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

Barrera, J. A.; Song, L.; Safi, A.; Yun, Y. J.; Garrett, M. E.; Gamache, J. E.; Premasinghe, I.; Sprague, D.; Chipman, D.; Li, J.; Fradin, H.; Soldano, K.; Gordan, R.; Ashley-Koch, A. E.; Crawford, G. E.; Chiba-Falek, O.

doi:10.1101/2021.04.07.438835

bioRxiv · 10.1101/2021.04.07.438835

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

Barrera, J. A.·Song, L.·Safi, A.·Yun, Y. J.·Garrett, M. E.·Gamache, J. E.·Premasinghe, I.·Sprague, D.·Chipman, D.·Li, J.·Fradin, H.·Soldano, K.·Gordan, R.·Ashley-Koch, A. E.·Crawford, G. E.·Chiba-Falek, O.

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Abstract

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

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Barrera, J. A., Song, L., Safi, A., Yun, Y. J., Garrett, M. E., Gamache, J. E., Premasinghe, I., Sprague, D., Chipman, D., Li, J., Fradin, H., Soldano, K., Gordan, R., Ashley-Koch, A. E., Crawford, G. E., Chiba-Falek, O.. 2021-04-09. Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer's disease brains. https://doi.org/10.1101/2021.04.07.438835

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