Neuronal identity genes regulated by super-enhancers are preferentially down-regulated in the striatum of Huntington's disease mice

Abstract

Huntington's disease (HD) is a neurodegenerative disease associated with extensive down-regulation of genes controlling neuronal function, particularly in the striatum. Whether altered epigenetic regulation underlies transcriptional defects in HD is unclear. Integrating RNA-sequencing (RNA-seq) and chromatin-immunoprecipitation followed by massively parallel sequencing (ChIP-seq), we show that down-regulated genes in HD mouse striatum associate with selective decrease in H3K27ac, a mark of active enhancers, and RNA Polymerase II (RNAPII). In addition, we reveal that decreased genes in HD mouse striatum display a specific epigenetic signature, characterized by high levels and broad patterns of H3K27ac and RNAPII. Our results indicate that this signature is that of super-enhancers, a category of broad enhancers regulating genes defining tissue identity and function. Specifically, we reveal that striatal super-enhancers display extensive H3K27 acetylation within gene bodies, drive transcription characterized by low levels of paused RNAPII, regulate neuronal function genes and are enriched in binding motifs for Gata transcription factors, such as Gata2 regulating striatal identity genes. Together, our results provide evidence for preferential down-regulation of genes controlled by super-enhancers in HD striatum and indicate that enhancer topography is a major parameter determining the propensity of a gene to be deregulated in a neurodegenerative disease.

Enhancers and chromatin structures: regulatory hubs in gene expression and diseases

“…Like typical enhancers, super-enhancers are enriched for H3K27ac with high H3K4me1 to H3K4me3 ratio and are sensitive to DNase I cleavage [8,109]. However, when compared with typical enhancers, super-enhancers tend to show higher enrichment for transcriptional co-activators such as MED1 and stronger enhancer activity (Figure 1B) [49,108,110–112]. Nevertheless, whether super-enhancers truly represent a novel transcriptional entity that is functionally different from typical enhancers that can act in isolation or additive, remains debatable [113].…”

“…Apart from cancers, super-enhancers have been implicated in many complex human diseases such as Alzheimer’s disease, Type 1 diabetes and autoimmune disorders [108,112,129,130]. For example, reduced activity of super-enhancers, indicated by decreased H3K27ac enrichment, have also been found to down-regulate the expression of neuronal identity genes in the striatum of Huntington’s disease in mice [110]. …”

Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

“…Further, our in vitro studies using an embryonic stem cell line carrying mutant huntingtin (mHtt) demonstrates that this protein impairs the specification and maturation of organ-specific cellular lineages, as well as those of region-specific neural cellular subtypes (Nguyen et al, 2013a; Nguyen et al, 2013b). Accordingly, recent transcriptomic studies have reported that genes with key developmental and neural functions are preferentially impacted in specimens carrying mHtt (Achour et al, 2015; Jin et al, 2012; Labadorf et al, 2015; Ng et al, 2013). …”

Nuclear organization and 3D chromatin architecture in cognition and neuropsychiatric disorders

“…Other alterations may not cause prominent structural changes but still affect function. For example, mouse models for Huntington’s disease (HD) exhibit diminished super-enhancer function of striatum-specific genes governed by Gata2 and display reduced H3K27ac and paused RNAPII binding [82]. …”