Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of HuntingtonM-bM-^@M-^Ys disease

ABSTRACT: Abstract - Huntingtin (Htt) protein interacts with many transcriptional regulators, with widespread disruption to the transcriptome in HuntingtonM-bM-^@M-^Ys disease (HD) brought about by altered interactions with the mutant Htt (muHtt) protein. Repressor Element-1 Silencing Transcription Factor (REST) is a repressor whose association with Htt in the cytoplasm is disrupted in HD, leading to increased nuclear REST and concomitant repression of several neuronal-specific genes, including brain-derived neurotrophic factor (Bdnf). Here, we explored a wide set of HD dysregulated genes to identify direct REST targets whose expression is altered in a cellular model of HD but that can be rescued by knock-down of REST activity. We found many direct REST target genes encoding proteins important for nervous system development, including a cohort involved in synaptic transmission, at least two of which can be rescued at the protein level by REST knock-down. We also identified several microRNAs (miRNAs) whose aberrant repression is directly mediated by REST, including miR-137, which has not previously been shown to be a direct REST target in mouse. These data provide evidence of the contribution of inappropriate REST-mediated transcriptional repression to the widespread changes in coding and non-coding gene expression in a cellular model of HD that may affect normal neuronal function and survival. Biological replicates total RNA samples from 2 cell types (Hdh7/7 and Hdh109/109) cells were used. Expression in 'HD' cells (Hdh109/109) was compared with expression in wildtype (Hdh7/7) cells.

ORGANISM(S): Mus musculus

SUBMITTER: Caroline Johnston

PROVIDER: E-GEOD-42107 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Purpose: In Huntington disease (HD) subtle symptoms in patients may occur years or even decades prior to diagnosis. HD changes at a molecular level may begin as early as in cells that are non-lineage committed such as stem cells or HD patients induced pluripotent stem cells (iPSCs) offering opportunity to enhance the understanding of the HD pathogenesis. In addition, juvenile HD non-linage committed cells were previously not directly investigated in detail by RNA-seq. Methods: Strand-specific RNA-seq of the whole transcriptome was performed using 3 clonal lines from each of 2 HD patients (6 HD iPSC lines) with 71 or 109 CAG repeats in exon 1 of the HTT gene, and 2 healthy individuals, with 17/18 (2 clonal iPSC lines) and 21 CAG repeats (one iPSC line), to comprehensively identify mRNAs related to HD. A DESeq2 pipeline for transcripts of HD was developed to identify significantly dysregulated mRNAs. During the RNA-seq data analysis, we compared 6 HD iPSC lines vs control lines and also compared separately each set of 3 HD lines from one patient vs 3 control lines. As a result of such an approach, we generated statistical values for three comparison groups, HD vs WT, HD71Q vs WT and HD109Q vs WT Methods: 9 pM-indexed libraries were sequenced with the use of Illumina HiSeq2000, rapid run with paired-end 75 bp reads. On average, 65 mln reads were collected per library Results: We identified 107 (6 HD lines), 198 (3 HD71Q lines) and 217 (3 HD109Q lines) significantly dysregulated mRNAs in each comparison group. Conclusion: The analyses showed that many of dysregulated transcripts in HD109Q iPSC lines are involved in DNA damage response and apoptosis, such as CCND1, CDKN1A, TP53, BAX, TNFRSF10B, TNFRSF10C, TNFRSF10D, DDB2, PLCB1, PRKCQ, HSH2D, ZMAT3, PLK2, and RPS27L. Most of them were identified as downregulated and their proteins are direct interactors with TP53. HTT probably alters the level of several TP53 interactors influencing apoptosis.This may lead to accumulation of an excessive number of progenitor cells and potential disruption of cell differentiation and production of mature neurons. In addition, HTT effects on cell polarization also demonstrated in the analysis may result in a generation of incorrect progenitors.

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Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of HuntingtonM-bM-^@M-^Ys disease

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