Cell type-specific gene regulatory atlas prioritizes drug targets and repurposable medicines in Alzheimer's disease.
The 6 matches
- [1] § Methods › snATAC-seq data quality control, dimensionality reduction, and clustering ↔ snATAC_QC_Clustering.R, lines 1–45 · score 0.75 · Quality control, ArchR, UMAP, fragment, clustering, TSS
- [2] § Methods › Peak calling and annotation ↔ Peak_annotation.R, lines 43–81 · score 0.71 · peakAnnoEnrichment, addMotifAnnotations, motif enrichment, cisBP, peaks
- [3] § Methods › snRNA-seq data quality control, dimensionality reduction, and clustering ↔ Processing4DEG.R, lines 65–111 · score 0.65 · qc metrics, detected genes, snRNA, Outliers
- [4] § Methods › snRNA-seq data quality control, dimensionality reduction, and clustering ↔ snRNA_QC.py, lines 24–34 · score 0.59 · calculate_qc_metrics, Scanpy, ribosomal, mitochondrial, genes
- [5] § Results › Identifying TF–target gene networks involved in AD progression ↔ Peak_annotation.R, lines 177–227 · score 0.55 · Positive TF regulators, TF motifs, genes linked, peaks, score
- [6] § Results › Identifying AD progression–associated targets enriched by cCREs with AD GWAS ↔ fun4p2g.r, lines 40–70 · score 0.52 · bp downstream, kb, promoters, upstream, TSS
Paper
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The authors' code
R · 272 lines · 8.9 KB · no license · 2 matches
- #####################################################################
- # 0. Load libarary and archR proj
- #####################################################################
- library(ArchR)
- library(Seurat)
- library(dplyr)
- library(tidyr)
- library(ComplexHeatmap)
- library(BSgenome.Hsapiens.UCSC.hg38)
- set.seed(1)
- addArchRThreads(threads = 32)
- addArchRGenome("hg38")
- # Define the input path
- atac_dir = "NotAD_out"
- ##########################################################################################
- # 1. Load Previously Prepared ArchR project
- ##########################################################################################
- atac_proj3 <- loadArchRProject(atac_dir, force=TRUE)
- print(colnames(getCellColData(atac_proj3)))
- table(atac_proj3$NamedClust)
- getAvailableMatrices(atac_proj3)
- ##########################################################################################
- # 2. Identifying Marker Peaks with ArchR
- ##########################################################################################
- markersPeaks <- getMarkerFeatures(
- ArchRProj = atac_proj3,
- useMatrix = "PeakMatrix",
- groupBy = "NamedClust",
- bias = c("TSSEnrichment", "log10(nFrags)"),
- testMethod = "wilcoxon"
- )
- markersPeaks
- ## get markers and save it
- markerList_all <- getMarkers(markersPeaks)
- markerList_all
- saveRDS(markerList_all, file = "./marker_peak_all.rds")
- markerList_sig <- getMarkers(markersPeaks, cutOff = "FDR <= 0.05 & Log2FC >= 0.5")
- markerList_sig
- saveRDS(markerList_sig, file = "./marker_peak_sig.rds")
- ##########################################################################################
- # 3. Motif Enrichment
- ##########################################################################################
- atac_proj3 <- addMotifAnnotations(ArchRProj = atac_proj3, motifSet = "cisbp", name = "Motif",force=TRUE)
- ##########################################################################################
- # 3.1 Motif Enrichment in Marker Peaks
- enrichMotifs <- peakAnnoEnrichment(
- seMarker = markersPeaks,
- ArchRProj = atac_proj3,
- peakAnnotation = "Motif",
- cutOff = "FDR <= 0.05 & Log2FC >= 0.5"
- )
- enrichMotifs
- # Plot a different style heatmap
- plot_mat <- plotEnrichHeatmap(enrichMotifs[,column_order], n=5, transpose=FALSE, cutOff=10, returnMatrix=TRUE)
- # Extract top 5 enriched genes for each column
- top_genes <- lapply(1:ncol(plot_mat), function(i) {
- top_indices <- order(plot_mat[, i], decreasing = TRUE)[1:5] # Get indices of top 5 values
- return(rownames(plot_mat)[top_indices]) # Return gene names
- })
- # Create a new matrix with the selected genes in the specific order
- new_mat <- do.call(rbind, lapply(1:length(top_genes), function(i) {
- plot_mat[top_genes[[i]], , drop = FALSE] # Subsetting and maintaining as matrix
- }))
- # Adjust column and row names if needed
- colnames(new_mat) <- colnames(plot_mat)
