Show simple item record

dc.contributor.authorMalaiya, Sonia
dc.contributor.authorCortes-Gutierrez, Marcia
dc.contributor.authorHerb, Brian R
dc.contributor.authorCoffey, Sydney R
dc.contributor.authorLegg, Samuel R W
dc.contributor.authorCantle, Jeffrey P
dc.contributor.authorColantuoni, Carlo
dc.contributor.authorCarroll, Jeffrey B
dc.contributor.authorAment, Seth A
dc.date.accessioned2021-07-16T13:08:41Z
dc.date.available2021-07-16T13:08:41Z
dc.date.issued2021-05-19
dc.identifier.urihttp://hdl.handle.net/10713/16197
dc.description.abstractHuntington'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.en_US
dc.description.urihttps://doi.org/10.1523/JNEUROSCI.2074-20.2021en_US
dc.description.urihttps://www.biorxiv.org/content/10.1101/2020.07.08.192880v1.full.pdfen_US
dc.language.isoenen_US
dc.publisherSociety for Neuroscienceen_US
dc.relation.ispartofJournal of Neuroscience : the Official Journal of the Society for Neuroscienceen_US
dc.rightsCopyright © 2021 the authors.en_US
dc.subjectHuntington's diseaseen_US
dc.subjectgene regulationen_US
dc.subjectpolycomb repressive complex 2en_US
dc.subjectsingle-nucleus RNA-seqen_US
dc.subjectstriatumen_US
dc.titleSingle-Nucleus RNA-Seq Reveals Dysregulation of Striatal Cell Identity Due to Huntington's Disease Mutationsen_US
dc.typeArticleen_US
dc.identifier.doi10.1523/JNEUROSCI.2074-20.2021
dc.identifier.pmid34011527
dc.source.volume41
dc.source.issue25
dc.source.beginpage5534
dc.source.endpage5552
dc.source.countryUnited States


This item appears in the following Collection(s)

Show simple item record