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Parallel single-nucleus chromatin accessibility and transcriptomic profiling of human late-onset Alzheimer's disease brains

Publication ,  Journal Article
Gamache, J; Barrera, J; Gingerich, D; Garrett, M; Chipman, D; Fradin, H; Ashley-Koch, A; Crawford, G; Chiba-Falek, O
Published in: Alzheimer's & dementia : the journal of the Alzheimer's Association
December 1, 2021

BACKGROUND: In the post-GWAS era for late-onset Alzheimer's disease (LOAD), the precise disease-causing genes, the specific causal variants, and molecular mechanisms mediating their pathogenic effects remain unknown. Recent studies using single-nucleus (sn)RNA-seq on human LOAD tissue have achieved unprecedented resolution in identifying cell type-specific gene dysregulation, however the regulatory mechanisms and genetic variability underlying these LOAD-specific transcriptomic signatures remain to be identified. METHOD: Nuclei were isolated from frozen post-mortem human temporal cortex tissue from LOAD patients and cognitively healthy controls (n = 24, all Caucasian and APOE 3/3). 10X Genomics technology was used to generate single-nucleus (sn)RNA-seq and snATAC-seq libraries in parallel from the same pool of nuclei isolated from each brain sample. RESULT: Uniform manifold approximation and projection (UMAP) analysis showed a total of 29 clusters assigned to 8 cell types including astrocytes, excitatory neurons, inhibitory neurons, microglia, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) in both snRNA-seq and snATAC-seq datasets. We identified differentially expressed genes (DEGs) and differentially accessible peaks (DAPs) for each cluster and found overlaps with known LOAD GWAS regions (SNP+/- 1Mb) as well as new LOAD loci that were not discovered previously. We next performed co-accessibility analysis and identified co-accessible peaks that were more open in LOAD and corresponded to dysregulation of nearby target genes. This analysis also produced networks of co-accessible LOAD peaks that were enriched in transcription factor (TF) motifs of TFs that are specifically overexpressed in LOAD samples. CONCLUSION: Integrative multi-omics is a powerful strategy to identify regulatory elements underlying gene dysregulation in LOAD. By integrating single-nucleus transcriptomic and open chromatin profiles from the same pool of nuclei, we are able to identify cell subtype-specific molecular mechanisms contributing to LOAD pathogenesis. This new genetic knowledge will progress the identification of new therapeutic targets.

Duke Scholars

Published In

Alzheimer's & dementia : the journal of the Alzheimer's Association

DOI

EISSN

1552-5279

Publication Date

December 1, 2021

Volume

17

Start / End Page

e057261

Related Subject Headings

  • Geriatrics
  • 1109 Neurosciences
  • 1103 Clinical Sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Gamache, J., Barrera, J., Gingerich, D., Garrett, M., Chipman, D., Fradin, H., … Chiba-Falek, O. (2021). Parallel single-nucleus chromatin accessibility and transcriptomic profiling of human late-onset Alzheimer's disease brains. Alzheimer’s & Dementia : The Journal of the Alzheimer’s Association, 17, e057261. https://doi.org/10.1002/alz.057261
Gamache, J., J. Barrera, D. Gingerich, M. Garrett, D. Chipman, H. Fradin, A. Ashley-Koch, G. Crawford, and O. Chiba-Falek. “Parallel single-nucleus chromatin accessibility and transcriptomic profiling of human late-onset Alzheimer's disease brains.” Alzheimer’s & Dementia : The Journal of the Alzheimer’s Association 17 (December 1, 2021): e057261. https://doi.org/10.1002/alz.057261.
Gamache J, Barrera J, Gingerich D, Garrett M, Chipman D, Fradin H, et al. Parallel single-nucleus chromatin accessibility and transcriptomic profiling of human late-onset Alzheimer's disease brains. Alzheimer’s & dementia : the journal of the Alzheimer’s Association. 2021 Dec 1;17:e057261.
Gamache, J., et al. “Parallel single-nucleus chromatin accessibility and transcriptomic profiling of human late-onset Alzheimer's disease brains.” Alzheimer’s & Dementia : The Journal of the Alzheimer’s Association, vol. 17, Dec. 2021, p. e057261. Scopus, doi:10.1002/alz.057261.
Gamache J, Barrera J, Gingerich D, Garrett M, Chipman D, Fradin H, Ashley-Koch A, Crawford G, Chiba-Falek O. Parallel single-nucleus chromatin accessibility and transcriptomic profiling of human late-onset Alzheimer's disease brains. Alzheimer’s & dementia : the journal of the Alzheimer’s Association. 2021 Dec 1;17:e057261.
Journal cover image

Published In

Alzheimer's & dementia : the journal of the Alzheimer's Association

DOI

EISSN

1552-5279

Publication Date

December 1, 2021

Volume

17

Start / End Page

e057261

Related Subject Headings

  • Geriatrics
  • 1109 Neurosciences
  • 1103 Clinical Sciences