Divergent transcriptional regulation of astrocyte reactivity across disorders

Joshua E. Burda (), Timothy M. O’Shea, Yan Ao, Keshav B. Suresh, Shinong Wang, Alexander M. Bernstein, Ashu Chandra, Sandeep Deverasetty, Riki Kawaguchi, Jae H. Kim, Sarah McCallum, Alexandra Rogers, Shalaka Wahane and Michael V. Sofroniew ()
Additional contact information
Joshua E. Burda: University of California
Timothy M. O’Shea: University of California
Yan Ao: University of California
Keshav B. Suresh: Cedars-Sinai Medical Center
Shinong Wang: University of California
Alexander M. Bernstein: University of California
Ashu Chandra: University of California Los Angeles
Sandeep Deverasetty: University of California Los Angeles
Riki Kawaguchi: University of California Los Angeles
Jae H. Kim: University of California
Sarah McCallum: Cedars-Sinai Medical Center
Alexandra Rogers: University of California
Shalaka Wahane: University of California
Michael V. Sofroniew: University of California

Nature, 2022, vol. 606, issue 7914, 557-564

Abstract: Abstract Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder1–4. These changes include differentially expressed genes (DEGs) whose contextual diversity and regulation are poorly understood. Here we combined biological and informatic analyses, including RNA sequencing, protein detection, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and conditional gene deletion, to predict transcriptional regulators that differentially control more than 12,000 DEGs that are potentially associated with astrocyte reactivity across diverse central nervous system disorders in mice and humans. DEGs associated with astrocyte reactivity exhibited pronounced heterogeneity across disorders. Transcriptional regulators also exhibited disorder-specific differences, but a core group of 61 transcriptional regulators was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific interactions between transcriptional regulators. Notably, the same reactivity transcriptional regulators can regulate markedly different DEG cohorts in different disorders; changes in the access of transcriptional regulators to DNA-binding motifs differ markedly across disorders; and DEG changes can crucially require multiple reactivity transcriptional regulators. We show that, by modulating reactivity, transcriptional regulators can substantially alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted transcriptional regulators. Our findings show that transcriptional changes associated with astrocyte reactivity are highly heterogeneous and are customized from vast numbers of potential DEGs through context-specific combinatorial transcriptional-regulator interactions.

Date: 2022
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DOI: 10.1038/s41586-022-04739-5

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