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Leo, a rising junior at Dickinson College studying neuroscience and psychology, investigated how human astrocytes are affected by a heterozygous, loss-of-function mutation in SETD1A, an epigenetic regulator.

SETD1A is a major epigenetic regulator, controlling gene expression particularly of neurodevelopment-associated genes. A rare heterozygous loss-of-function SETD1A variant is associated with a greater risk for schizophrenia (SCZ). SETD1A is also involved with cell proliferation by protecting fork degradation during mitosis, as well as resistance to oxidative stress. However, the functional effects of the mutation are not well-studied in human astrocytes, which highly express SETD1A.

The Ó³»­´«Ã½ Summer Research Program truly changed my life. Surrounded by a supportive cohort of other undergraduate students, I developed my abilities in leadership, science communication, and research. I gained several impactful mentors that have shown me how to both learn and teach while challenging me to grow. This program sharpened my research interests in neuroscience, biology, and genetics, as well as community outreach and ethics. I am so honored to have been a part of the BSRP and I will carry on the skills I develop to apply to my future.Our work seeks to characterize a measurable phenotype of human astrocytes carrying a SETD1A mutation. We hypothesize that the mutation will reduce cell proliferation and decrease resilience to stress. We first obtained cells from SCZ patients with the mutation (n = 3) along with age- and sex-matched controls. We differentiated induced pluripotent stem cells into astrocytes, then validated the mutation using RT-qPCR. Finally, we conducted a proliferation assay by exposing cells to 10 µM EdU (5-ethynyl-2'-deoxyuridine) for various timepoints, and an oxidative stress resistance experiment by exposing cells to various concentrations of hydrogen peroxide for 3 hours, followed by a viability assay. Our results showed that two out of three variant cell lines demonstrated low expression of SETD1A, indicating consistency with loss of function. We also found that all variant cell lines showed reduced viability after exposure to stress compared to their controls, and that variant cell lines will show decreased proliferation compared to controls. Identifying a measurable phenotype in human astrocytes carrying the SETD1A mutation strengthens the translational relevance of our in vitro model, bridging cellular findings to patient biology.

Project: Functional Characterization of SETD1A Loss-of-Function in Human iPSC-Derived Astrocytes

Mentor: Diogo Ferri Marques, Stanley Center for Psychiatric Research