- # Modify row names by removing characters after "_"
- rownames(new_mat) <- unlist(top_genes) # Flattening the list to set row names
- rownames(new_mat) <- sub("_.*", "", rownames(new_mat))
- saveRDS(new_mat, file = "marker_Topmotif.rds")
- library(ComplexHeatmap)
- library(circlize)
- # Assuming `enrichMotifs` is a matrix or can be converted to one
- pdf("Plots/Motifs-Enriched-Marker-Heatmap_Advanced.pdf",width = 6, height = 8)
- Heatmap(new_mat,
- col = colorRampPalette(c("#E6E7E8", "#3A97FF", "#8816A7","#000436"))(100),
- cluster_rows = FALSE, # Disables clustering of rows
- cluster_columns = FALSE,
- show_row_names = TRUE,
- show_column_names = TRUE,
- name = "Norm.Enrichment -log10(P-adj)[0-Max]", # Sets the legend title
- row_names_side = "left", # Puts row names on the left
- border = TRUE, # Adds a border around the heatmap
- #use_raster = FALSE
- )
- dev.off()
- ##########################################################################################
- # 5. ChromVAR Deviations
- ##########################################################################################
- if("Motif" %ni% names(atac_proj3@peakAnnotation)){
- atac_proj3 <- addMotifAnnotations(ArchRProj = atac_proj3, motifSet = "cisbp", name = "Motif",force = TRUE)
- }
- ## background peaks
- atac_proj3 <- addBgdPeaks(atac_proj3)
- ## compute per-cell deviations accross all of motif annotations
- atac_proj3 <- addDeviationsMatrix(
- ArchRProj = atac_proj3,
- peakAnnotation = "Motif",
- force = TRUE
- )
- ## access these deviations, set plot = TRUE, return a ggplot object
- plotVarDev <- getVarDeviations(atac_proj3, name = "MotifMatrix", plot = TRUE)
- plotVarDev
- plotPDF(plotVarDev, name = "Variable-Motif-Deviation-Scores", width = 5, height = 5, ArchRProj = atac_proj3, addDOC = TRUE)
- # Save project
- saveArchRProject(atac_proj3)
- ##########################################################################################
- # 8. Peak2GeneLinkage
- ##########################################################################################
- atac_proj3 <- addPeak2GeneLinks(
- ArchRProj = atac_proj3,
- reducedDims = "IterativeLSI"
- )
- p2g <- getPeak2GeneLinks(
- ArchRProj = atac_proj3,
- corCutOff = 0.45,
- resolution = 1,
- returnLoops = FALSE
- )
- p2g
- markerGenes <- c(
- "SPIB", "SPI1", "BCL11A", "BCL11B", "SPIC",
- "CTCF","CTCFL","SOX13","SOX9","SOX4",
- "NFIC","NFIX","NFIB","NFIA","ZFX",
- "ZBTB7A","ZNF148","PATZ1",
- "TCF12","NHLH2","ASCL2","ASCL1","TFAP4",
- "JUNB", "JUN","FOSL2","FOS", "JUND"
- )
- p <- plotBrowserTrack(
- ArchRProj = atac_proj3,
- groupBy = "NamedClust",
- geneSymbol = markerGenes,
- upstream = 50000,
- downstream = 50000,
- loops = getPeak2GeneLinks(atac_proj3)
- )
- plotPDF(plotList = p,
- name = "Plot-Tracks-Marker-Genes-with-Peak2GeneLinks.pdf",
- ArchRProj = atac_proj3,
- addDOC = FALSE, width = 5, height = 5)
- ## Plotting a heatmap of peak-to-gene links
- p <- plotPeak2GeneHeatmap(ArchRProj = atac_proj3, groupBy = "NamedClust")
- p
- ggsave("Plots/PlotPeak2GeneHeatmap.pdf")
- ##########################################################################################
- # 9. Identification of Positive TF-Regulators
- ##########################################################################################
- seGroupMotif <- getGroupSE(ArchRProj = atac_proj3, useMatrix = "MotifMatrix", groupBy = "NamedClust")
- seGroupMotif
- seZ <- seGroupMotif[rowData(seGroupMotif)$seqnames=="z",]
- rowData(seZ)$maxDelta <- lapply(seq_len(ncol(seZ)), function(x){
- rowMaxs(assay(seZ) - assay(seZ)[,x])
- }) %>% Reduce("cbind", .) %>% rowMaxs
- corGSM_MM <- correlateMatrices(
- ArchRProj = atac_proj3,
- useMatrix1 = "GeneScoreMatrix",
- useMatrix2 = "MotifMatrix",
- reducedDims = "IterativeLSI"
- )
- corGSM_MM
- corGSM_MM$maxDelta <- rowData(seZ)[match(corGSM_MM$MotifMatrix_name, rowData(seZ)$name), "maxDelta"]
- corGSM_MM <- corGSM_MM[order(abs(corGSM_MM$cor), decreasing = TRUE), ]
- corGSM_MM <- corGSM_MM[which(!duplicated(gsub("\\-.*","",corGSM_MM[,"MotifMatrix_name"]))), ]
- corGSM_MM$TFRegulator <- "NO"
- corGSM_MM$TFRegulator[which(corGSM_MM$cor > 0.5 & corGSM_MM$padj < 0.01 & corGSM_MM$maxDelta > quantile(corGSM_MM$maxDelta, 0.75))] <- "YES"
- sort(corGSM_MM[corGSM_MM$TFRegulator=="YES",1])
- p <- ggplot(data.frame(corGSM_MM), aes(cor, maxDelta, color = TFRegulator)) +
