Pathological reprogramming of the m6A epitranscriptome in uterine fibroids

子宫肌瘤中 m6A 表观转录组的病理重编程

基本信息

批准号：
10641809
负责人：
Ayman Al-Hendy
金额：
$ 64.78万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-09 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641809
关键词：
Acute Address Benign Bromodomain Catalytic Domain Cell Death Cell Survival Cells ChIP-seq Chemicals Chromatin Chromosomes Chronic Complex Data Set Development Disease Progression Enhancers Epigenetic Process Etiology Expression Profiling Fibroid Tumor Fibrous capsule of kidney Gene Expression Genetic Determinism Genetic Transcription Growth Habitual Abortion Health Care Costs Homeostasis In Vitro Infertility Knowledge Leiomyoma Link Measures Mediating Medical Menorrhagia Messenger RNA Methylation Methyltransferase Modification Molecular Morbidity - disease rate Mus Myometrial Onset of illness Operative Surgical Procedures Pathogenesis Pathologic Pathway interactions Patients Pelvic Pain Phenotype Premature Labor RNA RNA Binding RNA immunoprecipitation sequencing RNA methylation Role Safety Testing Therapeutic Therapeutic Intervention Time Toxic effect Transcriptional Regulation Translations Treatment Efficacy Tumor Biology Tumor Tissue Up-Regulation Uterine Fibroids Women&apos s Health Xenograft procedure cell growth cell transformation comparative effective therapy epigenome epitranscriptome epitranscriptomics histone methylation histone modification human disease human model in vivo inhibitor inhibitor therapy insight mRNA Decay mRNA Stability mRNA Translation methylome methylomics mouse model mutant myometrium neoplastic new therapeutic target novel overexpression posttranscriptional pre-clinical programs reproductive organ stem cells transcriptome sequencing tumor tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT Uterine fibroids (UFs) are the most important benign neoplastic threat to women’s health worldwide. As no long- term non-invasive treatment option currently exists for UFs, deeper insight into tumor etiology is key to develop more effective therapies. In this regard, while the epi/genetic determinants of UFs have been characterized extensively, their underlying pathogenesis nonetheless remains obscure, implicating additional factors in disease onset. Herein, we propose a novel basis to explain UF development through pathological reprogramming of the myometrial epitranscriptome and offer proof of concept for therapeutic intervention using inhibitors of tumorigenic enhancer activity driven by unanticipated m6A-chromatin crosstalk. As the most abundant internal chemical modification in mRNA, N6-methyladenosine (m6A) is a key determinant of posttranscriptional mRNA fate and thus cell identity and function. Accordingly, disruption of m6A homeostasis is implicated in a diverse range of chronic and acute human disease conditions. However, nothing is known about the role of m6A in the pathogenesis of UFs. We now show that m6A writers METTL3 and RBM15 are aberrantly upregulated in UFs compared to adjacent myometrium (MM). Further, we show that METTL3 depletion triggers UF cell death and global upregulation of transcriptionally repressive histone methylation, linking m6A for the first time with UF tumor biology and revealing its novel crosstalk with the UF epigenome. Integrated RNA methylation and expression profiling in METTL3-deficient UF cells revealed a profoundly altered m6A modification landscape and identified high-confidence m6A-modified mRNA effectors of METTL3-driven UF cell growth and survival. Based on these findings, we hypothesize that aberrant METTL3-dependent RNA methylation reprograms the MM epitranscriptome, leading to epigenetic dysregulation and altered expression of genes that drive UF initiation and progression. Accordingly, we propose that epigenetic inhibitors, through suppression of m6A-driven pro- tumorigenic pathways, will provide therapeutic benefit in UFs. To test these hypotheses we will: (1) Establish the basis of epitranscriptomic reprogramming in UFs. We will comparatively profile the m6A modification landscape of mRNAs and chromosome-associated regulatory RNAs (carRNAs) from paired MM and UF tumor tissues and investigate functional cooperativity between METTL3 and RBM15 in methylomic reprogramming; (2) Delineate the role of METTL3-dependent RNA methylation in fibrotic transformation. We will ask if METTL3, in a manner dependent upon its overexpression and methyltransferase activity, can trigger MM stem cell transformation in vitro and UF tumor formation in vivo; (3) Elucidate the impact of METTL3-dependent RNA methylation on gene expression in UFs. We will assess the global impact of m6A on mRNA stability and translation as well as carRNA- dependent control of chromatin state and transcription; (4) Examine the therapeutic potential of BRD inhibitors in a preclinical mouse model of human UFs. We will evaluate select BRD inhibitors for therapeutic efficacy, safety, and mechanism of anti-tumor activity, including impact on chromatin status and transcription.

