组蛋白 H3K27me3 去甲基酶 KDM6A 和 KDM6B 通过调节 WNT 信号通路调节人 ESC 向终末内胚层的分化。
Histone H3K27me3 demethylases KDM6A and KDM6B modulate definitive endoderm differentiation from human ESCs by regulating WNT signaling pathway.
机构信息
Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA.
出版信息
Cell Res. 2013 Jan;23(1):122-30. doi: 10.1038/cr.2012.119. Epub 2012 Aug 21.
Abstract
Definitive endoderm differentiation is crucial for generating respiratory and gastrointestinal organs including pancreas and liver. However, whether epigenetic regulation contributes to this process is unknown. Here, we show that the H3K27me3 demethylases KDM6A and KDM6B play an important role in endoderm differentiation from human ESCs. Knockdown of KDM6A or KDM6B impairs endoderm differentiation, which can be rescued by sequential treatment with WNT agonist and antagonist. KDM6A and KDM6B contribute to the activation of WNT3 and DKK1 at different differentiation stages when WNT3 and DKK1 are required for mesendoderm and definitive endoderm differentiation, respectively. Our study not only uncovers an important role of the H3K27me3 demethylases in definitive endoderm differentiation, but also reveals that they achieve this through modulating the WNT signaling pathway.
摘要
确定内胚层分化对于产生包括胰腺和肝脏在内的呼吸和胃肠道器官至关重要。然而，表观遗传调控是否对此过程有贡献尚不清楚。在这里，我们表明 H3K27me3 去甲基化酶 KDM6A 和 KDM6B 在人 ESC 的内胚层分化中发挥重要作用。KDM6A 或 KDM6B 的敲低会损害内胚层分化，而用 WNT 激动剂和拮抗剂进行顺序处理可以挽救这种情况。当 WNT3 和 DKK1 分别需要中胚层和确定内胚层分化时，KDM6A 和 KDM6B 在不同的分化阶段有助于 WNT3 和 DKK1 的激活。我们的研究不仅揭示了 H3K27me3 去甲基化酶在确定内胚层分化中的重要作用，还表明它们通过调节 WNT 信号通路来实现这一作用。
相似文献
1
Histone H3K27me3 demethylases KDM6A and KDM6B modulate definitive endoderm differentiation from human ESCs by regulating WNT signaling pathway.组蛋白 H3K27me3 去甲基酶 KDM6A 和 KDM6B 通过调节 WNT 信号通路调节人 ESC 向终末内胚层的分化。
Cell Res. 2013 Jan;23(1):122-30. doi: 10.1038/cr.2012.119. Epub 2012 Aug 21.
2
Elevated H3K27me3 levels sensitize osteosarcoma to cisplatin.H3K27me3 水平升高使骨肉瘤对顺铂敏感。
Clin Epigenetics. 2019 Jan 16;11(1):8. doi: 10.1186/s13148-018-0605-x.
3
Histone demethylases Kdm6ba and Kdm6bb redundantly promote cardiomyocyte proliferation during zebrafish heart ventricle maturation.组蛋白去甲基化酶Kdm6ba和Kdm6bb在斑马鱼心室成熟过程中冗余促进心肌细胞增殖。
Dev Biol. 2017 Jun 1;426(1):84-96. doi: 10.1016/j.ydbio.2017.03.030. Epub 2017 Apr 1.
4
Synergistic triad epistasis of epigenetic H3K27me modifier genes, EZH2, KDM6A, and KDM6B, in gastric cancer susceptibility.表观遗传 H3K27me 修饰基因 EZH2、KDM6A 和 KDM6B 的协同三重态上位性在胃癌易感性中的作用。
Gastric Cancer. 2019 May;22(3):640-644. doi: 10.1007/s10120-018-0888-9. Epub 2018 Oct 29.
