Understanding epigenetic factors involved in complex disorders.
Understanding epigenetic factors involved in complex disorders.
DNA methylation plays a vital role in the regulation of gene expression and other cellular processes. Numerous studies have found links between abnormal patterns of methylation and certain human diseases. We are interested in assessing the effect of altered methylation on key genes involved in complex diseases, including obesity and Alzheimer’s disease. We have developed a method that can effectively integrate viral vectors into the genome to stably express a mutated form of CRISPR/Cas9 (dCas9-DNMT3A and guide RNA). This system allows us to methylate specific loci throughout the genome. We have integrated this dCas9 system into stem cells derived from healthy controls and patients with Alzheimer’s disease and have shown altered methylation patterns throughout differentiation into neurons, which may impact key processes involved in Alzheimer’s disease. We are currently expanding our work to include the CRISPRon/CRISPRoff system to allow for more tightly regulated inducible methylation changes.
ADD STEMCELLS OR CRISPR IMAGE
There is substantive evidence that risk for neuropsychiatric diseases may begin during neural development, and epigenetic mechanisms likely drive this risk. We are interested in the effect of hydroxymethylation on disease risk, due to its integral role in early neural development and high specificity within the developing and adult brain. We have generated preliminary data that suggests hydroxymethylation signatures, in known neuropsychiatric-related genes, are altered during neural differentiation, and that hydroxymethylation patterns may differ between iPSC-derived neuronal cells of adolescents with bipolar I disorder, and their unaffected siblings. We are interested in exploring this relationship more thoroughly using iPSC-derived cortical organoids to assess hydroxymethylation changes associated with neurodevelopment and bipolar disorder disease risk.
Age-related neurodegenerative disorders like Alzheimer’s disease affect millions worldwide and pose a major burden to the healthcare system. Neuronal and non-neuronal cells play an important role in disease progression and epigenetic modifications, such as DNA methylation, are known contributors to both healthy aging and neurodegeneration. While iPSC-derived models of AD provide valuable insight into the molecular basis for the disease, they lack the inherent ability to recapitulate age-associated DNA methylation, transcription, and cellular phenotypes that are highly relevant in such late-stage, age-associated brain disorders. Direct conversion of fibroblasts to neurons retains such age-associated methylomic and transcriptomic patterns. Our lab is trying to extend such work by developing an efficient direct conversion strategy for astrocytes and other non-neuronal cells. We plan to use this model to further elucidate the association of age and disease-related changes in DNA methylation to astrocyte functionality.
Our lab has identified epigenome-wide DNA methylation changes associated with metabolic syndrome and its components (i.e., diabetes, obesity, dyslipidemia and hypertension) in a large Mexican American cohort. We identified CpG sites whose methylation profiles were heritable, associated with age and sex, and associated with several metabolic phenotypes. We confirmed differential methylation in several genes implicated in other (predominantly European American) cohorts, as well as identified novel associations. In a subset of individuals, for whom we have DNA methylation data at two time points, we determined that longitudinal DNA methylation changes within TXNIP were associated with increased fasting glucose levels and development of diabetes. We are now continuing this longitudinal assessment of DNA methylation to understand the role of DNA methylation at five target regions over four time points spanning 20 years.
We are also studying the contribution of DNA methylation to obesity and energy expenditure in a childhood cohort of Mexican Americans. We are using MethylSeq to investigate the role of DNA methylation signatures in obesity, energy expenditure, and substrate utilization. Findings from this study will be further validated using epigenetic editing techniques to understand the functional role of such DNA methylation changes on mitochondrial function and cellular bioenergetics.
Researchers have shown that expression levels of certain miRNAs are altered in many diseases. Furthermore, miRNAs can be found in the blood and other peripheral body fluids which are relatively easy tissues to collect from patients. These factors make miRNAs ideally suited as potential biomarkers of certain diseases. Our lab is investigating the associations between blood-based miRNA expression profiles and neuroanatomical and neurocognitive phenotypes in a large family-based cohort of Mexican Americans. Our preliminary data highlights the heritability of miRNA expression and has identified several miRNAs associated with structural variation in brain regions important for neuropsychiatric diseases. Our work in this area has also spawned a number of collaborations, investigating the role of miRNAs in bipolar disorder, schizophrenia, and post-traumatic stress disorder. In addition, we are working with a non-human primate model (baboons) to assess neuroanatomical variation through MRI, examine associations with peripheral miRNA biomarkers, and define correlations between peripheral and brain miRNA expression profiles. Overall, our goal is to better define peripheral miRNA biomarkers that may also have implications for brain pathology.