Langfelder, P.; Wang, N.; Ramanathan, L.; Oh, Y. M.; Lee, S.; Gao, F.; Gu, X.; Stricos, M.; Plascencia, M.; Vaca, R.; Richman, J.; Vogt, T. F.; Horvath, S.; Yoo, A. S.; Aaronson, J.; Rosinski, J.; Yang, X. W.

In Huntington's disease (HD), disease-driver genes are broadly expressed, but pathogenic players specific to vulnerable neurons remain poorly defined. Leveraging a previously defined mutant huntingtin (mHtt) CAG-length-associated gene network, we perturbed 115 module hub genes with heterozygous knockout (KO-het) to assess their striatal transcriptomic modifier effects in wildtype and Q140 HD mice. We generated 3,592 striatal RNA-seq datasets, mapped 6,517 perturbagen-responder gene pairs, and uncovered regulators of medium spiny neuron (MSN) identity gene expression and DNA-methylase/demethylase-sensitive genes. We developed a bioinformatic pipeline to rank the perturbations with significant impacts on striatal transcriptome and HD-associated gene networks in wildtype or Q140 mice. KO-het for FoxP1 and Scn4b (two MSN-selective genes) exacerbated, whereas Pdp1 KO-het ameliorated, Q140 striatal pathology. Importantly, knockdown of functionally opposing ion channels, SCN4B and KCNH4, dichotomously affected aggregation and neurodegeneration in reprogrammed HD patient MSNs. Together, our study rigorously evaluated systems biology-derived candidates to identify modifiers of HD-associated molecular networks and pathology, providing an in vivo perturbation-transcriptome resource and highlighting genes involved in MSN excitability, transcription, calcium signaling, and mitochondrial metabolism in HD pathogenesis.