5
OCT4 Coordinates with WNT Signaling to Pre-pattern Chromatin at the SOX17 Locus during Human ES Cell Differentiation into Definitive Endoderm.OCT4 与 WNT 信号协同作用，在人胚胎干细胞向 definitive endoderm 分化过程中预先形成 SOX17 基因座的染色质。
Stem Cell Reports. 2015 Oct 13;5(4):490-8. doi: 10.1016/j.stemcr.2015.08.014. Epub 2015 Sep 24.
6
SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade.SMARCA4 缺陷型肿瘤对 KDM6A/UTX 和 KDM6B/JMJD3 抑制敏感。
Nat Commun. 2021 Jul 14;12(1):4319. doi: 10.1038/s41467-021-24618-3.
7
Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate.组蛋白去甲基化酶 KDM6A 直接感知氧气以控制染色质和细胞命运。
Science. 2019 Mar 15;363(6432):1217-1222. doi: 10.1126/science.aaw1026. Epub 2019 Mar 14.
8
Hyperglycemia impedes definitive endoderm differentiation of human embryonic stem cells by modulating histone methylation patterns.高血糖通过调节组蛋白甲基化模式阻碍人类胚胎干细胞向确定内胚层的分化。
Cell Tissue Res. 2017 Jun;368(3):563-578. doi: 10.1007/s00441-017-2583-2. Epub 2017 Mar 10.
9
Lysine Demethylase KDM6A in Differentiation, Development, and Cancer.赖氨酸去甲基化酶 KDM6A 在分化、发育和癌症中的作用。
Mol Cell Biol. 2020 Sep 28;40(20). doi: 10.1128/MCB.00341-20.
10
Demethylation of H3K27 Is Essential for the Induction of Direct Cardiac Reprogramming by miR Combo.H3K27去甲基化对于miR组合诱导直接心脏重编程至关重要。
Circ Res. 2017 Apr 28;120(9):1403-1413. doi: 10.1161/CIRCRESAHA.116.308741. Epub 2017 Feb 16.
引用本文的文献
1
Single-nuclei transcriptome analysis of IgM cells isolated from channel catfish () spleen.从斑点叉尾鮰脾脏分离的IgM细胞的单核转录组分析。
Front Immunol. 2025 Mar 17;16:1547193. doi: 10.3389/fimmu.2025.1547193. eCollection 2025.
2
Role and mechanisms of histone methylation in osteogenic/odontogenic differentiation of dental mesenchymal stem cells.组蛋白甲基化在牙间充质干细胞成骨/成牙分化中的作用及机制
Int J Oral Sci. 2025 Mar 26;17(1):24. doi: 10.1038/s41368-025-00353-z.
3
Cell size regulates human endoderm specification through actomyosin-dependent AMOT-YAP signaling.细胞大小通过肌动球蛋白依赖性 AMOT-YAP 信号调节人类内胚层的特化。
Stem Cell Reports. 2024 Aug 13;19(8):1137-1155. doi: 10.1016/j.stemcr.2024.07.001. Epub 2024 Aug 1.
4
H3K27me3-mediated epigenetic regulation in pluripotency maintenance and lineage differentiation.H3K27me3介导的表观遗传调控在多能性维持和谱系分化中的作用
Cell Insight. 2024 Jun 27;3(4):100180. doi: 10.1016/j.cellin.2024.100180. eCollection 2024 Aug.
5
Conserved Genes in Highly Regenerative Metazoans Are Associated with Planarian Regeneration.高度再生后生动物中的保守基因与扁形动物再生有关。
Genome Biol Evol. 2024 May 2;16(5). doi: 10.1093/gbe/evae082.
6
KDM6A/UTX promotes spermatogenic gene expression across generations and is not required for male fertility†.KDM6A/UTX 可跨代促进生精基因的表达，并且雄性生育力并非必需的†。
Biol Reprod. 2024 Feb 10;110(2):391-407. doi: 10.1093/biolre/ioad141.
7
Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis.新生染色质结构的变化调节器官纤维化中促纤维化转录组的激活和成肌纤维细胞的出现。
iScience. 2023 Apr 6;26(5):106570. doi: 10.1016/j.isci.2023.106570. eCollection 2023 May 19.
