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Divergent transcriptional regulation of astrocyte reactivity across disorders

Author

Listed:
  • Joshua E. Burda

    (University of California
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Timothy M. O’Shea

    (University of California)

  • Yan Ao

    (University of California)

  • Keshav B. Suresh

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    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
    University of California Los Angeles)

  • Riki Kawaguchi

    (University of California Los Angeles
    University of California Los Angeles)

  • Jae H. Kim

    (University of California)

  • Sarah McCallum

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Alexandra Rogers

    (University of California)

  • Shalaka Wahane

    (University of California)

  • Michael V. Sofroniew

    (University of California)

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.

Suggested Citation

  • 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 , 2022. "Divergent transcriptional regulation of astrocyte reactivity across disorders," Nature, Nature, vol. 606(7914), pages 557-564, June.
  • Handle: RePEc:nat:nature:v:606:y:2022:i:7914:d:10.1038_s41586-022-04739-5
    DOI: 10.1038/s41586-022-04739-5
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    Citations

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    Cited by:

    1. Noriko Itoh & Yuichiro Itoh & Cassandra E. Meyer & Timothy Takazo Suen & Diego Cortez-Delgado & Michelle Rivera Lomeli & Sophia Wendin & Sri Sanjana Somepalli & Lisa C. Golden & Allan MacKenzie-Graham, 2023. "Estrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Hyosung Kim & Kun Leng & Jinhee Park & Alexander G. Sorets & Suil Kim & Alena Shostak & Rebecca J. Embalabala & Kate Mlouk & Ketaki A. Katdare & Indigo V. L. Rose & Sarah M. Sturgeon & Emma H. Neal & , 2022. "Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. T. M. O’Shea & Y. Ao & S. Wang & A. L. Wollenberg & J. H. Kim & R. A. Ramos Espinoza & A. Czechanski & L. G. Reinholdt & T. J. Deming & M. V. Sofroniew, 2022. "Lesion environments direct transplanted neural progenitors towards a wound repair astroglial phenotype in mice," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    4. Eiji Shigetomi & Hideaki Suzuki & Yukiho J. Hirayama & Fumikazu Sano & Yuki Nagai & Kohei Yoshihara & Keisuke Koga & Toru Tateoka & Hideyuki Yoshioka & Youichi Shinozaki & Hiroyuki Kinouchi & Kenji F., 2024. "Disease-relevant upregulation of P2Y1 receptor in astrocytes enhances neuronal excitability via IGFBP2," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    5. Amy J. Gleichman & Riki Kawaguchi & Michael V. Sofroniew & S. Thomas Carmichael, 2023. "A toolbox of astrocyte-specific, serotype-independent adeno-associated viral vectors using microRNA targeting sequences," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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