Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice

Abstract

Temporal dynamics and mechanisms underlying epigenetic changes in Huntington’s disease (HD), a neurodegenerative disease primarily affecting the striatum, remain unclear. Using a slowly progressing knockin mouse model, we profile the HD striatal chromatin landscape at two early disease stages. Data integration with cell type-specific striatal enhancer and transcriptomic databases demonstrates acceleration of age-related epigenetic remodelling and transcriptional changes at neuronal- and glial-specific genes from prodromal stage, before the onset of motor deficits. We also find that 3D chromatin architecture, while generally preserved at neuronal enhancers, is altered at the disease locus. Specifically, we find that the HD mutation, a CAG expansion in the Htt gene, locally impairs the spatial chromatin organization and proximal gene regulation. Thus, our data provide evidence for two early and distinct mechanisms underlying chromatin structure changes in the HD striatum, correlating with transcriptional changes: the HD mutation globally accelerates age-dependent epigenetic and transcriptional reprogramming of brain cell identities, and locally affects 3D chromatin organization.

Metabolic regulation of the neural stem cell fate: Unraveling new connections, establishing new concepts

“…Epigenetic modifications, including DNA and histone modifications have also been shown to play a crucial role in the regulation of NSC fate (Yao et al, 2016) with histone demethylation and acetylation being the main modifications promoting NSC proliferation and self-renewal and methyl-CpG binding protein 2 (MECP2)-mediated histone methylation promoting terminal neuronal differentiation and synaptogenesis (Niklison-Chirou et al, 2020). Histone methylation has been shown to influence Notch1 (Zhang et al, 2015) and Huntingtin expression (Irmak et al, 2018;Lu et al, 2020;Alcalá-Vida et al, 2021). Histone acetylases and deacetylase also regulate proper NSC function through huntingtin expression regulation (Yildirim et al, 2019).…”

G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis

“…In this context, transcriptional reprogramming via stable epigenetic marks like histone modifications ( 56 ) or DNA methylation ( 23 ) is a plausible underlying molecular mechanism. Epigenetic dysregulation has been implicated in several neurodegenerative diseases including Huntington’s disease ( 57 ), Alzheimer’s disease ( 58 ), and MS ( 25 ). As a result, histone methyltransferases have become promising therapeutic targets in neurodegenerative diseases ( 48 ).…”

The emerging role of long non-coding RNAs, microRNAs, and an accelerated epigenetic age in Huntington’s disease

“…For example, the binding of LSD1 enzyme to target genes, mediated by HOTAIR, has been shown to affect the repression of target genes by changing the methylation level of the histone H3 lysine 27 (H3K27) (Tsai et al, 2010). While, decreased acetylation of H3K27 showed an association with the downregulation of neuronal identity genes in the striatum of HD patients and mice (Achour et al, 2015;Alcalá-Vida et al, 2021). Also, an association is shown between aberrant DNA methylation levels correlated with aberrant expression of different lncRNAs with susceptibility to different diseases.…”

“…Most recently, exploration of the HD-associated epigenetic signatures using the slowly progressing knockin (KI) mouse model of HD, revealed that even before the onset of HD motor problems, age-related epigenetic remodeling and transcriptional alteration of neuronal and glial-specific genes are accelerated. This might suggest that the progressive HD striatal epigenetic signatures develop from the earliest stages of HD ( Alcalá-Vida et al, 2021 ).…”