Individuals with Down Syndrome are known to be at risk for a number of adverse health conditions, including dementia, leukemia, Type 1 diabetes, and congenital heart disease. Evidence suggests many of these adverse conditions are due to abnormal regulation of the pool of RNA within various cell types and during development. However, the details of how RNA regulation is being altered are not well understood. It is not clear if transcription rates, RNA degradation rates, or both are being altered. Furthermore, it is unclear which genes are experiencing this abnormal behavior. Our objective is to identify these genes and quantify the degree to which their transcription and degradation rates are altered by trisomy. Cognitive defects and early dementia are common in Down syndrome, so we focus on the development of neurons and how this process is regulated. To do so, we have developed a method of calculating RNA degradation rates using two different sequencing measurements, collected simultaneously. One sequencing assay (PRO-seq) measure the rate of RNA production, while the other (RNA-seq) measures the total RNA levels in the cell. By collecting times series data of these paired sequencing assays during iPSC differentiation into neural progenitors and applying our model, we can compute the RNA degradation rates for all genes within the transcriptome. For validation and con?rmation, we will also measure RNA degradation rates more directly. By quantifying these RNA regulation processes and comparing them between Down syndrome and typical cell lines, we can help to shed light on the root causes of cognitive defects in Down syndrome.
Individuals with Down Syndrome are at higher risks for many adverse health conditions and evidence suggests many of these conditions are due to abnormal regulation of RNA during development. We have developed a method of quantifying transcription and RNA degradation using a time series of paired sequencing assays, analyzed with a differential model. We apply this method to the development of neural progenitor cells, which we anticipate will help to shed light on the root causes of cognitive defects in Down syndrome.
