Early alteration of epigenetic-related transcription in Huntington’s disease mouse models

Abstract

Transcriptional dysregulation in Huntington’s disease (HD) affects the expression of genes involved in survival and neuronal functions throughout the progression of the pathology. In recent years, extensive research has focused on epigenetic and chromatin-modifying factors as a causative explanation for such dysregulation, offering attractive targets for pharmacological therapies. In this work, we extensively examined the gene expression profiles in the cortex, striatum, hippocampus and cerebellum of juvenile R6/1 and N171-82Q mice, models of rapidly progressive HD, to retrieve the early transcriptional signatures associated with this pathology. These profiles were largely consistent across HD datasets, contained tissular and neuronal-specific genes and showed significant correspondence with the transcriptional changes in mouse strains deficient for epigenetic regulatory genes. The most prominent cases were the conditional knockout of the lysine acetyltransferase CBP in post-mitotic forebrain neurons, the double knockout of the histone methyltransferases Ezh1 and Ezh2, components of the polycomb repressor complex 2 (PRC2), and the conditional mutants of the histone methyltransferases G9a (Ehmt2) and GLP (Ehmt1). Based on these observations, we propose that the neuronal epigenetic status is compromised in the prodromal stages of HD, leading to an altered transcriptional programme that is prominently involved in neuronal identity.

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

“…This is in agreement with a recent study demonstrating that HD neuronal and glial cells are affected in opposite ways at transcriptional level 50 . Our R6/1 hippocampal transcriptional data showed a great overlap with previously generated data in additional HD models 29,52 and, according to a recent study, these common transcriptional signatures present high homology with those found in knockouts for histone acetyltransferases and methyltransferases 28 . Being shown the interplay between lamin B1 protein levels and H3K9me3, highly dependent on the activity of methyltransferases, it can be speculated that nuclear lamina alterations could play a role in a particular subset of the HD transcriptional signature.…”

“…In addition, we found a substantial overlap with previously identified sets of altered expressed genes in other HD mouse models ( Supplementary Fig. 6f) 28,29 . As expected, we found that only genes showing the highest transcriptional dysregulation (adjusted p value <0.001, |fold change| >2) displayed significant changes in chromatin accessibility at their TSS as compared with genes only filtered according to their adjusted p value ( Fig.…”

“…The accumulation of lamin B1 in neuronal nuclei from HD brain could be produced by different mechanisms such as increased transcription and/or translation, or decreased degradation. Increased transcription seems improbable since RNA-seq data generated from hippocampus of 30-week old R6/1 mice do not show alterations in lamin B1 RNA levels (present results) 28 . In addition, although we have recently showed increased translation in the striatum of HD mouse models and patients, the proteomic analysis did not reveal lamin B1 as one of the proteins with increased translation 37 .…”

The CBP KIX domain regulates long-term memory and circadian activity

“…While restoring CREB activity in the CA1 of the dorsal hippocampus enables recovery from spatial memory deficits in an amyloid beta model of Alzheimer's disease (29), pharmacological activation of CBP/p300 HAT function also improves spatial learning in wildtype (WT) mice and restores spatial long-term memory retention and hippocampal plasticity in a tauopathy mouse model (30,31). Decreased levels or dysregulation of CBP have also been associated with neurodegenerative diseases including Huntington's Disease (32,33) and Alzheimer's disease (34)(35)(36). Previous research on Alzheimer's disease using rodent models found that decreases in hippocampal CBP activity levels are accompanied by decreased CREB activation, i.e.…”

Hdac4 Interactions in Huntington's Disease Viewed Through the Prism of Multiomics

“…In both human and mouse HD models, down-regulation of specific genes is observed, largely because of decreased transcription from gene promoters (14 -16). As a result, cellular factors that modulate gene expression and chromatin states, such as histone acetyltransferases and lysine deacetylases, have been the subject of intense investigation (17). Moreover, the lysine acetyltransferase CREB-binding protein (CBP) has been found to colocalize with huntingtin inclusions (18), whereas histone deacetylase interaction partners were found to have altered subcellular distribution patterns in HD brains (19).…”