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Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer's disease brains.

Publication ,  Journal Article
Gamache, J; Gingerich, D; Shwab, EK; Barrera, J; Garrett, ME; Hume, C; Crawford, GE; Ashley-Koch, AE; Chiba-Falek, O
Published in: Cell Biosci
October 3, 2023

BACKGROUND: The genetic underpinnings of late-onset Alzheimer's disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD. METHODS: Here, we present the largest parallel single-nucleus (sn) multi-omics study to simultaneously profile gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) to date, using nuclei from 12 normal and 12 LOAD brains. We identified cell subtype clusters based on gene expression and chromatin accessibility profiles and characterized cell subtype-specific LOAD-associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) and cis co-accessibility networks (CCANs). RESULTS: Integrative analysis defined disease-relevant CCANs in multiple cell subtypes and discovered LOAD-associated cell subtype-specific candidate cis regulatory elements (cCREs), their candidate target genes, and trans-interacting transcription factors (TFs), some of which, including ELK1, JUN, and SMAD4 in excitatory neurons, were also LOAD-DEGs. Finally, we focused on a subset of cell subtype-specific CCANs that overlap known LOAD-GWAS regions and catalogued putative functional SNPs changing the affinities of TF motifs within LOAD-cCREs linked to LOAD-DEGs, including APOE and MYO1E in a specific subtype of microglia and BIN1 in a subpopulation of oligodendrocytes. CONCLUSIONS: To our knowledge, this study represents the most comprehensive systematic interrogation to date of regulatory networks and the impact of genetic variants on gene dysregulation in LOAD at a cell subtype resolution. Our findings reveal crosstalk between epigenetic, genomic, and transcriptomic determinants of LOAD pathogenesis and define catalogues of candidate genes, cCREs, and variants involved in LOAD genetic etiology and the cell subtypes in which they act to exert their pathogenic effects. Overall, these results suggest that cell subtype-specific cis-trans interactions between regulatory elements and TFs, and the genes dysregulated by these networks contribute to the development of LOAD.

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Published In

Cell Biosci

DOI

ISSN

2045-3701

Publication Date

October 3, 2023

Volume

13

Issue

1

Start / End Page

185

Location

England
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Gamache, J., Gingerich, D., Shwab, E. K., Barrera, J., Garrett, M. E., Hume, C., … Chiba-Falek, O. (2023). Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer's disease brains. Cell Biosci, 13(1), 185. https://doi.org/10.1186/s13578-023-01120-5
Gamache, Julia, Daniel Gingerich, E Keats Shwab, Julio Barrera, Melanie E. Garrett, Cordelia Hume, Gregory E. Crawford, Allison E. Ashley-Koch, and Ornit Chiba-Falek. “Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer's disease brains.Cell Biosci 13, no. 1 (October 3, 2023): 185. https://doi.org/10.1186/s13578-023-01120-5.
Gamache J, Gingerich D, Shwab EK, Barrera J, Garrett ME, Hume C, et al. Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer's disease brains. Cell Biosci. 2023 Oct 3;13(1):185.
Gamache, Julia, et al. “Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer's disease brains.Cell Biosci, vol. 13, no. 1, Oct. 2023, p. 185. Pubmed, doi:10.1186/s13578-023-01120-5.
Gamache J, Gingerich D, Shwab EK, Barrera J, Garrett ME, Hume C, Crawford GE, Ashley-Koch AE, Chiba-Falek O. Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer's disease brains. Cell Biosci. 2023 Oct 3;13(1):185.
Journal cover image

Published In

Cell Biosci

DOI

ISSN

2045-3701

Publication Date

October 3, 2023

Volume

13

Issue

1

Start / End Page

185

Location

England