A014 Transcriptomic analysis of Huntington disease cellular models with different numbers of the CAG repeats and effects of genistein treatments

<h3>Background</h3> Although the primary cause of monogenic diseases are mutations in single genes, recent studies demonstrated that secondary changes in expression of other genes can significantly influence the pathophysiology and cause previously unattended challenges in developing therapeutic approaches.¹ Therefore, monogenic disease might be considered as not simple, but complex disorders where dysregulated expression of many genes may contribute to unexpected changes in the regulatory network. Such a complex picture must be considered when attempting to develop effective treatment. <h3>Aims</h3> To determine changes in the global pattern of gene expression in cellular models of Huntington disease (HD), and to test whether treatment with genistein (an autophagy stimulator which was recently demonstrated to decrease storage of mutant huntingtin and correct behaviour of the R6/1 mouse model of the disease²) can normalize the levels of expression of selected genes. <h3>Methods/Techniques</h3> HEK (human embryonic kidney)-derived cell lines with either normal of increased (41, 53, 84) number of the CAG repeats in the HTT gene were used, the latter considered as HD models. The cells were either untreated or treated with genistein at the 50 micromolar concentration. Total RNA was isolated, and transcriptomic analyses were performed using the RNAseq method. <h3>Results/Outcome</h3> We found that there are hundreds of dysregulated genes in HD model cells relative to healthy controls. Expression of some genes was over 10-times up- or down-regulated in HD cells in comparison to controls. Functions of genes involved in some cellular processes were especially heavily affected, with autophagy being a well-pronounced example. Importantly, treatment with genistein could correct expression of some of these genes to the levels observed in controls while improving expression of others. <h3>Conclusions</h3> There are many genes which expression is significantly changed in HD cells relative to controls, with more pronounced dysregulation in cells with higher number of CAG repeats. Treatment with genistein can normalize expression of some genes and improve that of others. <h3>References</h3> Wisniewska K, <i>et al. Curr Issues Mol Biol</i> 2024;<b>46</b>:2678-2700. Pierzynowska K, <i>et al. Autophagy</i> 2024;<b>20</b>:1159-1182.