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Cited by 164Neuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology ResearchGenomics and Chromatin Dynamics

Divergent transcriptional regulation of astrocyte reactivity across disorders

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Burda, Joshua E., O’Shea, Timothy M., Ao, Yan, Suresh, Keshav B., Wang, Shinong, Bernstein, Alexander M., Chandra, Ashu, Deverasetty, Sandeep +6 more·2022·Nature
DOI 10.1038/s41586-022-04739-5PMC PMC10027402
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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.

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Cited by

Sorted by citations

Authors
Burda, J. E., O’Shea, T. M., Ao, Y., Suresh, K. B., Wang, S., Bernstein, A. M., Chandra, A., Deverasetty, S., Kawaguchi, R., Kim, J. H., McCallum, S., Rogers, A., Wahane, S., & Sofroniew, M. V.
Affiliations
  • Cedars-Sinai Medical Center (US)
  • University of California, Los Angeles (US)
Corresponding author
  • Burda, Joshua E.
  • Sofroniew, Michael V.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2022-05-25
Volume
606
Issue
7914
Pages
557-564
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-022-04739-5
PMC
PMC10027402
OpenAlex
W4281488487
Cited by
164
References
13
Citations by year
2026: 31 · 2025: 39 · 2024: 47 · 2023: 34 · 2022: 13
FWCI
11.61
Type
journal article
Language
en
Update notices
correction (2023-03-28)
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (K99NS105915, R00NS105915, F32NS096858, R01NS084030)
  • Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103557)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
astrocyte activation, transcriptional regulation, transcription factors, differentially expressed genes, central nervous system disorders, combinatorial gene regulation, DNA-binding motifs, disease heterogeneity, therapeutic target, human-mouse comparison
MeSH terms
Animals, Astrocytes, Central Nervous System Diseases, Chromatin, Gene Expression Regulation, Humans, Transcription Factors, Transcription, Genetic, Sequence Analysis, RNA, Mice, High-Throughput Nucleotide Sequencing

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