Subtle Variations in Expression of Imprinted Genes to Explain Newborn Health Outcomes

Newswise — In the first and largest studies to examine subtle variation of imprinted gene expression and control, investigators from Dartmouth’s Norris Cotton Cancer Center, led by Carmen Marsit, PhD and Jia Chen, Sc.D. of Mt. Sinai School of Medicine, report in two papers published recently in Epigenetics on a subgroup of imprinted genes expressed in the placenta. The papers are, “Expression of imprinted genes in placenta is associated with infant neurobehavioral development,” and “Placental expression profile of imprinted genes impacts birth weight.”

“We asked if it is possible that there is subtle variation in the expression of imprinted genes in a relatively normal, healthy population of infants,” said Marsit. “If there is such variation, our intent was to investigate whether it could explain immediately discernable health outcomes in newborns including birth weight and neurobehavioral functioning.”

Imprinted genes are known to play critical roles in growth control and fetal development, and when these genes exhibit complete inappropriate loss or gain of their imprinting regulation, the affected child presents with severe syndromic conditions often characterized by significant morphological abnormalities, developmental delays, and deficiencies.

The Dartmouth and Mt. Sinai team hypothesized that amongst the general population, there may be subtle variation in the control and expression of imprinted genes and that such variability may contribute to the more widespread, but less dramatic increased risk for various health outcomes. Undertaking the largest and most comprehensive examination of the expression of imprinted genes in any human population, Marsit and colleagues made use of highly sensitive, reproducible new methods to examine the question.

Among the two papers are three main findings:Increases in expression of a group of co-expressed genes, including MEST and NNAT, were associated with birth weight, particularly with weight at the highest 10th decile for gestational age.A group of ten highly correlated genes was identified whose expression pattern was indicative of infants who exhibited poor movement quality, non-optimal reflexes, and increased signs of physiologic stress, providing evidence of their potential role in neurological development.Some data may suggest that DNA methylation of regions beyond the canonical imprinting control regions may be important in controlling subtle variability in expression.

“We are now expanding this profiling to the New Hampshire Birth Cohort, where we will have the opportunity to not only replicate these findings, but to also carefully examine how specific exposures during pregnancy, including to carcinogens like arsenic, may be contributing to this variability in expression,” explained Marsit.

Looking forward, Marsit and colleagues will add whole transcriptome assessments using Next-generation sequencing on approximately 200 of the previous samples. The goal is to capture the allele-specificity of the expression of the imprinted genes, as well as to define and examine gene networks driven by critical imprinted genes with respect to environmental influence and its influence on downstream health.

“In the long term, we will be following children in the New Hampshire cohort to link these expression patterns and long-term childhood health outcomes such as obesity, growth, cardiovascular effects, and neurobehavioral health,” said Marsit.

Carmen Marsit is Associate Professor of Pharmacology and Toxicology and of Epidemiology at Dartmouth’s Geisel School of Medicine. His work in cancer is facilitated by Dartmouth’s Norris Cotton Cancer Center where he is the director of the Cancer Epidemiology Research Program.

Support for this work was provided by National Institutes of Health grant R01 ES022223, R01MH094609, P01 ES022832 and US EPA grant RD83544201.

About Norris Cotton Cancer Center at Dartmouth-Hitchcock Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 45 centers nationwide to earn the National Cancer Institute’s “Comprehensive Cancer Center” designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at cancer.dartmouth.edu.