Sequestration of the transcriptional coactivator CREBbinding protein (CBP), a histone acetyltransferase, has been implicated in the pathogenesis of polyglutamine expansion neurodegenerative disease. We used a Drosophila model to demonstrate that polyglutamine-induced neurodegeneration is accompanied by a defect in histone acetylation and a substantial alteration in the transcription profile. Furthermore, we demonstrate complete functional and morphological rescue by up-regulation of endogenous Drosophila CBP (dCBP). Rescue of the degenerative phenotype is associated with eradication of polyglutamine aggregates, recovery of histone acetylation, and normalization of the transcription profile. These findings suggest that histone acetylation is an early target of polyglutamine toxicity and indicate that transcriptional dysregulation is an important part of the pathogenesis of polyglutamine-induced neurodegeneration.Supplemental material is available at http://www.genesdev.org. Huntington's disease, spinobulbar muscular atrophy, dentatorubro-pallidoluysian atrophy, and six forms of spinocerebellar ataxia are caused by expansion of CAG trinucleotide repeats, resulting in pathological polyglutamine expansion in the disease proteins . These diseases likely share a common mechanism involving a toxic gain of function by the expanded polyglutamine tract. Evidence indicates that the nucleus is an important site of polyglutamine toxicity and that transcriptional dysregulation may be a primary pathogenic process in polyglutamine disease (Klement et al. 1998;Saudou et al. 1998;Lin et al. 2000; Luthi-Carther et al. 2000). Mutant proteins with expanded polyglutamine have been shown to bind and sequester the transcriptional coactivator CREB-binding protein (CBP) in cell culture, animal models, and tissue derived from patients with these diseases (McCampbell et al. 2000;Steffan et al. 2000;Nucifora et al. 2001). Physical interaction between CBP and mutant protein has been found to depend on the acetyltransferase domain of the former and the polyglutamine tract of the latter . Sequestration of CBP results in reduced acetyltransferase activity and loss of CBP-mediated coactivation in cell culture models of polyglutamine disease (McCampbell et al. 2000;Nucifora et al. 2001;Steffan et al. 2001). Live-cell dynamic imaging showed that coexpression of GFP-CBP with various proteins with polyglutamine expansions in cell cultures results in not merely colocalization, but functional sequestration of CBP in polyglutamine inclusions (Chai et al. 2002). CBP is an important cofactor in transcriptional activation mediated by CREB (Chrivia et al. 1993). A recent report demonstrates that disruption of CREB function leads to progressive neurodegeneration in a pattern similar to that observed in transgenic mouse models of polyglutamine disease (Mantamadiotis et al. 2002). CBP also serves as a cofactor for other transcription factors in addition to CREB, but this finding indicates that disruption of the CREB pathway alone is sufficient to lead to neu...

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Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods1. Here we applied multiple single-cell and single-nucleus assays (>400,000 nuclei or cells) and spatial imaging technologies to a broad spectrum of healthy reference kidneys (45 donors) and diseased kidneys (48 patients). This has provided a high-resolution cellular atlas of 51 main cell types, which include rare and previously undescribed cell populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors and spatial localizations spanning the entire kidney. We also define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive (successful or maladaptive repair), transitioning and degenerative states. Molecular signatures permitted the localization of these states within injury neighbourhoods using spatial transcriptomics, while large-scale 3D imaging analysis (around 1.2 million neighbourhoods) provided corresponding linkages to active immune responses. These analyses defined biological pathways that are relevant to injury time-course and niches, including signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function. This integrated multimodal spatial cell atlas of healthy and diseased human kidneys represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations.