دورية أكاديمية
A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition.
| العنوان: | A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition. |
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| المؤلفون: | Gao CW; Department of Genetic Medicine.; Department of Molecular Biology and Genetics, and., Lin W; Department of Genetic Medicine., Riddle RC; Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Research and Development Service, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA., Kushwaha P; Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Boukas L; Department of Genetic Medicine.; Department of Biostatistics, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA., Björnsson HT; Department of Genetic Medicine.; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Faculty of Medicine, University of Iceland, Reykjavík, Iceland.; Landspítali University Hospital, Reykjavík, Iceland., Hansen KD; Department of Genetic Medicine.; Department of Biostatistics, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA.; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Fahrner JA; Department of Genetic Medicine.; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. |
| المصدر: | JCI insight [JCI Insight] 2024 Jan 09; Vol. 9 (1). Date of Electronic Publication: 2024 Jan 09. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- |
| مواضيع طبية MeSH: | Osteogenesis*/physiology , Fibroblasts*/metabolism, Animals ; Mice ; Polycomb Repressive Complex 2 ; Disease Models, Animal ; Histone Demethylases |
| مستخلص: | Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in EZH2, which encodes the predominant H3K27 methyltransferase and key enzymatic component of Polycomb repressive complex 2 (PRC2). Weaver syndrome is characterized by striking overgrowth and advanced bone age, intellectual disability, and distinctive facies. We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C. Ezh2R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. Ezh2R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts showed increased osteogenic activity. RNA-Seq comparing osteoblasts differentiated from Ezh2R684C/+, and Ezh2+/+ BM-mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation. Inhibition of the opposing H3K27 demethylases KDM6A and KDM6B substantially reversed the excessive osteogenesis in Ezh2R684C/+ cells both at the transcriptional and phenotypic levels. This supports both the ideas that writers and erasers of histone marks exist in a fine balance to maintain epigenome state and that epigenetic modulating agents have therapeutic potential for the treatment of MDEMs. |
| التعليقات: | Update of: bioRxiv. 2023 Jun 30;:. (PMID: 37425751) |
| References: | PLoS Comput Biol. 2020 Feb 25;16(2):e1007664. (PMID: 32097405) Hum Mol Genet. 2019 Nov 21;28(R2):R254-R264. (PMID: 31595951) Blood. 2011 Feb 24;117(8):2451-9. (PMID: 21190999) Nature. 2012 Sep 6;489(7414):57-74. (PMID: 22955616) Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):532-547. (PMID: 31736240) Nat Genet. 2002 Apr;30(4):365-6. (PMID: 11896389) Mol Cell Biol. 2001 Jul;21(13):4330-6. (PMID: 11390661) Am J Hum Genet. 2009 Apr;84(4):524-33. (PMID: 19344873) Mol Cell. 2012 Nov 30;48(4):572-86. (PMID: 23063525) Bioinformatics. 2012 Mar 15;28(6):882-3. (PMID: 22257669) J Med Genet. 1992 May;29(5):332-7. (PMID: 1583661) Nat Protoc. 2009;4(8):1184-91. (PMID: 19617889) Nature. 2007 Oct 11;449(7163):731-4. (PMID: 17713478) Genome Res. 2012 Sep;22(9):1798-812. (PMID: 22955990) PLoS Comput Biol. 2013;9(8):e1003118. (PMID: 23950696) Am J Hum Genet. 2018 Jan 4;102(1):156-174. (PMID: 29304373) Cold Spring Harb Perspect Biol. 2016 Sep 01;8(9):. (PMID: 27194046) Cells. 2022 Dec 18;11(24):. (PMID: 36552882) Stem Cells. 2014 Mar;32(3):802-15. (PMID: 24123378) Genome Res. 2019 Apr;29(4):532-542. (PMID: 30858344) Stem Cell Res Ther. 2013;4(5):117. (PMID: 24073831) Neuron. 2004 Jun 24;42(6):947-59. (PMID: 15207239) Am J Hum Genet. 2017 May 4;100(5):773-788. (PMID: 28475860) Nucleic Acids Res. 2002 Jan 1;30(1):207-10. (PMID: 11752295) Hum Genet. 2023 Mar 23;:. (PMID: 36952035) Hum Mutat. 