- geom_point() +
- theme_ArchR() +
- geom_vline(xintercept = 0, lty = "dashed") +
- scale_color_manual(values = c("NO"="darkgrey", "YES"="firebrick3")) +
- xlab("Correlation To Gene Score") +
- ylab("Max TF Motif Delta") +
- scale_y_continuous(
- expand = c(0,0),
- limits = c(0, max(corGSM_MM$maxDelta)*1.05)
- )
- p
- library(ggplot2)
- library(ggrepel) # Ensure ggrepel is loaded
- # Your existing plot code
- p <- ggplot(data.frame(corGSM_MM), aes(cor, maxDelta, color = TFRegulator)) +
- geom_point() +
- theme_ArchR() +
- geom_vline(xintercept = 0, lty = "dashed") +
- scale_color_manual(values = c("NO"="darkgrey", "YES"="firebrick3")) +
- xlab("Correlation To Gene Score") +
- ylab("Max TF Motif Delta") +
- scale_y_continuous(
- expand = c(0,0),
- limits = c(0, max(corGSM_MM$maxDelta)*1.05)
- ) +
- geom_text(data = subset(data.frame(corGSM_MM), GeneScoreMatrix_name %in% markerGenes & TFRegulator == "YES"),
- aes(label = GeneScoreMatrix_name), # Use your specific label column here
- vjust = -1) # Adjust text positioning
- ggsave("Plots/Pos_TF_corGSM.pdf")
- p <- ggplot(data.frame(corGSM_MM), aes(cor, maxDelta, color = TFRegulator)) +
- geom_point() +
- theme_ArchR() +
- geom_vline(xintercept = 0, lty = "dashed") +
- scale_color_manual(values = c("NO"="darkgrey", "YES"="firebrick3")) +
- xlab("Correlation To Gene Score") +
- ylab("Max TF Motif Delta") +
- scale_y_continuous(
- expand = c(0,0),
- limits = c(0, max(corGSM_MM$maxDelta)*1.05)
- )
- # Filtering and sorting for the text labels
- top_labels <- as.data.frame(corGSM_MM) %>%
- filter(TFRegulator == "YES") %>%
- arrange(desc(cor)) %>%
- head(5)
- p + geom_text(data = top_labels,
- aes(label = GeneScoreMatrix_name), # Use your specific label column here
- vjust = -1) # Adjust text positioning
- ggsave("Plots/Pos_TF_corGSM2.pdf")
Peak_annotation.R at commit baf2d2b, no license · at the source
Overview
13 affiliations
- Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland Clinic, Cleveland, Ohio 44195, USA
- Department of Genomic Sciences and Systems Biology, Cleveland Clinic Research, Cleveland Clinic, Cleveland, Ohio 44195, USA
- Department of Quantitative Health Sciences, Cleveland Clinic Research, Cleveland Clinic, Cleveland, Ohio 44195, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio 44195, USA
- Department of Neurosurgery and Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA
- Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio 44106, USA
- Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio 44106, USA
- Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio 44106, USA
- Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106, USA
- Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106, USA
- Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, Kirk Kerkorian School of Medicine, University of Nevada–Las Vegas, Las Vegas, Nevada 89154, USA
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
Abstract
Alzheimer's disease (AD) is a complex and poorly understood neurodegenerative disorder that lacks sufficiently effective treatments. Computational and integrative analyses that leverage multiomic data provide a promising strategy to uncover disease mechanisms and identify therapeutic opportunities. Here, we develop a cell type–specific regulatory atlas of the human middle temporal gyrus via leveraging single-nucleus RNA-seq (1,197,032 nuclei) and ATAC-seq (740,875 nuclei) data sets from 84 donors across four stages of AD neuropathological change (ADNC). We observe differential gene expression for six major cell types intensified at severe ADNC. Integrating peak-to-gene linkages and motif enrichment analyses, we reconstruct transcription factor (TF)–target gene networks across six major brain cell types. By integrating genome-wide association study (GWAS) loci with cell type–specific cis-regulatory DNA elements (CREs), we pinpoint 141 ADNC-associated genes. Using gene set enrichment analysis (GSEA) and network proximity analysis, we further identify nine candidate repurposable drugs that were associated with these ADNC-related genes. In summary, this cell type–specific multiomic atlas provides a comprehensive resource for mechanistic understanding, target prioritization, and therapeutic hypothesis generation in AD and AD-related dementia if broadly applied.