项目概要/摘要子宫肌瘤（UF）是全球女性健康最重要的良性肿瘤威胁。目前对于 UF 存在术语非侵入性治疗选择，深入了解肿瘤病因是开发的关键在这方面，UF 的表观/遗传决定因素已得到表征。一般来说，它们的潜在发病机制仍然不清楚，暗示疾病的其他因素在此，我们提出了通过病理性重编程来解释 UF 发展的新基础。子宫肌层表观转录组，并为使用致瘤抑制剂的治疗干预提供概念证明由意外的 m6A-染色质串扰驱动的增强子活性作为最丰富的内部化学物质。 mRNA 修饰，N6-甲基腺苷 (m6A) 是转录后 mRNA 命运的关键决定因素，因此，m6A 稳态的破坏与多种细胞特性和功能有关。然而，对于 m6A 在慢性和急性人类疾病中的作用尚不清楚。我们现在表明 m6A writer METTL3 和 RBM15 在 UF 中异常上调。与邻近的子宫肌层 (MM) 相比，我们还发现 METTL3 耗尽会触发 UF 细胞死亡和转录抑制组蛋白甲基化的整体上调，首次将 m6A 与 UF 肿瘤联系起来生物学并揭示其与 UF 表观基因组的新型串扰。 METTL3 缺陷的 UF 细胞的分析揭示了 m6A 修饰格局的深刻改变，并确定了 METTL3 驱动的 UF 细胞生长和存活的高置信度 m6A 修饰的 mRNA 效应子。研究结果表明，异常的 METTL3 依赖性 RNA 甲基化会重新编程 MM 表观转录组，导致表观遗传失调和驱动 UF 启动的基因表达因此，我们建议表观遗传抑制剂通过抑制 m6A 驱动的亲致瘤途径，将为 UF 提供治疗益处为了检验这些假设，我们将： (1) 建立我们将比较描述 UF 表观转录组重编程的基础。来自配对 MM 和 UF 肿瘤组织的 mRNA 和染色体相关调节 RNA (carRNA) 研究 METTL3 和 RBM15 在甲基组重编程中的功能协同性；(2) 描述 METTL3 依赖性 RNA 甲基化在纤维化转化中的作用我们会问 METTL3 是否以某种方式发挥作用。依赖于其过度表达和甲基转移酶活性，可以触发 MM 干细胞转化 (3)阐明METTL3依赖的RNA甲基化对基因的影响我们将评估 m6A 对 mRNA 稳定性和翻译以及 carRNA 的整体影响。 (4)检验BRD抑制剂的治疗潜力我们将在人类 UF 的临床前小鼠模型中评估选定的 BRD 抑制剂的治疗效果，安全性和抗肿瘤活性机制，包括对染色质状态和转录的影响。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Simvastatin inhibits stem cell proliferation in human leiomyoma via TGF-β3 and Wnt/β-Catenin pathways.

DOI：
10.1111/jcmm.17211
发表时间：
2022-03
期刊：
Journal of cellular and molecular medicine
影响因子：
5.3
作者：
Afrin S;Ali M;El Sabeh M;Yang Q;Al-Hendy A;Borahay MA
通讯作者：
Borahay MA

Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids.

DOI：
10.3390/ijms24065778
发表时间：
2023-03-17
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
通讯作者：

Epigenetic Regulation in Uterine Fibroids-The Role of Ten-Eleven Translocation Enzymes and Their Potential Therapeutic Application.

DOI：
10.3390/ijms23052720
发表时间：
2022-02-28
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Włodarczyk M;Nowicka G;Ciebiera M;Ali M;Yang Q;Al-Hendy A
通讯作者：
Al-Hendy A

Endocrine-disrupting chemicals and epigenetic reprogramming in developmental origin of uterine fibroids.

DOI：
10.1177/00368504231215601
发表时间：
2023-10
期刊：
SCIENCE PROGRESS
影响因子：
2.1
作者：
Yang, Qiwei;Ali, Mohamed;Bariani, Maria Victoria;Vafaei, Somayeh;Al-Hendy, Ayman
通讯作者：
Al-Hendy, Ayman

Erratum to: Comprehensive Review of Uterine Fibroids: Developmental Origin, Pathogenesis, and Treatment.