R01HD106285

Pathological Reprogramming of the m6A Epitranscriptome in Uterine Fibroids - 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.

The University Of Texas Health Science Center At San Antonio

TO CONDUCT AND SUPPORT LABORATORY RESEARCH, CLINICAL TRIALS, AND STUDIES WITH PEOPLE THAT EXPLORE HEALTH PROCESSES. NICHD RESEARCHERS EXAMINE GROWTH AND DEVELOPMENT, BIOLOGIC AND REPRODUCTIVE FUNCTIONS, BEHAVIOR PATTERNS, AND POPULATION DYNAMICS TO PROTECT AND MAINTAIN THE HEALTH OF ALL PEOPLE. TO EXAMINE THE IMPACT OF DISABILITIES, DISEASES, AND DEFECTS ON THE LIVES OF INDIVIDUALS. WITH THIS INFORMATION, THE NICHD HOPES TO RESTORE, INCREASE, AND MAXIMIZE THE CAPABILITIES OF PEOPLE AFFECTED BY DISEASE AND INJURY. TO SPONSOR TRAINING PROGRAMS FOR SCIENTISTS, DOCTORS, AND RESEARCHERS TO ENSURE THAT NICHD RESEARCH CAN CONTINUE. BY TRAINING THESE PROFESSIONALS IN THE LATEST RESEARCH METHODS AND TECHNOLOGIES, THE NICHD WILL BE ABLE TO CONDUCT ITS RESEARCH AND MAKE HEALTH RESEARCH PROGRESS UNTIL ALL CHILDREN, ADULTS, FAMILIES, AND POPULATIONS ENJOY GOOD HEALTH. THE MISSION OF THE NICHD IS TO ENSURE THAT EVERY PERSON IS BORN HEALTHY AND WANTED, THAT WOMEN SUFFER NO HARMFUL EFFECTS FROM REPRODUCTIVE PROCESSES, AND THAT ALL CHILDREN HAVE THE CHANCE TO ACHIEVE THEIR FULL POTENTIAL FOR HEALTHY AND PRODUCTIVE LIVES, FREE FROM DISEASE OR DISABILITY, AND TO ENSURE THE HEALTH, PRODUCTIVITY, INDEPENDENCE, AND WELL-BEING OF ALL PEOPLE THROUGH OPTIMAL REHABILITATION.

93.865 - Child Health and Human Development Extramural Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

San Antonio, Texas 782293901 United States

Single Zip Code

The Role of Epitranscriptomics in Development and Disease (R01 - Clinical Trial Not Allowed) (PAR-18-830)

Amendment Since initial award the total obligations have increased 391% from $661,325 to $3,245,895.