Reproduced under the paper's license (CC BY-NC), from the paper cited above.
Repository
Its files are read in the Code ↔ Paper reader above, with 6 matches between paragraphs and lines of code.
ChengF-Lab/AD-digitaltwins
baf2d2be68b69974489ad2272572436f0b5a34ad, 16 January 2026Availability: 1 check, the latest on 30 September 2026: the link answers
- 30 September 2026: the link answers
10 files
- DEG.R, R, 55 lines
- PeakCalling.R, R, 63 lines
- Peak_annotation.R, R, 272 lines, 2 matches
- Processing4DEG.R, R, 189 lines, 1 match
- fun4TFtargerGene.r, R, 444 lines
- fun4p2g.r, R, 72 lines, 1 match
- snATAC_QC_Clustering.R, R, 169 lines, 1 match
- snRNA_QC.py, Python, 179 lines, 1 match
- snRNA_snATAC_integration
.R , R, 95 lines - README.md, Text, 24 lines
Code availability
All source code and custom scripts used in this study are available at GitHub (https://
Reproduced under the paper's license (CC BY-NC), from the paper cited above.
Tracing map
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Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 7 MeSH terms, 5 funders, 87 references.
Cite
This paper
Ren, Y., Hu, M., Li, Y. E., Pieper, A. A., Cummings, J., & Cheng, F. (2026). Cell type-specific gene regulatory atlas prioritizes drug targets and repurposable medicines in Alzheimer's disease. Genome research, 36(3), 645-659. https://
BibTeX
@article{ren2026cell,
author = {Ren, Yunxiao and Hu, Ming and Li, Yang E. and Pieper, Andrew A. and Cummings, Jeffrey and Cheng, Feixiong},
title = {{Cell type-specific gene regulatory atlas prioritizes drug targets and repurposable medicines in Alzheimer's disease}},
journal = {Genome research},
year = {2026},
month = mar,
volume = {36},
number = {3},
pages = {645--659},
publisher = {Cold Spring Harbor Laboratory Press},
issn = {1088-9051},
doi = {10.1101/
url = {https://
pmid = {41565468},
pmcid = {PMC12951949}
}
RIS
TY - JOUR
AU - Ren, Yunxiao
AU - Hu, Ming
AU - Li, Yang E.
AU - Pieper, Andrew A.
AU - Cummings, Jeffrey
AU - Cheng, Feixiong
TI - Cell type-specific gene regulatory atlas prioritizes drug targets and repurposable medicines in Alzheimer's disease
T2 - Genome research
J2 - Genome Res
PY - 2026
DA - 2026/
VL - 36
IS - 3
SP - 645
EP - 659
SN - 1088-9051
PB - Cold Spring Harbor Laboratory Press
DO - 10.1101/
UR - https://
LA - en
ER -
CSL-JSON
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"id": "10.1101/
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"title": "Cell type-specific gene regulatory atlas prioritizes drug targets and repurposable medicines in Alzheimer's disease",
"container-title": "Genome research",
"author": [
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"family": "Ren",
"given": "Yunxiao"
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{
"family": "Hu",
"given": "Ming"
},
{
"family": "Li",
"given": "Yang E."
},
{
"family": "Pieper",
"given": "Andrew A."
},
{
"family": "Cummings",
"given": "Jeffrey"
},
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}
],
"container-title-short":
"volume": "36",
"issue": "3",
"page": "645-659",
"DOI": "10.1101/
"PMID": "41565468",
"PMCID": "PMC12951949",
"ISSN": "1088-9051",
"publisher": "Cold Spring Harbor Laboratory Press",
"URL": "https://
"language": "en",
"issued": {
"date-parts": [
[
2026,
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]
}
}
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