2017 Jun;38(6):637-648. (PMID: 28229514) Sci Transl Med. 2014 Oct 1;6(256):256ra135. (PMID: 25273096) Proc Natl Acad Sci U S A. 2017 Jan 3;114(1):125-130. (PMID: 27999180) PLoS One. 2013 Dec 19;8(12):e83737. (PMID: 24367611) J Bone Miner Res. 2013 Jan;28(1):2-17. (PMID: 23197339) Am J Med Genet A. 2017 Oct;173(10):2731-2735. (PMID: 28696078) Clin Genet. 2023 Apr;103(4):383-391. (PMID: 36645289) Mamm Genome. 2012 Dec;23(11-12):749-57. (PMID: 22926222) Genome Biol. 2014;15(12):550. (PMID: 25516281) Mol Cell. 2008 Nov 21;32(4):491-502. (PMID: 19026780) Genome Biol. 2005;6(8):227. (PMID: 16086857) Hum Mutat. 2016 Mar;37(3):301-7. (PMID: 26694085) Elife. 2018 Jun 22;7:. (PMID: 29932419) J Bone Miner Res. 2001 Oct;16(10):1754-64. (PMID: 11585338) JCI Insight. 2019 Oct 17;4(20):. (PMID: 31465303) J Biol Chem. 2018 Aug 17;293(33):12894-12907. (PMID: 29899112) Elife. 2021 Aug 31;10:. (PMID: 34463256) J Clin Endocrinol Metab. 2018 Apr 1;103(4):1470-1478. (PMID: 29244146) J Biol Chem. 2008 Oct 10;283(41):27757-27766. (PMID: 18693240) Nature. 2012 Aug 16;488(7411):404-8. (PMID: 22842901) Nat Commun. 2015 Dec 22;6:10207. (PMID: 26690673) Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20980-5. (PMID: 21078963) Am J Med Genet A. 2013 Dec;161A(12):2972-80. (PMID: 24214728) Nature. 2012 Sep 6;489(7414):91-100. (PMID: 22955619) J Biol Chem. 2016 Nov 18;291(47):24594-24606. (PMID: 27758858) J Biol Chem. 2015 Nov 13;290(46):27604-17. (PMID: 26424790) Int J Biochem Cell Biol. 2008;40(1):46-62. (PMID: 17659995) Stem Cells Dev. 2016 Jun 15;25(12):909-21. (PMID: 27168161) Annu Rev Genet. 2020 Nov 23;54:265-285. (PMID: 32870732) Cell. 2017 Jun 15;169(7):1177-1186. (PMID: 28622505) Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18439-44. (PMID: 18003914) Curr Opin Genet Dev. 2017 Apr;43:31-37. (PMID: 27940208) PLoS One. 2008 Sep 09;3(9):e3174. (PMID: 18779865) Annu Rev Genomics Hum Genet. 2014;15:269-93. (PMID: 25184531) Mol Ther Methods Clin Dev. 2021 Feb 18;20:779-791. (PMID: 33738331) J Hum Genet. 2016 Sep;61(9):831-4. (PMID: 27193220) Nature. 2000 Aug 10;406(6796):593-9. (PMID: 10949293) Cell. 2017 Sep 21;171(1):34-57. (PMID: 28938122) Genes Brain Behav. 2020 Apr;19(4):e12637. (PMID: 31909872) Front Biosci. 2007 May 01;12:3068-92. (PMID: 17485283) Oncotarget. 2011 Dec;2(12):1127-33. (PMID: 22190405) J Bone Miner Res. 2010 Jul;25(7):1468-86. (PMID: 20533309) Nucleic Acids Res. 2020 Jan 8;48(D1):D882-D889. (PMID: 31713622) J Pediatr. 1974 Apr;84(4):547-52. (PMID: 4366187) NPJ Genom Med. 2021 Nov 8;6(1):92. (PMID: 34750377) J Hum Genet. 2015 Jun;60(6):339-42. (PMID: 25787343) JCI Insight. 2019 Oct 17;4(20):. (PMID: 31557133) Nat Methods. 2017 Apr;14(4):417-419. (PMID: 28263959) Stem Cell Res Ther. 2020 Dec 9;11(1):529. (PMID: 33298158) Nucleic Acids Res. 2013 Jan;41(Database issue):D171-6. (PMID: 23203885) Am J Hum Genet. 2020 May 7;106(5):596-610. (PMID: 32243864) J Bone Miner Res. 2020 Jun;35(6):1149-1162. (PMID: 32022326) Am J Hum Genet. 2012 Jan 13;90(1):110-8. (PMID: 22177091) Biol Proced Online. 2018 Aug 01;20:14. (PMID: 30078998) Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3632-E3641. (PMID: 28416686) Bioinformatics. 2005 Aug 15;21(16):3439-40. (PMID: 16082012) Am J Med Genet A. 2019 Apr;179(4):588-594. (PMID: 30793471) Am J Hum Genet. 2017 May 4;100(5):725-736. (PMID: 28475857) Nucleic Acids Res. 2018 Jan 4;46(D1):D1062-D1067. (PMID: 29165669) |
| معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; I01 BX003724 United States BX BLRD VA; K08 HD086250 United States HD NICHD NIH HHS; T32 GM136577 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: Epigenetics; Genetic diseases; Genetics |
| المشرفين على المادة: | EC 2.1.1.43 (Polycomb Repressive Complex 2) EC 1.14.11.- (Histone Demethylases) |
| SCR Disease Name: | Weaver syndrome |
| تواريخ الأحداث: | Date Created: 20231128 Date Completed: 20240110 Latest Revision: 20240303 |
| رمز التحديث: | 20240303 |
| مُعرف محوري في PubMed: | PMC10906465 |
| DOI: | 10.1172/jci.insight.173392 |
| PMID: | 38015625 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2379-3708 |
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| DOI: | 10.1172/jci.insight.173392 |