Biology subjects

Gamache, J. E.

Publications and source records attributed to Gamache, J. E..

3 recordsLinked to original sources

bioRxiv2024

Comparative mapping of single-cell transcriptomic landscapes in neurodegenerative diseases

INTRODUCTIONAlzheimers disease (AD), Dementia with Lewy bodies (DLB), and Parkinsons disease (PD) represent a spectrum of neurodegenerative disorders (NDDs). Here, we performed the first direct comparison of their transcriptomic landscapes. METHODSWe profiled the whole transcriptomes of NDD cortical tissue by snRNA-seq. We used computational analyses to identify common and distinct differentially expressed genes (DEGs), biological pathways, vulnerable and disease-driver cell subtypes, and alteration in cell-to-cell interactions. RESULTSThe same vulnerable inhibitory neuron subtype was depleted in both AD and DLB. Potentially disease-driving neuronal cell subtypes were present in both PD and DLB. Cell-cell communication was predicted to be increased in AD but decreased in DLB and PD. DEGs were most commonly shared across NDDs within inhibitory neuron subtypes. Overall, we observed the greatest transcriptomic divergence between AD and PD, while DLB exhibited an intermediate transcriptomic signature. DISCUSSIONThese results help explain the clinicopathological spectrum of this group of NDDs and provide unique insights into the shared and distinct molecular mechanisms underlying the pathogenesis of NDDs.

neuroscience↗

bioRxiv2023

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

BackgroundThe genetic underpinnings of late-onset Alzheimers 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. MethodsHere, 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). ResultsIntegrative 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 were LOAD-DEG, for example, ELK1 in excitatory neurons (Exc1) and KLF13 and JUN, found in multiple cell subtypes. 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. ConclusionsTo 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 revealed crosstalk between epigenetic, genomic, and transcriptomic determinates 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.

neuroscience↗

bioRxiv2021

Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer's disease brains

In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimers disease (LOAD) and translate the associations to causation. Toward that goal, we conducted ATAC-seq profiling using neuronal nuclear protein (NeuN) sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions ({+/-}100kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets. In conclusion, using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci. Furthermore, our results convey mechanistic insights into sex differences in LOAD risk and clinicopathology. GRAPHICAL ABSTRACT O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