Aline Petrin, assistant professor at the University of Iowa College of Dentistry, has received a National Institutes of Health (NIH) award to advance understanding of the biological mechanisms underlying nonsyndromic orofacial clefts, the most common craniofacial birth defect worldwide.

Orofacial clefts affect approximately 1 in 700 individuals and require extensive, often lifelong care that may include surgical, dental, speech, nutritional, and behavioral interventions. Although researchers have identified more than 60 genetic risk loci associated with these conditions, much of the underlying risk remains unexplained. Recent evidence suggests that epigenetic factors, particularly DNA methylation, may play an important role in cleft development and severity. 

Dr. Petrin's NIH-funded project will focus on understanding how genetic variation influences DNA methylation and gene expression during craniofacial development. Her team hypothesizes that specific genetic variants known as methylation quantitative trait loci (meQTLs) alter DNA methylation at critical genomic sites, ultimately affecting the expression of genes involved in facial development and increasing the risk of orofacial clefts.

The project builds on the Petrin laboratory's previous identification and replication of nine cleft-associated meQTLs in large study populations. Using advanced CRISPR-based gene-editing approaches, researchers will investigate how these genetic variants influence DNA methylation and downstream gene activity in both established craniofacial cell models and patient-derived tissues. The team has also established a unique collection of patient samples, including tissues obtained during surgical procedures, which will strengthen the clinical relevance of the research findings.

The study includes two primary objectives. First, researchers will determine whether specific meQTL variants directly alter DNA methylation patterns. Second, they will evaluate how changes in DNA methylation affect gene expression and cellular behaviors important for craniofacial development, including cell migration, proliferation, and differentiation. 

According to the project summary, the research is designed to address a critical gap in understanding how genetic and epigenetic factors interact to contribute to orofacial clefts. By functionally validating these mechanisms, the study has the potential to explain the biological significance of genetic variants that have been linked to cleft risk but whose roles remain unclear.

Ultimately, the findings could help bridge the gap between genetic discoveries and clinical applications. Improved understanding of the molecular pathways involved in cleft development may support future advances in risk assessment, prevention strategies, genetic counseling, and targeted therapeutic approaches for affected individuals and families. The project is also expected to provide a foundation for larger future studies of gene-epigenome networks involved in craniofacial development.

Dr. Petrin's research program focuses on the genetics and epigenetics of craniofacial birth defects, with particular emphasis on nonsyndromic cleft lip and palate. Her work seeks to better understand how genetic and epigenetic factors contribute to the development of these conditions and how that knowledge can ultimately improve patient care.

Research reported in this publication is supported by the National Institute of Dental and Craniofacial Research of the National Institutes of Health under Award Number 1R03DE035519-01A1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.