In:
Alzheimer's & Dementia, Wiley, Vol. 18, No. S4 ( 2022-12)
Abstract:
Alzheimer’s disease (AD) genome‐wide association studies (GWAS) identified 75 disease‐associated loci. The vast majority of risk variants are located in non‐coding genomic regions, suggesting a regulatory function (i.e. enhancer activity). Enhancers can regulate distal genes via DNA loops, bringing elements millions of base pairs away into close physical proximity in three‐dimensional (3D) space. Mapping 3D chromatin contact frequencies using Hi‐C can reveal enhancer‐promoter connections and assign disease‐associated variants to putative causal genes. Because enhancer and 3D chromatin structures are cell‐type specific, it is critical to map these features in the relevant cell type and biological context. Genetic risk factors for AD are located within microglia and macrophages chromatin‐accessible regions. The aim of this work was to map 3D chromatin structures in human microglia and macrophages and intersect them with AD GWAS to identify novel genes regulated by non‐coding AD risk variants. Method We performed deeply sequenced Hi‐C, RNA‐seq, ATAC‐seq, and Cut & Run targeting histone H3K27 acetylation to map regulatory networks in THP‐1 macrophages and human iPSC‐derived microglia‐like cells (IMGLs). Next, we performed differential analysis to identify cell‐type specific differences in 3D chromatin structure, enhancer activity, and gene expression. Finally, we intersected these regulatory networks with AD GWAS to identify variants that may disrupt these networks and reveal novel AD risk genes for further study. Result We identified 19,608 chromatin loops, 766 of which were specific to either cell type. These loops connected 14,413 enhancers (8,023 of which were cell‐type specific) to 7,548 genes (2,280 of which differed between cell types). Cell‐type specific regulatory features correlated with cell‐type specific gene expression. For example, a microglia‐specific loop connected a distal regulatory loci to the promoter of PER1, which was also upregulated in microglia and has a known role in circadian rhythm regulation, underscoring microglia’s known circadian‐regulated behavior. Conclusion We identified cell‐type specific regulatory networks in human macrophages and microglia. While these networks exhibited similarities, we identified thousands of enhancer‐promoter connections that differed. Intersecting with AD GWAS enables us to identify cell‐type specific genes regulated by non‐coding AD risk variants and reveal novel regulatory connections that would be otherwise unknown.
Type of Medium:
Online Resource
ISSN:
1552-5260
,
1552-5279
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2201940-6
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