8
A desert lncRNA HIDEN regulates human endoderm differentiation via interacting with IMP1 and stabilizing FZD5 mRNA.一个荒漠长链非编码 RNA HIDEN 通过与 IMP1 相互作用并稳定 FZD5 mRNA 来调节人类内胚层分化。
Genome Biol. 2023 Apr 24;24(1):92. doi: 10.1186/s13059-023-02925-w.
9
The role of noncoding RNAs in pancreatic birth defects.非编码 RNA 在胰腺发育缺陷中的作用。
Birth Defects Res. 2023 Nov 15;115(19):1785-1808. doi: 10.1002/bdr2.2178. Epub 2023 Apr 17.
10
KDM6B cooperates with Tau and regulates synaptic plasticity and cognition via inducing VGLUT1/2.KDM6B 通过诱导 VGLUT1/2 与 Tau 合作调节突触可塑性和认知。
Mol Psychiatry. 2022 Dec;27(12):5213-5226. doi: 10.1038/s41380-022-01750-0. Epub 2022 Aug 26.
本文引用的文献
1
Wnt/β-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4.Wnt/β-catenin 信号通路促进人类胚胎干细胞的分化，而非自我更新，其受转录因子 Oct4 抑制。
Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4485-90. doi: 10.1073/pnas.1118777109. Epub 2012 Mar 5.
2
UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program.UTX，一种组蛋白 H3-赖氨酸 27 去甲基化酶，作为激活心脏发育程序的关键开关。
Dev Cell. 2012 Jan 17;22(1):25-37. doi: 10.1016/j.devcel.2011.11.009. Epub 2011 Dec 20.
3
Chromatin and transcriptional signatures for Nodal signaling during endoderm formation in hESCs.胚胎干细胞中内胚层形成过程中 Nodal 信号的染色质和转录特征。
Dev Biol. 2011 Sep 15;357(2):492-504. doi: 10.1016/j.ydbio.2011.06.009. Epub 2011 Jun 29.
4
Targeting SOX17 in human embryonic stem cells creates unique strategies for isolating and analyzing developing endoderm.在人类胚胎干细胞中靶向 SOX17 为分离和分析发育中的内胚层创造了独特的策略。
Cell Stem Cell. 2011 Mar 4;8(3):335-46. doi: 10.1016/j.stem.2011.01.017.
5
Stage-specific signaling through TGFβ family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells.TGFβ 家族成员和 WNT 的阶段特异性信号转导调节人多能干细胞的模式形成和胰腺特化。
Development. 2011 Mar;138(5):861-71. doi: 10.1242/dev.055236. Epub 2011 Jan 26.
6
Recent advances and prospects in the differentiation of pancreatic cells from human embryonic stem cells.人胚胎干细胞向胰腺细胞分化的最新进展和前景。
Diabetes. 2010 Sep;59(9):2094-101. doi: 10.2337/db10-0439.
7
The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection.Jmjd3-Irf4 轴调节 M2 巨噬细胞极化和宿主对寄生虫感染的反应。
Nat Immunol. 2010 Oct;11(10):936-44. doi: 10.1038/ni.1920. Epub 2010 Aug 22.
8
Nodal morphogens.节状形态发生素。
Cold Spring Harb Perspect Biol. 2009 Nov;1(5):a003459. doi: 10.1101/cshperspect.a003459.
9
Vertebrate endoderm development and organ formation.脊椎动物内胚层发育与器官形成。
Annu Rev Cell Dev Biol. 2009;25:221-51. doi: 10.1146/annurev.cellbio.042308.113344.
10
Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells.人类胚胎干细胞和诱导多能干细胞高效分化为成熟的胰腺胰岛素分泌细胞。
Cell Res. 2009 Apr;19(4):429-38. doi: 10.1038/cr.2009.28.
Zotero 插件