对儿科泌尿病理学的表观遗传学见解:庆祝托尼·库里的基本生物学愿景。
Epigenetic insights to pediatric uropathology: Celebrating the fundamental biology vision of Tony Khoury.
发表日期:2024 Jun 19
作者:
K J Aitken, Annette Schröder, Ahmed Haddad, Martin Sidler, Frank Penna, Nicolas Fernandez, Tabina Ahmed, Vincent Marino, Matthew Bechbache, Jia-Xin Jiang, Cornelia Tolg, Darius J Bägli
来源:
Cellular & Molecular Immunology
摘要:
许多儿科泌尿科疾病会影响假定的正常组织,或者看起来太常见而不能仅基于特定的 DNA 突变。因此,了解儿科泌尿科的表观遗传机制具有许多意义,可以影响细胞和组织对环境的反应,例如环境和激素对尿道发育的影响、尿路致病性感染、阻塞性刺激,所有这些都起源于外部或细胞外。事实上,细胞对外部刺激的反应通常是表观遗传介导的。在这篇评论中,我们重点介绍了表观遗传机制的关键作用,例如 DNA 甲基转移酶 (DNMT)、Zeste 多梳抑制复合物 2 亚基增强剂 (EZH2) 等在三种泌尿系统中调节基因表达和细胞功能中发挥的关键作用。动物和细胞结构用于模拟临床儿科泌尿病理学。使用使用无序与正常细胞外基质(ECM)的平滑肌细胞模型以及保留其病理特征的新的慢性阻塞性膀胱疾病(COBD)动物模型来探索慢性阻塞性膀胱的肥大、小梁化和纤维化即使膀胱解除梗阻后。来自人和小鼠尿道下裂或生殖器结节(GT)的细胞模型被用来说明关键发育基因的发育反应和表观遗传依赖性。最后,使用膀胱尿路上皮和类器官培养系统,我们检查了表观遗传机制对非尿路致病性与尿路致病性大肠杆菌(UPEC)的反应活性。在这些模型系统中对 DNMT 和 EZH2 的表达和功能进行了研究。紊乱的 ECM 在体外和体内 CODB 中对膀胱平滑肌发挥着主要的有丝分裂和表观遗传作用。 BDNF 和 KCNB2 等关键基因在活跃进化的梗阻和 COBD 中受到表观遗传调控,尽管每种情况都表现出不同的表观遗传反应。在尿道下裂模型中,雌激素严重失调 WNT 和 Hox 表达,通过表观遗传抑制使 WNT 和 Hox 表达正常化。最后,尿路上皮中的 DNA 甲基化机制在受到尿路致病性大肠杆菌的攻击时表现出特异性激活。同样,UPEC 诱导生长抑制因子 p16INK4A 的过度甲基化和下调。此外,暴露于 UPEC 的宿主细胞产生分泌因子,诱导表观遗传反应从一个受影响的细胞传播到另一个细胞,而没有持续的细菌存在。微环境影响改变了所描述的三种泌尿系统环境中的表观遗传活性。考虑到许多阻塞的膀胱继续表现出异常的结构和功能障碍,尽管阻塞的缓解类似于后瓣膜或 BPH 切除后,所描述的表观遗传机制突出了了解这一关键临床问题的潜在平滑肌肌病的新方法。同样,有证据表明异雌激素对尿道下裂的发生、尿路感染诱导的表观遗传标记的全尿路上皮改变以及随后(复发性)尿路感染的倾向具有表观遗传基础。机械、激素、感染触发因素对泌尿生殖表观遗传机制活动的影响,为针对泌尿科这些非癌症疾病相关的表观遗传修饰提供了新的途径。这包括使用基于 CRISPR 的失活技术进行精确的表观基因组定位和编辑。总的来说,我们强调了解儿科泌尿科表观遗传调控对于制定创新治疗和管理策略的重要性。版权所有 © 2024。由 Elsevier Ltd 出版。
Many pediatric urology conditions affect putatively normal tissues or appear too commonly to be based solely on specific DNA mutations. Understanding epigenetic mechanisms in pediatric urology, therefore, has many implications that can impact cell and tissue responses to settings, such as environmental and hormonal influences on urethral development, uropathogenic infections, obstructive stimuli, all of which originate externally or extracellularly. Indeed, the cell's response to external stimuli is often mediated epigenetically. In this commentary, we highlight work on the critical role that epigenetic machinery, such as DNA methyltransferases (DNMTs), Enhancer of Zeste Polycomb Repressive Complex 2 Subunit (EZH2), and others play in regulating gene expression and cellular functions in three urological contexts.Animal and cellular constructs were used to model clinical pediatric uropathology. The hypertrophy, trabeculation, and fibrosis of the chronically obstructed bladder was explored using smooth muscle cell models employing disorganised vs. normal extracellular matrix (ECM), as well as a new animal model of chronic obstructive bladder disease (COBD) which retains its pathologic features even after bladder de-obstruction. Cell models from human and murine hypospadias or genital tubercles (GT) were used to illustrate developmental responses and epigenetic dependency of key developmental genes. Finally, using bladder urothelial and organoid culture systems, we examined activity of epigenetic machinery in response to non uropathogenic vs. uropathogenic E.coli (UPEC). DNMT and EZH2 expression and function were interrogated in these model systems.Disordered ECM exerted a principal mitogenic and epigenetic role for on bladder smooth muscle both in vitro and in CODB in vivo. Key genes, e.g., BDNF and KCNB2 were under epigenetic regulation in actively evolving obstruction and COBD, though each condition showed distinct epigenetic responses. In models of hypospadias, estrogen strongly dysregulated WNT and Hox expression, which was normalized by epigenetic inhibition. Finally, DNA methylation machinery in the urothelium showed specific activation when challenged by uropathogenic E.coli. Similarly, UPEC induces hypermethylation and downregulation of the growth suppressor p16INK4A. Moreover, host cells exposed to UPEC produced secreted factors inducing epigenetic responses transmissible from one affected cell to another without ongoing bacterial presence.Microenvironmental influences altered epigenetic activity in the three described urologic contexts. Considering that many obstructed bladders continue to display abnormal architecture and dysfunction despite relief of obstruction similar to after resection of posterior valves or BPH, the epigenetic mechanisms described highlight novel approaches for understanding the underlying smooth muscle myopathy of this crucial clinical problem. Similarly, there is evidence for an epigenetic basis of xenoestrogen on development of hypospadias, and UTI-induced pan-urothelial alteration of epigenetic marks and propensity for subsequent (recurrent) UTI. The impact of mechanical, hormonal, infectious triggers on genitourinary epigenetic machinery activity invite novel avenues for targeting epigenetic modifications associated with these non-cancer diseases in urology. This includes the use of deactivated CRISPR-based technologies for precise epigenome targeting and editing. Overall, we underscore the importance of understanding epigenetic regulation in pediatric urology for the development of innovative therapeutic and management strategies.Copyright © 2024. Published by Elsevier Ltd.