 in regulation of pluripotency |
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