A010 Huntingtin loss-of-function contributes to transcriptional deregulation in Huntington’s disease
Year: 2024
Type: conference-paper
Abstract: Background Transcriptional dysregulation has been proposed to be one of the earliest and central molecular mechanisms underlying HD pathogenesis. Aims Our study aimed to search for networks of deregulated RNAs that contribute to initial transcriptional changes in HD and HTT-deficient neuronal cells. Methods We used RNA-seq (including small RNA sequencing) to analyze a set of isogenic, human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs). Results We observed numerous changes in gene expression and substantial dysregulation of miRNA expression in HD and HTT-knockout (HTT-KO) cell lines. The gene set that was upregulated in both HD and HTT-KO cells was enriched in genes associated with DNA binding and regulation of transcription. For both of these models, we confirmed the substantial upregulation of the transcription factors (TFs) TWIST1, SIX1, TBX1, TBX15, MSX2, MEOX2 and FOXD1 in NSCs and medium spiny neuron (MSN)-like cells. Moreover, we identified miRNAs that were consistently deregulated in HD and HTT-KO NSCs and MSN-like cells, including miR-214, miR-199, and miR-9. We suggest that these miRNAs function in the network that regulates TWIST1 and HTT expression via regulatory feed-forward loop (FFL) in HD. Additionally, we reported that the expression of selected TFs and miRNAs tended to progressively change during the neural differentiation of HD cells, what was not observed in HTT-KO model. Conclusions Based on comparing the HD and HTT-KO cell lines, we propose that early transcriptional deregulation in HD is largely caused by loss of HTT function. Funding: National Science Centre: 2015/17/N/NZ2/01916; 2015/17/D/NZ5/03443; 2021/41/B/NZ3/03803.
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402374115