Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin
- Sorbonne Université, Centre National de la Recherche Scientifique UMR 8256, INSERM ERL U1164, France
- Sorbonne Université, Centre National de la Recherche Scientifique, Laboratoire Jacques-Louis Lyons (LJLL), France
- MIT, Broad Institute, MIT, Picower Institute for Learning and Memory, United States
- CHDI Foundation, United States
Figures
Figure 1 with 4 supplements
Application of shape deformation concepts to the detection of molecular responses in the striatum of Huntington’s disease (HD) knock-in model mice.
The Geomic protocol integrates three main steps for the integration of transcriptomic and cell survival data into a model that distinguishes the nature and temporal evolution of gene deregulation …
Figure 1—figure supplement 1
Shape deformation principle applied to the comparison of curves defined by genomic data.
This figure illustrates the shape deformation principle, applied to the comparison of curves defined by genomic data, that to map the blue curve onto the red curve (left panel), only one deformation …
Figure 1—figure supplement 2
Cumulative distribution of the deformation distances between gene deregulation curves in the striatum of Hdh model mice.
This figure shows that the data-driven threshold (see Materials and methods) used for matching the whole-striatum gene deregulation curves to the cell-type-specific curves, that is, a threshold …
Figure 1—figure supplement 3
Centroids of the gene deregulation surface clusters associated with specific cell types in the striatum of Hdh model mice.
This figure is related to step 2 in Figure 1.
Figure 1—figure supplement 4
Validation studies of the cost distance for clustering gene expression surfaces.
Shown are the two types of simulation performed, each simulation involving three simulation profiles (SPs), where each profile contains 50 toy surfaces that resemble the reference surface associated …
Figure 2
Mapping of whole-striatum gene deregulation surfaces to striatal cell types in Huntington’s disease (HD) knock-in model mice.
Geomic analysis of whole-striatum and cell-type-specific RNA-seq data using gene deregulation curves at 6 months of age (see Figure 1) attributed a total of 1390 whole-striatum gene deregulation …
Figure 3 with 1 supplement
Networks associated with the most frequent temporal subtypes of molecular responses in the Drd1-expressing neurons of Huntington’s disease (HD) knock-in model mice.
Network representations of the most frequent subtypes (i.e., increased-then-reduced responses) of molecular responses that developed in Drd1-expressing neurons in the striatum of Hdh model mice. The …
Figure 3—figure supplement 1
Networks associated with the most frequent temporal subtypes of molecular responses in the astrocytes of Hdh model mice.
Network representations of the most frequent subtypes (i.e., increased-then-reduced responses) of molecular responses developed by astrocytes in the striatum of Hdh model mice. The genes retained in …
Figure 4
Comparison of molecular responses in the striatum of Hdh model mice to Huntington’s disease (HD) datasets.
Overlaps between the molecular responses identified by Geomic analysis in the striatum of Hdh model mice and other HD datasets. We performed these comparisons for the genes implicated in molecular …
Additional files
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Supplementary file 1
List of genes for which the whole-striatum gene deregulation in Hdh model mice is assigned to a specific cell type with false discovery rate (FDR) < 0.1.
Cellular assignments are based on matching whole-striatum gene expression dysregulation curves to cell-type-specific gene expression dysregulation curves in the striatum of Hdh model mice at 6 months of age using the cost distance, after linear interpolation (see Figure 1: step 1). Data are shown for each cell type with indication of p-values and FDR values.
- https://cdn.elifesciences.org/articles/64984/elife-64984-supp1-v1.xlsx
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Supplementary file 2
List of genes recruited in the clusters of gene deregulation surfaces and their centroids.
Data are shown for each striatal cell type in Hdh model mice. Top biological annotations (KEGG pathways and gene ontology biological processes upon STRING database analysis; see Materials and methods) are also indicated for each gene deregulation surface cluster and each cell type.
- https://cdn.elifesciences.org/articles/64984/elife-64984-supp2-v1.xlsx
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Supplementary file 3
List of genes underlying the molecular responses defined by the integration of cluster centroid data and in vivo functional data in the striatum of Hdh model mice.
Data are shown for compensatory responses and for pathogenic responses, with indication of the evolution (increased then maintained, increased then reduced, transition) over time. The three columns labeled ‘Information on cellular assignment’ provides the cell type(s) to which gene deregulation in the whole striatum at 6 months is attributed, the weighted distance between whole-striatum and cell-type-specific log-fold-change (LFC) curves, and the false discovery rate (FDR) for the cellular assignments of gene deregulation. The six columns labeled ‘Information on molecular response in Q175 mice’ provide information on the functional effect of shRNA treatment (p-value and rank), the identity number of the gene deregulation surface (GDS) centroid to which the gene belongs, temporal subtype of molecular response, strength of mitigation (if applicable), and maximum deregulation of gene expression across age points.
- https://cdn.elifesciences.org/articles/64984/elife-64984-supp3-v1.xlsx
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Transparent reporting form
- https://cdn.elifesciences.org/articles/64984/elife-64984-transrepform-v1.docx
