Overview
The goal of the Cowley Lab is to understand how the developmental environment impacts the epigenetic regulation of the genome and disrupts molecular processes to program metabolic disease susceptibility in later life.
We use mouse and cell-based models of environmental stress in combination with genetic tools, targeted and whole genome approaches, and bioinformatic analyses to understand the molecular basis of environmentally-induced disease.
A primary focus of the lab is the role of genomic imprinting in connecting the developmental environment to metabolic disease. We propose that these genes play important roles in this process for three reasons:
We use mouse and cell-based models of environmental stress in combination with genetic tools, targeted and whole genome approaches, and bioinformatic analyses to understand the molecular basis of environmentally-induced disease.
A primary focus of the lab is the role of genomic imprinting in connecting the developmental environment to metabolic disease. We propose that these genes play important roles in this process for three reasons:
- The unique epigenetic mechanisms at Imprinting Control Regions (ICRs), which regulate imprinted gene expression, are particularly susceptible to perturbation by the environment in development;
- Once established, the epigenetic profiles at ICRs persist throughout life providing a long-term memory of the developmental environment;
- Imprinted genes play critical roles in regulating metabolism in adulthood.
Project themes
Genomic imprinting in liver diseaseMetabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease. The prevalence of MASLD in the pediatric and adolescent populations is increasing, suggesting that environmental factors during development play a role in disease etiology. The nature of these stressors and the mechanisms through which they promote MASLD are not well understood, creating a barrier to identifying pathways and targets for therapeutic intervention.
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We have used mouse models to demonstrate that adverse developmental environments can be sufficient to induce MASLD in young animals. Leveraging these models in combination with in vitro and in vivo manipulations, we have identified the imprinted gene Zac1 (also called Plagl1) as a key mediator in this process. Our ongoing work is identifying the cellular mechanisms through which activation of Zac1 and other imprinted genes drives MASLD, as well as determining the epigenetic basis for their dysregulation by adverse developmental environments.
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Over-expression of Zac1 in hepatocytes in vivo activates neighboring heaptic stellate cells (HSCs), the major drivers of hepatic fibrosis. These data suggest that Zac1-expressing hepatocytes release factors that drive tissue remodeling, a hallmark of MASLD.
Zac1 or eGFP (control) were over-expressed in hepatocytes using AAV8 and a hepatocyte-specific promoter. The images show immunofluorescence for ZAC1 (using a FLAG tag), CK8/18 (hepatocyte marker) and alpha-SMA (activated HSC marker). ZAC1 expression in hepatocytes causes activation of HSCs, indicated by increased alpha-SMA, that drive fibrosis and tissue remodeling. From Baptissart et al, 2022, Hepatology, 76(4):1090. |
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Epigenetic and molecular mechanisms of disease from early life cadmium exposureCadmium (Cd) is a ubiquitous environmental pollutant and one of the top ten chemicals of major public health concern. Exposure during development impacts fetal growth and the health of multiple organ systems in later life. By understanding the epigenetic and molecular mechanisms that drive adverse outcomes in response to developmental Cd exposure, we hope to identify pathways that could be targeted to mitigate its effects.
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Through integrating data from unbiased high-throughput screens (transcriptomics, methylomics, proteomics, metabolomics) with targeted assays and genetic manipulations in mouse models, we have identified novel pathways that respond to Cd to drive fetal growth restriction, liver disease, and neurodevelopmental outcomes. Based on our findings, we proposed that many of the effects of developmental Cd exposure are driven by iron (Fe) deficiency. We recently demonstrated that dietary Fe supplementation can substantially lessen - and even completely rescue - the effects of Cd exposure.
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Dietary Fe supplementation protects against growth restriction and MASLD in mice exposed to Cd during development.
Dams were provided water and normal chow, or water with Cd in combination with normal chow or chow fortified with 2x or 5x Fe. Offspring of mice exposed to Cd alone developed iron deficiency (ID), ID anemia (IDA), restricted growth, and signatures of MASLD. These outcomes were largely rescued by supplemental dietary Fe. From Lichtler et al, 2025, FASEB BioAdvances, in press. |
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Molecular mechanisms of environmentally-induced placental dysfunction
As the interface between the mother and fetus, the placenta plays a critical role in regulating fetal growth and life long health. We aim to understand how placental structure and function are perturbed by adverse early life environments and to identify the underlying molecular mechanisms.
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Much of our work in this area has focused on developmental exposure to Cd which causes fetal growth restriction. Using mouse and cell culture models, we have shown that Cd exposure changes placental structure. We have used unbiased genome-wide approaches and targeted analyses to identify the underlying mechanisms. Through this work, we have identified a long non-coding RNA called Tuna that is activated by Cd to promote NRF2-mediated oxidative stress in the placenta. We propose that Tuna is an important regulator of the placental response to Cd and could potentially be targeted to mitigate the effects of exposure.
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Cd exposure alters placental structure.
Dams were exposed to 0 or 50 ppm cadmium chloride in drinking water. At e18.5, placentas were isolated and analyzed. Cd exposure increases the ratio of labyrinth to junctional zone, potentially impacting placental endocrine function and nutrient exchange with the fetus. From Simmers et al, 2023, Epigenetics 18:2088173. |
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