Epigenomic dissection of Alzheimer’s disease pinpoints causal variants and reveals epigenome erosion

Xiong, Xushen; James, Benjamin T.; Boix, Carles A.; Park, Yongjin P.; Galani, Kyriaki; Victor, Matheus B.; Sun, Na; Hou, Lei; Ho, Li-Lun; Mantero, Julio; Scannail, Aine Ni; Dileep, Vishnu; Dong, Weixiu; Mathys, Hansruedi; Bennett, David A.; Tsai, Li-Huei; Kellis, Manolis

doi:10.1016/j.cell.2023.08.040

Cited by 64 publications

(17 citation statements)

References 81 publications

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“…Such snRNA-seq data can address whether changes detected are characteristic of all cells, or are limited to neurons, or specific classes of neurons, or even seen in glia, which are emerging as critical players in Alzheimer’s disease 29,30 . Our data and other’s data together 8–10,12,13 note that there are clearly robust epigenetic changes associated with the Alzheimer’s brain. Because we have included normal aging (old vs young), we can interpret some of the changes as being protective to the genome, as they are seen in healthy aging.…”

Section: Discussionsupporting

confidence: 70%

“…Alzheimer’s disease leads to a deterioration of brain cognitive function, and ultimately loss of brain cells. To understand the changes that may occur to the genome with disease, our work 8,9 and others 10–13 has focused on epigenetic status of the brain in Alzheimer’s. Alzheimer’s is initially primarily characterized by a loss of memory, with a focus on the temporal and hippocampal regions of the brain.…”

Section: Introductionmentioning

confidence: 99%

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The chromatin conformation landscape of Alzheimer’s disease

Nativio,

Lan,

Donahue

et al. 2024

Preprint

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We have been investigating epigenetic alterations in the brain during human aging and Alzheimer's disease (AD), and have evidence for histone acetylation both protecting the aging epigenome and driving AD. Here we extend our studies to chromatin architecture via looping studies, and with binding studies of key proteins required for looping: CTCF and RAD21. We detected changes in CTCF and RAD21 levels and localization, finding major changes in CTCF in AD compared to fewer changes in healthy aging. In our study of 3D genome conformation changes, we identified stable topological associating domains (TADs) in Old and AD; in contrast, in AD, there is loss of interaction at genomic sites/loops within TADs, likely reflecting the loss of CTCF. We identified genes and potential transcription factor binding at the loops that are lost in AD. in addition, we found enrichment of CTCF peak losses for AD eQTLs, suggesting that architectural dysfunction has a role in Alzheimer's. Functional experiments lowering the homologues of several key genes in a Drosophila model of Aβ42 toxicity exacerbate neurodegeneration. Taken together, these data indicate both functional protections and losses occur in the Alzheimer's brain genome compared to normal aging.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

The chromatin conformation landscape of Alzheimer’s disease

Nativio,

Lan,

Donahue

et al. 2024

Preprint

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“…Donors with the steepest memory cognitive decline late in life showed particularly broad cellular dysfunction, suggesting that this was not due to poor quality samples but rather a biological outcome of AD pathology and subsequent cognitive decline. These severely affected donors had lower transcription and reduced chromatin accessibility that may correspond to senescent states 191 , or global epigenome dysregulation indicative of cell identity loss 143 .…”

Section: Discussionmentioning

confidence: 99%

“…GRNs allowed us to identify relevant microglia transcription factors (TFs). Next, we filtered these TFs by the specificity in their expression in microglia and their dynamic changes (requiring early upregulation), and identified 4 (RUNX1 143 , IKZF1, NFATC2, MAF) that are specifically expressed in Microglia, and are upregulated early in CPS (Fig. 7e, left).…”

Section: Microglia and Astrocyte Activation In Early Admentioning

confidence: 99%

Integrated multimodal cell atlas of Alzheimer’s disease

Gabitto,

Travaglini,

Rachleff

et al. 2023

Preprint

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Alzheimer’s disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research atSEA-AD.org.

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“…This evidence indicates that the chromatin landscapes are dynamically altered, causing the deregulation of transcriptomic pathways, resulting in cell-type specific dysfunction. Furthermore, genome instability has been found to modulate pathways related to synaptic signalling, neurogenesis, cell adhesion, immunity, cell signalling, and RNA metabolism (Dileep et al, 2023; Gazestani et al, 2023; Xiong et al, 2023). It is noteworthy that in our system, the modulation of Tau leads to a similar reorganization, suggesting that Tau dysfunction might be hierarchically upstream of these mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Tau alters global gene expression affecting chromatin in the early stages of Alzheimer’s disease

Siano,

Varisco,

Terrigno

et al. 2023

Preprint

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Recent research revealed that Tau plays critical roles in various neuronal functions. Our previous work demonstrated that destabilization and nuclear delocalization of Tau can alter the expression of glutamatergic genes, thereby mediating early neuronal damage.Upon analysing gene coexpression of AD temporal regions at different stages and the transcriptional output in differentiated neuroblastoma cells, we discovered that changes in Tau availability are linked to global alterations in gene expression that affect multiple neuronal pathways. Comparison with the human AD temporal region showed that the Tau-dependent modulation of gene expression closely resembles an intermediate stage of AD that precedes the definitive AD condition. Furthermore, we identified the chromatin remodelling pathway as being significantly affected by Tau in both our cellular model and AD brains, with reductions in heterochromatin markers.We propose that Tau is able to globally affect the neuronal transcriptome and that its availability is linked to changes in gene expression during intermediate stages of AD development. In addition, we found that the epigenetic pathway is strongly affected by Tau during the progression of AD.

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Epigenomic dissection of Alzheimer’s disease pinpoints causal variants and reveals epigenome erosion

Cited by 64 publications

References 81 publications

The chromatin conformation landscape of Alzheimer’s disease

The chromatin conformation landscape of Alzheimer’s disease

Integrated multimodal cell atlas of Alzheimer’s disease

Tau alters global gene expression affecting chromatin in the early stages of Alzheimer’s disease

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