Harnessing Chromatin 3D interactions to Understand Ancestry‐Specific Alzheimer Disease (AD) risk. (20th December 2022)

• Record Type: Journal Article
• Authors: Wang, Liyong; Liu, Xiaoxiao; Oron, Oded; Xu, Wanying; Trittipo, Jack; Rajabli, Farid; Dykxhoorn, Derek M.; Griswold, Anthony J.; Pericak‐Vance, Margaret A.; Young, Juan J; Jin, Fulai; Vance, Jeffery M.
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 4
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.064841
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Ancestry‐specific Alzheimer Disease (AD) genetic risk is well recognized. Chromatin 3D interaction map in AD‐relevant cells with different ancestries is lacking but needed to understand the genetic/epigenetic basis for AD in diverse populations. We have shown that the local ancestry (LA) block (∼2Mb in size) surrounding APOE confers differential genetic risk for APOE ε4 carriers in Non‐Hispanic Whites (NHW) and African Americans (AA). Recently, we reported that NHW APOE ε4 carriers have a higher APOE ε4 expression and higher number of astrocytes compared to their AA counterparts in the frontal cortex. We therefore sought to characterize chromatin 3D interactions in astrocytes within different APOE LA. Method: Induced pluripotent stem cells (iPSCs) with African or European LA block (N=2 individuals for each) were differentiated into astrocytes. Chromatin Hi‐C libraries were constructed with 4‐cutter enzyme and sequenced targeting 500 million pair‐end reads per library. Spatial genome structure was examined at compartment, topological associated domain (TAD), and loop levels. To better define enhancer‐promoter interaction (EPI), high‐resolution contact matrices were built using the HiCorr and DeepLoop algorithms. Result: Each library generated over 250 million uniquely mapped, non‐redundant reads for Hi‐C analysis. Compartment and TAD had limited variability among samples (correlation co‐efficiency = 0.62∼0.90 for compartment, 0.84∼0.94 for TAD). Chromatin loop, which usually represents EPI, displays higher variability among samples (correlation co‐efficiency = 0.38∼0.75). In the 5kb‐contact‐matrix analysis, a chromatin interactive event involving APOE was detected, which is supported by Capture‐C data. The higher‐resolution 500bp‐contact‐matrix analysis revealed multiple better‐defined interactions within the event. Of particular interest, an interaction between the 5'end of TOMM40 and CLPTM1 (about 100 kb apart from each other) surrounding APOE is only observed on European but not African LA background. Conclusion: Chromatin loop displays more inter‐individual variations compared to other spatial genome structures and therefore is more informative in elucidating the epigenetic basis for inter‐ancestry differences in gene expression regulation. While identifying chromatin loop from Hi‐C data at higher resolution is challenging, it has the potential to delimitate EPI and offers insights on the ancestry‐specific AD genetic risk by providing functional mechanisms underlying AD‐associated genetic variants.