Altered activity-regulated H3K9 acetylation at TGF-beta signaling genes during egocentric memory in Huntington's disease.

Molecular mechanisms underlying cognitive deficits in Huntington's disease (HD), a striatal neurodegenerative disorder, are unknown. Here, we generated ChIPseq, 4Cseq and RNAseq data on striatal tissue of HD and control mice during striatum-dependent egocentric memory process. Multi-omics analyses showed altered activity-dependent epigenetic gene reprogramming of neuronal and glial genes regulating striatal plasticity in HD mice, which correlated with memory deficit. First, our data reveal that spatial chromatin re-organization and transcriptional induction of BDNF-related markers, regulating neuronal plasticity, were reduced since memory acquisition in the striatum of HD mice. Second, our data show that epigenetic memory implicating H3K9 acetylation, which established during late phase of memory process (e.g. during consolidation/recall) and contributed to glia-mediated, TGFß-dependent plasticity, was compromised in HD mouse striatum. Specifically, memory-dependent regulation of H3K9 acetylation was impaired at genes controlling extracellular matrix and myelination. Our study investigating the interplay between epigenetics and memory identifies H3K9 acetylation and TGFß signaling as new targets of striatal plasticity, which might offer innovative leads to improve HD.

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

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.

Altered enhancer transcription underlies Huntington's disease striatal transcriptional signature.

Epigenetic and transcriptional alterations are both implicated in Huntington's disease (HD), a progressive neurodegenerative disease resulting in degeneration of striatal neurons in the brain. However, how impaired epigenetic regulation leads to transcriptional dysregulation in HD is unclear. Here, we investigated enhancer RNAs (eRNAs), a class of long non-coding RNAs transcribed from active enhancers. We found that eRNAs are expressed from many enhancers of mouse striatum and showed that a subset of those eRNAs are deregulated in HD vs control mouse striatum. Enhancer regions producing eRNAs decreased in HD mouse striatum were associated with genes involved in striatal neuron identity. Consistently, they were enriched in striatal super-enhancers. Moreover, decreased eRNA expression in HD mouse striatum correlated with down-regulation of associated genes. Additionally, a significant number of RNA Polymerase II (RNAPII) binding sites were lost within enhancers associated with decreased eRNAs in HD vs control mouse striatum. Together, this indicates that loss of RNAPII at HD mouse enhancers contributes to reduced transcription of eRNAs, resulting in down-regulation of target genes. Thus, our data support the view that eRNA dysregulation in HD striatum is a key mechanism leading to altered transcription of striatal neuron identity genes, through reduced recruitment of RNAPII at super-enhancers.

Contribution of Neuroepigenetics to Huntington's Disease.

Unbalanced epigenetic regulation is thought to contribute to the progression of several neurodegenerative diseases, including Huntington's disease (HD), a genetic disorder considered as a paradigm of epigenetic dysregulation. In this review, we attempt to address open questions regarding the role of epigenetic changes in HD, in the light of recent advances in neuroepigenetics. We particularly discuss studies using genome-wide scale approaches that provide insights into the relationship between epigenetic regulations, gene expression and neuronal activity in normal and diseased neurons, including HD neurons. We propose that cell-type specific techniques and 3D-based methods will advance knowledge of epigenome in the context of brain region vulnerability in neurodegenerative diseases. A better understanding of the mechanisms underlying epigenetic changes and of their consequences in neurodegenerative diseases is required to design therapeutic strategies more effective than current strategies based on histone deacetylase (HDAC) inhibitors. Researches in HD may play a driving role in this process.