Home » Abstracts » Human Health Proteomics » Tracking the possibly affected flux of glucose to histone acetylation in the striatum of a mouse model of Huntington’s disease

Tracking the possibly affected flux of glucose to histone acetylation in the striatum of a mouse model of Huntington’s disease

Human Health Proteomics PTM & Glycoproteomics

Abstract #259 Posted on28 March 202528 April 2025 28 April 2025 14h00

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by abnormal CAG repeat expansions (>35) in the HTT gene. The pathogenic mechanism involves epigenetic dysregulation and metabolic disturbances. Notably, histone lysine hypoacetylation at neuronal identity genes and hyperacetylation at developmental genes, leading to their down- and up-regulation, are conserved epigenetic signatures in the striata of HD mice and human postmortem brains. These alterations contribute to accelerated aging, cellular identity loss, and ultimately, neurodegeneration.
Histone post-translational (hPTMs) modifications are key regulators of gene expression and serve as a link between metabolism and epigenetics. To investigate the relationship between metabolic disturbances and hPTMs in HD, we traced the incorporation of heavy-labeled acetyl into histones following in vivo 13C-glucose administration in wild type and R6/1 HD mice. Using trimethylacetic anhydride for histone derivatization prior to mass spectrometry e monitored the rate of incorporation of heavy acetyl groups by data processing using Skyline, in-house developed R scripts and Picor, to assess a possible difference in the flux from glucose to histone acetylation between the two mouse genotypes.
This study addresses how metabolic disturbances may influence histone acetylation dynamics, which could provide insights into HD pathomechanisms, and inform the search for potential therapeutic targets.

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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by abnormal CAG repeat expansions (&gt;35) in the HTT gene. The pathogenic mechanism involves epigenetic dysregulation and metabolic disturbances. Notably, histone lysine hypoacetylation at neuronal identity genes and hyperacetylation at developmental genes, leading to their down- and up-regulation, are conserved epigenetic signatures in the striata of HD mice and human postmortem brains. These alterations contribute to accelerated aging, cellular identity loss, and ultimately, neurodegeneration. 
Histone post-translational (hPTMs) modifications are key regulators of gene expression and serve as a link between metabolism and epigenetics. To investigate the relationship between metabolic disturbances and hPTMs in HD, we traced the incorporation of heavy-labeled acetyl into histones following in vivo 13C-glucose administration in wild type and R6/1 HD mice. Using trimethylacetic anhydride for histone derivatization prior to mass spectrometry e monitored the rate of incorporation of heavy acetyl groups by data processing using Skyline, in-house developed R scripts and Picor, to assess a possible difference in the flux from glucose to histone acetylation between the two mouse genotypes.
This study addresses how metabolic disturbances may influence histone acetylation dynamics, which could provide insights into HD pathomechanisms, and inform the search for potential therapeutic targets.

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