Dysregulation of REST‐regulated coding and non‐coding RNAs in a cellular model of Huntington's disease

Abstract

Huntingtin (Htt) protein interacts with many transcriptional regulators, with widespread disruption to the transcriptome in Huntington's 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 brainderived 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.

Transcriptional targets of the schizophrenia risk gene MIR137

“…8, 9, 10, 11 miR-137 has important roles in neural development 12, 13, 14, 15 and has been implicated in autism, intellectual disability, Rett syndrome, Alzheimer's disease, Huntington's disease and multiple cancers. 14,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 …”

KDM1 Histone Lysine Demethylases as Targets for Treatments of Oncological and Neurodegenerative Disease

“…A protein complex containing the wild-type HTT protein, Dynactin p150 Glued , HAP1 and REST/NRSF-interacting LIM domain protein (RILP), regulates the nuclear trafficking of the REST/NRSF factor [91]. Mutant HTT (mHTT) or HAP1 knockdown in neurons provokes translation of REST to the nucleus and aberrant repression of neuron-specific genes including Bdnf, Ascl1, Neurog2 and also miR-137 in HD patients or HD model systems (Figure 4) [92,93]. mHTT itself relocalizes to the nucleus of neurons of the striatum and cortex in YAC128 HD mice [94], and the nuclear localization of mHTT or its cleaved fragments have been associated with region-specific degeneration.…”

“…HTT has been described to interact with CtBP1, a well-known partner of RCOR1, KDM1A and REST in transcription regulatory complexes [95]. Strategies have been proposed to neutralize the detrimental effects of the gene expression changes in HD by targeting REST [93,96,97] or by interfering with the function of essential components of one of the REST complexes like HDAC1/2 and SIN3B [98][99][100]. Different cyclopropylamine-derived KDM1A inhibitors restored mHTT phenotypic effects in CAG repeat/HD flies, including male pupae lethality, composite eye development, motor effects and female life span.…”

Age-related epigenetic regulation in the brain and its role in neuronal diseases

“…A group of microRNAs are downregulated by REST, which has a repressor activity for many neuronal coding and non-coding genes. When translocated into the nucleus, REST represses the transcription of BDNF and several microRNAs, including miR-9, miR-29a, miR-29b, miR-124a, miR-132, and miR-330 (83, 84). Ago2, a component of the RISC complex, is another protein known to interact with HTT, and its dissociation from HTT leads to an increase in microRNA-mediated gene silencing in HD (85).…”