Epigenetic determinants in oligodendrocyte maturation in Down Syndrome

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Abstract Down Syndrome (DS) or trisomy 21 is caused by triplication of human chromosome 21 (HSA21), and it is the most common cause of intellectual disability. Triplication of HSA21 includes genes that are involved in cognition and brain function, as well as myelin production, and exerts global changes in the transcriptomic and epigenetic landscape in DS. Previous work on humans with DS and DS-mouse models have shown altered expression of myelin-related genes, as well as delayed OL maturation and disruption in myelin production, structure, and density. These changes, attributed partially to triplication of oligodendrocyte lineage transcription factors 1/2 (OLIG1/2), result in impaired myelination and abnormal neuronal conductivity, contributing to the intellectual deficits associated with DS. In addition to changes in the gene content caused by HSA21 triplication, there are well-recognized DS-related alterations of normal epigenetic landscape across the genome. These DS- related epigenetic changes can in turn influence myelination, because commitment and development of oligodendrocyte (OL) lineage is tightly regulated through the stage-dependent acquisition of repressive chromatin changes. In this project, we will provide the first examination of how changes in the epigenetic machinery alter OL biology in DS using human patient-derived induced pluripotent stem (iPS) cells. We will use a newly described 3D cellular model of OL spheroids (OLS) that contain oligodendrocyte, astrocyte, and neuronal populations, to provide a comprehensive, dynamic environment for studying myelination processes. Using this system, we will fully characterize changes in OL lineage commitment and development in human DS-derived isogenic lines and examine how these alterations are driven by changes in the epigenetic code regulating OL specification. Using fate- and differentiation-specific markers, we will fully characterize the generation and temporal development of OL lineage through the different maturational checkpoints, as well as the diversity of other constituent cell populations (including neurons and astrocytes) in trisomic and euploid OLS. Next, we will determine how the DS-associated epigenetic landscape shapes OL developmental and functional trajectory. We will reveal transcriptional dynamics and accessibility of chromatin in a variety of cellular populations developing within euploid and trisomic OLS using the Chromium Single Cell Multiome ATAC+Gene expression platform (10xGenomics), which combines RNA-seq and ATAC-seq profiling on the same population of cells. This will be the first study to directly link transcriptional changes in myelin-producing cells to the altered epigenomic circuitry in DS. Understanding the epigenetic mechanisms underlying the developmental vulnerability of these cells will point to novel therapeutic approaches that combine potential epidrugs and myelination-targeting approaches.