Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex
Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fascicul...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2018-12, Vol.115 (52), p.E12265-E12274 |
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| creator | Mathieu, Mickael Drelon, Coralie Rodriguez, Stéphanie Tabbal, Houda Septier, Amandine Damon-Soubeyrand, Christelle Dumontet, Typhanie Berthon, Annabel Sahut-Barnola, Isabelle Djari, Cyril Batisse-Lignier, Marie Pointud, Jean-Christophe Richard, Damien Kerdivel, Gwenneg Calméjane, Marie-Ange Boeva, Valentina Tauveron, Igor Lefrançois-Martinez, Anne-Marie Martinez, Antoine Val, Pierre |
| description | Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state. |
| doi_str_mv | 10.1073/pnas.1809185115 |
| format | Article |
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Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1809185115</identifier><identifier>PMID: 30541888</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Ablation ; Adrenal cortex ; Adrenal Cortex - enzymology ; Adrenal Cortex - metabolism ; Adrenal glands ; Adrenocorticotropic hormone ; Animal genetics ; Animals ; Biochemistry, Molecular Biology ; Biological Sciences ; Ca2+/calmodulin-dependent phosphodiesterase ; Cancer ; Cell Differentiation ; Cells (biology) ; Cyclic AMP-Dependent Protein Kinase RIbeta Subunit - genetics ; Cyclic AMP-Dependent Protein Kinase RIbeta Subunit - metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 1 - genetics ; Cyclic Nucleotide Phosphodiesterases, Type 1 - metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 3 - genetics ; Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 7 - genetics ; Cyclic Nucleotide Phosphodiesterases, Type 7 - metabolism ; Development Biology ; Differential equations ; Differentiation (biology) ; Embryology and Organogenesis ; Endocrinology and metabolism ; Enhancer of Zeste Homolog 2 Protein - genetics ; Enhancer of Zeste Homolog 2 Protein - metabolism ; Female ; Genetics ; Genomics ; Glucocorticoids ; Histone methyltransferase ; Homeostasis ; Human health and pathology ; Life Sciences ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; PNAS Plus ; Progenitor cells ; Protein kinase A ; Signal Transduction ; Signaling ; Stem cells ; Steroid hormones ; Steroids ; Steroids - metabolism ; Zona Fasciculata - cytology ; Zona Fasciculata - enzymology ; Zona Fasciculata - metabolism ; Zona Glomerulosa - cytology ; Zona Glomerulosa - enzymology ; Zona Glomerulosa - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2018-12, Vol.115 (52), p.E12265-E12274</ispartof><rights>Volumes 1–89 and 106–115, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Dec 26, 2018</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-61292d96542e6f2da0ba1661d417797f0ada90307758a33f47653012fd9d58533</citedby><cites>FETCH-LOGICAL-c477t-61292d96542e6f2da0ba1661d417797f0ada90307758a33f47653012fd9d58533</cites><orcidid>0000-0001-8353-542X ; 0000-0002-5576-9525 ; 0000-0002-1328-9515 ; 0000-0002-4382-7185 ; 0000-0001-7648-5567 ; 0000-0001-7666-9024 ; 0000-0001-9304-5061</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26573964$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26573964$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,724,777,781,800,882,27905,27906,53772,53774,57998,58231</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30541888$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02324493$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Mathieu, Mickael</creatorcontrib><creatorcontrib>Drelon, Coralie</creatorcontrib><creatorcontrib>Rodriguez, Stéphanie</creatorcontrib><creatorcontrib>Tabbal, Houda</creatorcontrib><creatorcontrib>Septier, Amandine</creatorcontrib><creatorcontrib>Damon-Soubeyrand, Christelle</creatorcontrib><creatorcontrib>Dumontet, Typhanie</creatorcontrib><creatorcontrib>Berthon, Annabel</creatorcontrib><creatorcontrib>Sahut-Barnola, Isabelle</creatorcontrib><creatorcontrib>Djari, Cyril</creatorcontrib><creatorcontrib>Batisse-Lignier, Marie</creatorcontrib><creatorcontrib>Pointud, Jean-Christophe</creatorcontrib><creatorcontrib>Richard, Damien</creatorcontrib><creatorcontrib>Kerdivel, Gwenneg</creatorcontrib><creatorcontrib>Calméjane, Marie-Ange</creatorcontrib><creatorcontrib>Boeva, Valentina</creatorcontrib><creatorcontrib>Tauveron, Igor</creatorcontrib><creatorcontrib>Lefrançois-Martinez, Anne-Marie</creatorcontrib><creatorcontrib>Martinez, Antoine</creatorcontrib><creatorcontrib>Val, Pierre</creatorcontrib><title>Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state.