# DNA methylation in orofacial clefting

> **NIH NIH R56** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $438,352

## Abstract

Understanding the role of malleable epigenetic mechanisms in birth defects is a direct path to prevention
strategies. Orofacial clefts (OFCs) of the lip and palate are common human structural birth defects, affecting 1
in 800 newborns, that pose serious individual, familial, and societal burdens. Prevention strategies for OFCs
are elusive because our current understanding of causative factors is inadequate. Epidemiologic and
traditional genetic studies have shown that OFCs are etiologically complex outcomes that result from
multifactorial genetic and environmental influences. Epigenetic mechanisms are an exciting new focus in
understanding the genesis of OFCs because they mediate the effect of environmental influences on the genome
during sensitive embryonic periods. This proposal specifically focuses on DNA methylation because this
epigenetic mechanism is environmentally sensitive and a practical target of prevention and therapeutic
strategies. While implicated by multiple lines of evidence, the biological role of DNA methylation in orofacial
development is unclear. We have established novel models and generated key proofs of concepts that poise us
to uncover how DNA methylation regulates orofacial morphogenesis and to define the role that DNA
methylation plays in modulating OFC susceptibility. We will apply integrated genome-wide methylation and
bulk and single-cell transcriptome approaches to a novel mouse model in which OFCs result from disruption of
DNA methylation in the cranial neural crest. We will also define the role of DNA methylation in multifactorial
OFC susceptibility by integrating multiple environmental and dietary modulators of DNA methylation to
genetic (Wnt9b KO) and chemical (Shh antagonist) mouse models of incompletely penetrant OFCs. Pursuit of
the proposed studies will bring fundamental insight into how DNA methylation regulates cranial neural crest
biology and orofacial morphogenesis and provide a critical foundation for future work interrogating the role of
specific methylation events. Completion of these studies will also define environmental- and dietary-mediated
methylome-transcriptome responses that alter OFC susceptibility and set the stage for definition of additional
environmental influences that modulate DNA methylation and contribute to OFC risk. Pursing this line of
investigation will advance our long-term goal of developing prevention strategies for etiologically complex birth
defects by identifying culpable environmental influences and defining their mechanisms of action.

## Key facts

- **NIH application ID:** 10667252
- **Project number:** 1R56DE030917-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Robert Lipinski
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $438,352
- **Award type:** 1
- **Project period:** 2022-08-03 → 2024-08-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10667252

## Citation

> US National Institutes of Health, RePORTER application 10667252, DNA methylation in orofacial clefting (1R56DE030917-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10667252. Licensed CC0.

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