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id #12216 - Dysregulation of the neuronal epigenome occurs prior to pathology-onset and alters with progressive amyloidosis

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Phipps, A and Giles, K and Mercer, T and Vickers, J and Robinson, M and Taberlay, P and Woodhouse, A, id #12216 - Dysregulation of the neuronal epigenome occurs prior to pathology-onset and alters with progressive amyloidosis, Australasian Neuroscience Society (ANS) 2019 Conference, 2-5 December, Adelaide Convention Centre (2019) [Conference Extract]


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Abstract

Epigenetic machinery is at the interface between our genes and the environment and is well placed to explain some of the heritability gap of sporadic Alzheimer’s disease (AD). The dysfunction and death of neurons underlie the symptoms of AD, yet few studies focus on neuronal epigenetic alterations in AD. We examined H3K4me3 and H3K27ac histone modifications (ChIP-seq) in neurons from 3, 6 and 12-month-old wild-type and APP/PS1 mice, representing pre-pathology, pathology-onset and pathology-rich time-points (n=5/genotype/timepoint). H3K27ac and H3K4me3 marking at promoters was increased in APP/PS1 versus wild-type neurons at the pre-pathology time-point. Enhancers and superenhancers were also differentially enriched for H3K27ac marking between APP/PS1 and wild-type neurons at both pre-pathology and pathology-onset time-points. Interestingly, promoters and enhancers followed a similar pattern of enrichment for H3K4me3 and H3K27ac across the time-course of amyloidosis, whereas super-enhancers exhibited a different pattern of H3K27ac enrichment over time. We observed a partial recapitulation of a pre-pathology/juvenile-like histone landscape in both aged wild-type and APP/PS1 neurons (>23% of differentially H3K4me3 and H3K27ac marked sites were shared). To validate our findings, we compared our data to human neuronal single-cell RNA-seq data (Mathys et al., 2019, Nature). Over 80% of the transcripts that were differentially expressed between neurons from human AD cases and controls exhibited differential promoter enrichment for H3K4me3 between wild-type and APP/PS1 neurons at the pathology-rich time-point. Our data provides a unique insight into the epigenetic dysregulation occurring in neurons in a milieu of amyloidosis.

Item Details

Item Type:Conference Extract
Keywords:neuron, histone modifications, amyloidosis, Alzheimer's disease
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurology and neuromuscular diseases
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biomedical and clinical sciences
UTAS Author:Phipps, A (Dr Andrew Phipps)
UTAS Author:Vickers, J (Professor James Vickers)
UTAS Author:Taberlay, P (Associate Professor Phillippa Taberlay)
UTAS Author:Woodhouse, A (Dr Adele Woodhouse)
ID Code:144039
Year Published:2019
Deposited By:Wicking Dementia Research and Education Centre
Deposited On:2021-04-15
Last Modified:2021-04-20
Downloads:0

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