The Histone H3 K4me3, K27me3, and K27ac Genome-Wide Distributions Are Differently Influenced by Sex in Brain Cortexes and Gastrocnemius of the Alzheimer's Disease PSAPP Mouse Model.

Francesca Casciaro,Stefano Amatori,Martina Rusin,Jon Ramsey,Claire Montgomery,Mirco Fanelli,Giuseppe Persico,Marco Giorgio,Gino Cortopassi,Jennifer Rutkowsky

doi:10.3390/epigenomes5040026

Francesca Casciaro, Stefano Amatori + Show 8 more

Open Access

https://doi.org/10.3390/epigenomes5040026

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Abstract

Background: Women represent the majority of Alzheimer’s disease patients and show typical symptoms. Genetic, hormonal, and behavioral mechanisms have been proposed to explain sex differences in dementia prevalence. However, whether sex differences exist in the epigenetic landscape of neuronal tissue during the progression of the disease is still unknown. Methods: To investigate the differences of histone H3 modifications involved in transcription, we determined the genome-wide profiles of H3K4me3, H3K27ac, and H3K27me3 in brain cortexes of an Alzheimer mouse model (PSAPP). Gastrocnemius muscles were also tested since they are known to be different in the two sexes and are affected during the disease progression. Results: Correlation analysis distinguished the samples based on sex for H3K4me3 and H3K27me3 but not for H3K27ac. The analysis of transcription starting sites (TSS) signal distribution, and analysis of bounding sites revealed that gastrocnemius is more influenced than brain by sex for the three histone modifications considered, exception made for H3K27me3 distribution on the X chromosome which showed sex-related differences in promoters belonging to behavior and cellular or neuronal spheres in mice cortexes. Conclusions: H3K4me3, H3K27ac, and H3K27me3 signals are slightly affected by sex in brain, with the exception of H3K27me3, while a higher number of differences can be found in gastrocnemius.

Highlights

According to the last World Alzheimer Report and most USA and EU statements, there are more than 55 million people living with dementia worldwide in 2021, with two-thirds of the clinically diagnosed cases in women [1,2,3]
We first checked the quality of sequencing results and no significant variability in the number of reads related to sex was revealed (Figure S1)
Differences in the H3K27ac signal on transcription starting sites (TSS) appeared on the X chromosome of gastrocnemius. These results indicate that sex differences of histone modifications distribution in the cortex of PSAPP mice occur to a lesser extent in comparison to the gastrocnemius, whose fiber composition and gene expression is influenced by sex [36,37]

Summary

Introduction

According to the last World Alzheimer Report and most USA and EU statements, there are more than 55 million people living with dementia worldwide in 2021, with two-thirds of the clinically diagnosed cases in women [1,2,3]. The most common type of dementia is Alzheimer’s disease (AD) whose prevalence is found to be higher in females than males according to several studies [3,4]. Methods: To investigate the differences of histone H3 modifications involved in transcription, we determined the genome-wide profiles of H3K4me, H3K27ac, and H3K27me in brain cortexes of an Alzheimer mouse model (PSAPP). The analysis of transcription starting sites (TSS) signal distribution, and analysis of bounding sites revealed that gastrocnemius is more influenced than brain by sex for the three histone modifications considered, exception made for H3K27me distribution on the X chromosome which showed sexrelated differences in promoters belonging to behavior and cellular or neuronal spheres in mice cortexes. Conclusions: H3K4me, H3K27ac, and H3K27me signals are slightly affected by sex in brain, with the exception of H3K27me, while a higher number of differences can be found in gastrocnemius

Methods

Results

Conclusion