Epigenetic control of region-specific transcriptional programs in mouse cerebellar and cortical astrocytes

Astrocytes from cortex (CTX) and cerebellum (CB) share basic molecular programs, but also form distinct spatial and functional subtypes. The regulatory basis for their regional diversity has not been systematically investigated in detail so far. Here, we present comprehensive integrated analyses of transcriptomes, methylomes and open chromatin sites of two astroglia populations isolated from the cortex or cerebellum of young adult mice. Besides shared astrocyte specific epigenetic programs we detect strong epigenetic differences which are most pronounced in a 12-fold increase of open chromatin sites in CTX astrocytes in comparison to astrocytes of the cerebellum. Integrated analyses reveal local epigenetic signatures that are linked to differences in transcriptional programs. Among the differentially regulated genes we identify extensive region-specific transcription factor networks centered around Lhx2/Foxg1 in CTX astrocytes and the Zic/Irx families in CB astrocytes. The combination of epigenetic signatures within the networks suggests a reciprocal and combinatorial regulation of these region-specific transcription factors. Noteworthy, these distinct epigenetically primed networks include transcription factors previously linked to temporal, regional, and spatial control of neurogenesis. Our study provides a valuable resource for understanding the molecular basis in the establishment and maintenance of regional astrocyte identity and therefore provides a perspective on a better understanding of astrocyte physiology and their regional functions