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CHAS, a deconvolution tool, infers cell type-specific signatures in bulk brain histone acetylation studies of brain disorders

View ORCID ProfileKitty B. Murphy, View ORCID ProfileAlexi Nott, View ORCID ProfileSarah J. Marzi
doi: https://doi.org/10.1101/2021.09.06.459142
Kitty B. Murphy
1UK Dementia Research Institute, Imperial College London, London, UK
2Department of Brain Sciences, Imperial College London, London, UK
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Alexi Nott
1UK Dementia Research Institute, Imperial College London, London, UK
2Department of Brain Sciences, Imperial College London, London, UK
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Sarah J. Marzi
1UK Dementia Research Institute, Imperial College London, London, UK
2Department of Brain Sciences, Imperial College London, London, UK
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  • For correspondence: s.marzi@imperial.ac.uk
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Abstract

Chromatin profiling studies have shown the importance of gene regulation in driving heritability and environmental risk of brain disorders. Acetylation of histone H3 lysine 27 (H3K27ac) has emerged as an informative disease-associated epigenetic mark. However, cell type-specific contributions to epigenetic dysregulation in disease are unclear as studies have often used bulk brain tissue. Therefore, methods for the deconvolution of bulk H3K27ac profiles are critical. Here we developed the Cell type-specific Histone Acetylation Score (CHAS), a computational tool for inferring cell type-specific signatures in bulk brain H3K27ac profiles. CHAS annotates peaks identified in bulk brain studies of H3K27ac to cell type-specific signals in four major brain cell types, and derives cell type-specific histone acetylation scores as a proxy for cell type proportion. Our method was validated in pseudo-bulk samples and applied to three brain disorder epigenome-wide association studies conducted on bulk brain tissue. CHAS exposed shifts in cellular proportions in Alzheimer’s disease (AD), in line with neuropathology, and identified disrupted gene regulatory elements in oligodendrocytes in AD and microglia in autism spectrum disorder (ASD). This contrasts with heritability-based enrichment analyses which indicate genetic risk is associated with microglia in AD and neurons in ASD. Our approach identified cell type specific signalling pathways and putative upstream transcription factors associated with these elements. CHAS enables deconvolution of H3K27ac in bulk brain tissue, yielding cell type-specific biological insights into brain disease-associated regulatory variation.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://github.com/neurogenomics/CHAS

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 06, 2021.
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CHAS, a deconvolution tool, infers cell type-specific signatures in bulk brain histone acetylation studies of brain disorders
Kitty B. Murphy, Alexi Nott, Sarah J. Marzi
bioRxiv 2021.09.06.459142; doi: https://doi.org/10.1101/2021.09.06.459142
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CHAS, a deconvolution tool, infers cell type-specific signatures in bulk brain histone acetylation studies of brain disorders
Kitty B. Murphy, Alexi Nott, Sarah J. Marzi
bioRxiv 2021.09.06.459142; doi: https://doi.org/10.1101/2021.09.06.459142

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