# Deciphering the role of METTL3 in Mammalian Placenta Development and Maintenance Across Pregnancy

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $526,008

## Abstract

Abstract
Placental dysfunction leads to pregnancy-associated disorders, including intrauterine growth restriction
(IUGR) and preeclampsia, and also serves as a developmental cause for postnatal and adult diseases. Often,
the causal alterations in the placentation process, which lead to defective pregnancies, occur early in
gestation. Defective development and differentiation of trophoblast progenitors are leading causes for
pathological pregnancies. However, we have a poor understanding of molecular mechanisms that regulate
trophoblast progenitor self-renewal, differentiation and function in postimplantation embryos. Studies on
mutant mouse models revealed that RNA Methyltransferase 3 (METTL3), which catalyzes N6-methyladenosine
(m6A) modification on eukaryotic RNAs, is important for embryonic development. Furthermore, METTL3
expression is upregulated in pathological pregnancies, associated with Preeclampsia and IUGR. However, the
importance of METTL3 in the context of mammalian placentation is poorly understood. Our preliminary findings
establish that METTL3 expression is conserved in trophoblast progenitors across mammalian species, including
humans. We also found that METTL3 is essential in human trophoblast self-renewal. Thus, the overarching goal
of this proposal is to investigate importance of METTL3 in the mammalian placental development and
maintenance. We will also test how altered METTL3 function in the placenta affects fetal development leading to
IUGR.
 Two specific aims are proposed. In Aim 1 we will study Mettl3 conditional knockout and Mettl3
conditional overexpression mouse models to test the hypothesis that trophoblast cell-autonomous function of
METTL3 is important placental development and maintenance. We will test role of METTL3 in trophoblast
differentiation, invasion and fetal development.
 In Aim 2, using CTB-derived human trophoblast stem cells, we will test the hypothesis that METTL3
establishes a conserved gene expression program in mouse and human trophoblast progenitors and impairment
of METTL3-dependent transcriptional program will impair self-renewal and differentiation potential of human
trophoblast progenitors. In addition, we will also interrogate significance of METTL3-dependent mechanisms in the
context of pathological pregnancies associated with IUGR , especially early-onset IUGR.

## Key facts

- **NIH application ID:** 10978088
- **Project number:** 1R01HD113673-01A1
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Soumen Paul
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $526,008
- **Award type:** 1
- **Project period:** 2024-08-07 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978088

## Citation

> US National Institutes of Health, RePORTER application 10978088, Deciphering the role of METTL3 in Mammalian Placenta Development and Maintenance Across Pregnancy (1R01HD113673-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10978088. Licensed CC0.

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