Divergent transcriptional regulation of astrocyte reactivity across disorders.
Publication Year:
2022
PubMed ID:
35614216
Funding Grants:
Public Summary:
This study explores how astrocytes—supportive brain cells that help maintain healthy brain function—react to different types of brain injury and disease. When the brain is damaged or diseased, astrocytes become “reactive”, changing their gene activity in ways that can either help or harm recovery. Using a combination of large-scale genetic and protein analyses in both mice and humans, researchers examined over 12,000 genes whose activity changes during astrocyte reactivity and identified the transcriptional regulators (TRs)—proteins that control gene expression—responsible for these changes. They found that the patterns of gene activation and the TRs involved differ widely across disorders, but a shared core of 61 regulators appears in many conditions. The study shows that astrocyte responses are shaped by complex, context-dependent interactions among multiple TRs, meaning the same regulators can control different genes depending on the disease context. Importantly, altering these regulators can change how diseases progress, suggesting they may be promising therapeutic targets. The authors also provide searchable datasets linking reactive genes and their predicted regulators across various brain disorders.
Scientific Abstract:
Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder(1-4). 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.