Project #2 Integrated single-nucleus multi-omics (ATAC-seq+RNA-seq or chromatin accessibility + RNA-seq) of human TGs

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Migraine is a prevalent primary headache disorder that impacts one out of every four households in the United States. This complex neurologic disorder is mediated in part by alterations in trigeminal somatosensation, which manifests as head and facial pain and/or trigeminal allodynia. Despite its prevalence, there are currently limited effective treatments available for migraine, and our knowledge about human trigeminal system under baseline and migraine conditions are sparse. In response to RFA-NS-22-018, HEAL Initiative: Discovery and Functional Evaluation of Human Pain-associated Genes & Cells, we propose to form the Penn Human Precision Pain Center (Penn HPPC) to focus on elucidating molecular, cellular, epigenetic, and physiolog- ical profiles of human trigeminal ganglion (TG), which contains primary somatosensory neurons governing the head sensation, under baseline and migraine conditions. The Penn HPPC will be composed of Penn and inter- national investigators with multidisciplinary expertise. The PI, two co-PIs, and two co-Is are currently collaborat- ing on a single-soma deep RNA-seq of human dorsal root ganglion (DRG) neuron project, which form a strong foundation for this application. The Penn HPPC will contain three cores and perform three projects. Dr. Hao Wu, an expert in neuroepigenetics and single-cell genomics, will lead project 2 with support from Dr. Mingyao Li, the PI of the data core. This project aims to use two single-nucleus multi-omics assays, including the mas- sively parallel 10x Genomics multiome assay (3’ biased mRNA and open chromatin) and snmCAT-seq (full- length mRNA, open chromatin, and DNA methylation), to comprehensively map transcriptomic and epigenomic (chromatin accessibility and/or DNA methylation) profiles at single-nucleus resolution in control donors and those with migraine. In project 2, Aim 1 will focus on control trigeminal ganglion (TG) tissues, while Aim 2 will focus on TG tissues from "migraine" donors. The anticipated results will produce a comprehensive epigenetic and transcriptomic atlas to understand normal and abnormal trigeminal sensations associated with migraine. This rich resource may also lead to the discovery of new biomarkers for migraine diagnosis and novel potential drug targets for migraine treatment.