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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：
10300115
负责人：
Ayman Al-Hendy
金额：
$ 66.13万
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/10300115
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 Genetic Translation 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 base cell growth cell transformation comparative effective therapy epigenome epitranscriptome epitranscriptomics histone methylation histone modification human disease human model in vivo inhibitor/antagonist insight mRNA Decay mRNA Stability methylome methylomics mouse model mutant myometrium neoplastic new therapeutic target novel overexpression pre-clinical 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.

项目总结/文摘