Integrative Meta-Analysis of Huntington’s Disease Transcriptome Landscape

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder with autosomal dominant inheritance caused by glutamine expansion in the Huntingtin gene (HTT). Striatal projection neurons (SPNs) in HD are more vulnerable to cell death. The executive striatal population is directly connected with the Brodmann Area (BA9), which is mainly involved in motor functions. Analyzing the disease samples from BA9 from the SRA database provides insights related to neuron degeneration, which helps to identify a promising therapeutic strategy. Most gene expression studies examine the changes in expression and associated biological functions. In this study, we elucidate the relationship between variants and their effect on gene/downstream transcript expression. We computed gene and transcript abundance and identified variants from RNA-seq data using various pipelines. We predicted the effect of genome-wide association studies (GWAS)/ novel variants on regulatory functions. We found that many variants affect the histone acetylation pattern in HD, thereby perturbing the transcription factor networks. Interestingly, some variants affect miRNA binding as well as their downstream gene expression. Tissue-specific network analysis showed that mitochondrial, neuroinflammation, vasculature, and angiogenesis-related genes are disrupted in HD. From this integrative omics analysis, we propose that abnormal neuroinflammation acts as a two-edged sword that indirectly affects the vasculature and associated energy metabolism. Rehabilitation of blood-brain barrier functionality and energy metabolism may secure the neuron from cell death.

Cracking the Code of Neuronal Cell Fate

“…The importance of Hoxd9 as master regulator of neuronal cell fate is highlighted by its early transcriptional activation following NF-mediated rescue ( Figure 1 and Figure 3 ) [ 43 ]. In accordance with these results, previous studies have demonstrated that Hoxd9 regulates the expression of several genes involved in neuronal apoptosis, displaying increased expression in unfavorable brain tumors, whereas its loss of function causes defects in axonal targeting and reduction in neural cell numbers, suggesting its utility as a potential therapeutic target at the crossroads between neurodegeneration and cancer [ 111 , 113 , 114 , 115 ]. To this regard, siRNA-induced silencing of Hoxd9 gene has been already employed to induce apoptosis in different types of brain tumors, including neuroblastoma [ 116 , 117 ].…”

Omics and Network-based Approaches in Understanding HD Pathogenesis

“…Other network and bioinformatics-based approaches conducted in HD include Sneha et al [132], Pirhaji et al [133], Pradhan et al [134], Xiang et al [135], Zaho et al [136], Fu et al [137], Shirasaki et al [138], Christodoulou [139][140][141], and Onisiforou [142].…”

Mechanism and Therapeutic Prospect of miRNAs in Neurodegenerative Diseases

“…HD is caused by an increase in CAG trinucleotide duplication of the HTT, which leads to protein aggregation and leads to impaired motor and cognitive function in patients. Therefore, in the treatment of neurodegenerative disease such as HD, the noncoding characteristics of RNA and the interference technology of miRNAs are used to inhibit the expression of mutant HTT and other mutant proteins at the posttranscriptional level to improve the migration defect of immune cells [62][63][64].…”