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

Julio Barrera, Lingyun Song, Alexias Safi, Young Yun, Melanie E. Garrett, View ORCID ProfileJulia Gamache, Ivana Premasinghe, Daniel Sprague, Danielle Chipman, Jeffrey Li, Hélène Fradin, Karen Soldano, Raluca Gordân, Allison E. Ashley-Koch, Gregory E. Crawford, Ornit Chiba-Falek
doi: https://doi.org/10.1101/2021.04.07.438835
Julio Barrera
1Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
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Lingyun Song
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
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Alexias Safi
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
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Young Yun
1Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
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Melanie E. Garrett
3Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, 27701, USA
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Julia Gamache
1Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
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  • ORCID record for Julia Gamache
Ivana Premasinghe
1Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
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Daniel Sprague
1Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
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Danielle Chipman
1Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
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Jeffrey Li
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
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Hélène Fradin
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
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Karen Soldano
3Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, 27701, USA
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Raluca Gordân
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
4Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, 27705, USA
5Department of Computer Science, Duke University, Durham, NC, 27705, USA
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Allison E. Ashley-Koch
3Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, 27701, USA
6Department of Medicine, Duke University Medical Center, Durham, NC, 27708, USA
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  • For correspondence: o.chibafalek@duke.edu greg.crawford@duke.edu allison.ashleykoch@duke.edu
Gregory E. Crawford
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
7Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, 27708
8Center for Advanced Genomic Technologies, Duke University Medical Center, Durham, NC, 27708, USA
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  • For correspondence: o.chibafalek@duke.edu greg.crawford@duke.edu allison.ashleykoch@duke.edu
Ornit Chiba-Falek
1Division of Translational Brain Sciences, Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA
2Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, 27708, USA
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  • For correspondence: o.chibafalek@duke.edu greg.crawford@duke.edu allison.ashleykoch@duke.edu
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Abstract

In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer’s 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.

Figure

Competing Interest Statement

The authors have declared no competing interest.

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Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains
Julio Barrera, Lingyun Song, Alexias Safi, Young Yun, Melanie E. Garrett, Julia Gamache, Ivana Premasinghe, Daniel Sprague, Danielle Chipman, Jeffrey Li, Hélène Fradin, Karen Soldano, Raluca Gordân, Allison E. Ashley-Koch, Gregory E. Crawford, Ornit Chiba-Falek
bioRxiv 2021.04.07.438835; doi: https://doi.org/10.1101/2021.04.07.438835
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Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains
Julio Barrera, Lingyun Song, Alexias Safi, Young Yun, Melanie E. Garrett, Julia Gamache, Ivana Premasinghe, Daniel Sprague, Danielle Chipman, Jeffrey Li, Hélène Fradin, Karen Soldano, Raluca Gordân, Allison E. Ashley-Koch, Gregory E. Crawford, Ornit Chiba-Falek
bioRxiv 2021.04.07.438835; doi: https://doi.org/10.1101/2021.04.07.438835

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