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    Single-Nucleus RNA-Seq Reveals Dysregulation of Striatal Cell Identity Due to Huntington's Disease Mutations

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    Author
    Malaiya, Sonia cc
    Cortes-Gutierrez, Marcia
    Herb, Brian R
    Coffey, Sydney R
    Legg, Samuel R W
    Cantle, Jeffrey P
    Colantuoni, Carlo
    Carroll, Jeffrey B
    Ament, Seth A
    Date
    2021-05-19
    Journal
    Journal of Neuroscience : the Official Journal of the Society for Neuroscience
    Publisher
    Society for Neuroscience
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1523/JNEUROSCI.2074-20.2021
    https://www.biorxiv.org/content/10.1101/2020.07.08.192880v1.full.pdf
    Abstract
    Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, Htt Q175/+, and from wild-type controls. We used 14- to 15-month-old male mice, a time point at which multiple behavioral, neuroanatomical, and neurophysiological changes are present but at which there is no known cell death. Thousands of differentially expressed genes (DEGs) were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell type-specific transcriptional networks revealed a striking pattern of bidirectional dysregulation for many cell type-specific genes. Typically, these genes were repressed in their primary cell type, yet de-repressed in other striatal cell types. Integration with existing epigenomic and transcriptomic data suggest that partial loss-of-function of the polycomb repressive complex 2 (PRC2) may underlie many of these transcriptional changes, leading to deficits in the maintenance of cell identity across virtually all cell types in the adult striatum.SIGNIFICANCE STATEMENT Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by specific loss of medium spiny neurons (MSNs) in the striatum, accompanied by more subtle changes in many other cell types. It is thought that changes in transcriptional regulation are an important underlying mechanism, but cell type-specific gene expression changes are not well understood, particularly at time points relevant to the onset of disease-related symptoms. Single-nucleus (sn)RNA-seq in a genetically precise mouse model enabled us to identify novel patterns of transcriptional dysregulation because of HD mutations, including bidirectional dysregulation of many cell type identity genes that may be driven by partial loss-of-function of the polycomb repressive complex (PRC). Identifying these regulators of transcriptional dysregulation in HD can be leveraged to design novel disease-modifying therapeutics.
    Rights/Terms
    Copyright © 2021 the authors.
    Keyword
    Huntington's disease
    gene regulation
    polycomb repressive complex 2
    single-nucleus RNA-seq
    striatum
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/16197
    ae974a485f413a2113503eed53cd6c53
    10.1523/JNEUROSCI.2074-20.2021
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