</description><subject>Ablation</subject><subject>Adrenal cortex</subject><subject>Adrenal Cortex - enzymology</subject><subject>Adrenal Cortex - metabolism</subject><subject>Adrenal glands</subject><subject>Adrenocorticotropic hormone</subject><subject>Animal genetics</subject><subject>Animals</subject><subject>Biochemistry, Molecular Biology</subject><subject>Biological Sciences</subject><subject>Ca2+/calmodulin-dependent phosphodiesterase</subject><subject>Cancer</subject><subject>Cell Differentiation</subject><subject>Cells (biology)</subject><subject>Cyclic AMP-Dependent Protein Kinase RIbeta Subunit - genetics</subject><subject>Cyclic AMP-Dependent Protein Kinase RIbeta Subunit - metabolism</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 1 - genetics</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 1 - metabolism</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 3 - genetics</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 7 - genetics</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 7 - metabolism</subject><subject>Development Biology</subject><subject>Differential equations</subject><subject>Differentiation (biology)</subject><subject>Embryology and Organogenesis</subject><subject>Endocrinology and metabolism</subject><subject>Enhancer of Zeste Homolog 2 Protein - genetics</subject><subject>Enhancer of Zeste Homolog 2 Protein - metabolism</subject><subject>Female</subject><subject>Genetics</subject><subject>Genomics</subject><subject>Glucocorticoids</subject><subject>Histone methyltransferase</subject><subject>Homeostasis</subject><subject>Human health and pathology</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>PNAS Plus</subject><subject>Progenitor cells</subject><subject>Protein kinase A</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Stem cells</subject><subject>Steroid hormones</subject><subject>Steroids</subject><subject>Steroids - metabolism</subject><subject>Zona Fasciculata - cytology</subject><subject>Zona Fasciculata - enzymology</subject><subject>Zona Fasciculata - metabolism</subject><subject>Zona Glomerulosa - cytology</subject><subject>Zona Glomerulosa - enzymology</subject><subject>Zona Glomerulosa - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUtvEzEUhS0EoqGwZgWyxAYW0_r92CBFVSGISCABGzaWM_bMOJrYqT2JyL_HUUqArnzl-91zHweAlxhdYSTp9TbacoUV0lhxjPkjMMM1bgTT6DGYIURkoxhhF-BZKWuEkOYKPQUXFHGGlVIzsP82-ZyCS72PoYUudJ3PPk7BTiFFaKODXz_PYQl9tGOIPbTZw21OfbabjXdwdYBDKFOKHm78NBzGKdtYqoYtHt7-XBAYIpwGD62rsnaEbcqT__UcPOnsWPyL-_cS_Phw-_1m0Sy_fPx0M182LZNyagQmmjgtOCNedMRZtLJYCOwYllLLDllnNaJISq4spR2TglOESee044pTegnen3S3u1Udt62bZTuabQ4bmw8m2WD-z8QwmD7tjaAYKcqqwLuTwPCgbDFfmuMfIpQwpukeV_btfbOc7na-TGYTSuvH0UafdsUQzLlGQmNe0TcP0HXa5XqfIyUI40IRUanrE9XmVEr23XkCjMzRf3P03_z1v1a8_nffM__H8Aq8OgHralo-54ngkmrB6G8Jz7Wc</recordid><startdate>20181226</startdate><enddate>20181226</enddate><creator>Mathieu, Mickael</creator><creator>Drelon, Coralie</creator><creator>Rodriguez, Stéphanie</creator><creator>Tabbal, Houda</creator><creator>Septier, Amandine</creator><creator>Damon-Soubeyrand, Christelle</creator><creator>Dumontet, Typhanie</creator><creator>Berthon, Annabel</creator><creator>Sahut-Barnola, Isabelle</creator><creator>Djari, Cyril</creator><creator>Batisse-Lignier, Marie</creator><creator>Pointud, Jean-Christophe</creator><creator>Richard, Damien</creator><creator>Kerdivel, Gwenneg</creator><creator>Calméjane, Marie-Ange</creator><creator>Boeva, Valentina</creator><creator>Tauveron, Igor</creator><creator>Lefrançois-Martinez, Anne-Marie</creator><creator>Martinez, Antoine</creator><creator>Val, Pierre</creator><general>National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8353-542X</orcidid><orcidid>https://orcid.org/0000-0002-5576-9525</orcidid><orcidid>https://orcid.org/0000-0002-1328-9515</orcidid><orcidid>https://orcid.org/0000-0002-4382-7185</orcidid><orcidid>https://orcid.org/0000-0001-7648-5567</orcidid><orcidid>https://orcid.org/0000-0001-7666-9024</orcidid><orcidid>https://orcid.org/0000-0001-9304-5061</orcidid></search><sort><creationdate>20181226</creationdate><title>Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex</title><author>Mathieu, Mickael ; Drelon, Coralie ; Rodriguez, Stéphanie ; Tabbal, Houda ; Septier, Amandine ; Damon-Soubeyrand, Christelle ; Dumontet, Typhanie ; Berthon, Annabel ; Sahut-Barnola, Isabelle ; Djari, Cyril ; Batisse-Lignier, Marie ; Pointud, Jean-Christophe ; Richard, Damien ; Kerdivel, Gwenneg ; Calméjane, Marie-Ange ; Boeva, Valentina ; Tauveron, Igor ; Lefrançois-Martinez, Anne-Marie ; Martinez, Antoine ; Val, Pierre</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-61292d96542e6f2da0ba1661d417797f0ada90307758a33f47653012fd9d58533</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Ablation</topic><topic>Adrenal cortex</topic><topic>Adrenal Cortex - enzymology</topic><topic>Adrenal Cortex - metabolism</topic><topic>Adrenal glands</topic><topic>Adrenocorticotropic hormone</topic><topic>Animal genetics</topic><topic>Animals</topic><topic>Biochemistry, Molecular Biology</topic><topic>Biological Sciences</topic><topic>Ca2+/calmodulin-dependent phosphodiesterase</topic><topic>Cancer</topic><topic>Cell Differentiation</topic><topic>Cells (biology)</topic><topic>Cyclic AMP-Dependent Protein Kinase RIbeta Subunit - genetics</topic><topic>Cyclic AMP-Dependent Protein Kinase RIbeta Subunit - metabolism</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 1 - genetics</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 1 - metabolism</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 3 - genetics</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 7 - genetics</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 7 - metabolism</topic><topic>Development Biology</topic><topic>Differential equations</topic><topic>Differentiation (biology)</topic><topic>Embryology and Organogenesis</topic><topic>Endocrinology and metabolism</topic><topic>Enhancer of Zeste Homolog 2 Protein - 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PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2018-12-26</date><risdate>2018</risdate><volume>115</volume><issue>52</issue><spage>E12265</spage><epage>E12274</epage><pages>E12265-E12274</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>30541888</pmid><doi>10.1073/pnas.1809185115</doi><orcidid>https://orcid.org/0000-0001-8353-542X</orcidid><orcidid>https://orcid.org/0000-0002-5576-9525</orcidid><orcidid>https://orcid.org/0000-0002-1328-9515</orcidid><orcidid>https://orcid.org/0000-0002-4382-7185</orcidid><orcidid>https://orcid.org/0000-0001-7648-5567</orcidid><orcidid>https://orcid.org/0000-0001-7666-9024</orcidid><orcidid>https://orcid.org/0000-0001-9304-5061</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2018-12, Vol.115 (52), p.E12265-E12274 |
| issn | 0027-8424 1091-6490 |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6310834 |
| source | MEDLINE; Jstor Complete Legacy; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Ablation Adrenal cortex Adrenal Cortex - enzymology Adrenal Cortex - metabolism Adrenal glands Adrenocorticotropic hormone Animal genetics Animals Biochemistry, Molecular Biology Biological Sciences Ca2+/calmodulin-dependent phosphodiesterase Cancer Cell Differentiation Cells (biology) Cyclic AMP-Dependent Protein Kinase RIbeta Subunit - genetics Cyclic AMP-Dependent Protein Kinase RIbeta Subunit - metabolism Cyclic Nucleotide Phosphodiesterases, Type 1 - genetics Cyclic Nucleotide Phosphodiesterases, Type 1 - metabolism Cyclic Nucleotide Phosphodiesterases, Type 3 - genetics Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism Cyclic Nucleotide Phosphodiesterases, Type 7 - genetics Cyclic Nucleotide Phosphodiesterases, Type 7 - metabolism Development Biology Differential equations Differentiation (biology) Embryology and Organogenesis Endocrinology and metabolism Enhancer of Zeste Homolog 2 Protein - genetics Enhancer of Zeste Homolog 2 Protein - metabolism Female Genetics Genomics Glucocorticoids Histone methyltransferase Homeostasis Human health and pathology Life Sciences Male Mice, Inbred C57BL Mice, Knockout PNAS Plus Progenitor cells Protein kinase A Signal Transduction Signaling Stem cells Steroid hormones Steroids Steroids - metabolism Zona Fasciculata - cytology Zona Fasciculata - enzymology Zona Fasciculata - metabolism Zona Glomerulosa - cytology Zona Glomerulosa - enzymology Zona Glomerulosa - metabolism |
| title | Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-21T06%3A44%3A22IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Steroidogenic%20differentiation%20and%20PKA%20signaling%20are%20programmed%20by%20histone%20methyltransferase%20EZH2%20in%20the%20adrenal%20cortex&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Mathieu,%20Mickael&rft.date=2018-12-26&rft.volume=115&rft.issue=52&rft.spage=E12265&rft.epage=E12274&rft.pages=E12265-E12274&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.1809185115&rft_dat=%3Cjstor_pubme%3E26573964%3C/jstor_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2162456826&rft_id=info:pmid/30541888&rft_jstor_id=26573964&rfr_iscdi=true |