NOVEL ROLES OF YY1 IN ASTROCYTES

Astrocytes tile the entire central nervous system, are diverse across brain regions, and perform specialized functions fine-tuned for their neuronal circuit. Initially, astrocyte heterogeneity is generated through intrinsic programs specified by their progenitors. Then, as astrocyte mature, they are specialized by region-specific communication with surrounding cells. The molecular programs that regulate this diversity and allow for the accommodation to the needs of the local environment remains elusive. We explored a ubiquitously expressed zinc finger transcription factor, Yin Yang 1 (YY1), that both activates and represses transcription by regulating loops of active chromatin. This report describes the diverse functions of astrocytic YY1 in the development of the cerebellum, after persistent reactive astrogliosis, and during glioma formation. To start, deletion of YY1 specifically in astrocytes resulted in motor deficits, Bergmann gliosis, and reduced expression of GFAP in velate astrocytes and fibrous astrocytes in the adult cerebellum of mice. Interestingly, we showed through single cell RNA-sequencing that YY1 has specific effects on subpopulations of astrocytes. We established that YY1 is dispensable for the initial stages of astrocyte development but regulates astrocyte maturation through subgroup specific expression profiles. Further, in the adult cerebellum YY1 is continuously needed to maintain astrocyte identity. In the second part of this project, we focused on the effect of persistent reactive astrogliosis in the cerebellum due to the initial loss of astrocytic YY1. We found significant neurodegeneration in the cerebellum in 5-to-6-month-old mice. Additionally, the astrocytes lost the expression of glutamate transporters, which are critical for their function. In the third part of this project, we aimed to determine the role of YY1 on chronic inflammation which drives glioblastoma multiforme progression. After spontaneously generating gliomas in wildtype mice, we surprisingly were unable to generate YY1 deficient tumors, suggesting that YY1 is required for glioma generation. These projects demonstrate the crucial functions of YY1 in astrocytes in both the healthy and diseased brain