Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington’s disease

Yildirim, Ferah; Ng, Christopher; Kappès, Vincent; Ehrenberger, Tobias; Rigby, Siobhan K.; Stivanello, Victoria; Gipson, Theresa A.; Soltis, Anthony R.; Vanhoutte, Peter; Caboche, Jocelyne; Housman, David E.; Fraenkel, Ernest

doi:10.1073/pnas.1908113116

Cited by 36 publications

(41 citation statements)

References 61 publications

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“…R6/1 transgenic mice faithfully recapitulate many of the disease features of human HD, such as transcriptional dysregulation, progressive impairments of both motor and cognitive functions ( Naver et al, 2003 ; Hodges et al, 2008 ; Brooks et al, 2012 ; Yildirim et al, 2019 ), brain atrophy and mutant HTT accumulation ( Bayram-Weston et al, 2012 ). In our study, to evaluate if the specific HDAC inhibitor RGFP109 could alleviate the transcriptional dysregulation in HD in vivo and improve the characteristic neuroanatomical HD features and behavioral deficits, we treated R6/1 mice (11–14 weeks of age) with 30 mg/kg (i.p.)…”

Section: Resultsmentioning

confidence: 99%

“…Histone hyperacetylation by histone acetyltransferases (HATs) is generally associated with gene expression and histone hypoacetylation by histone deacetylases (HDACs) with gene repression ( Kurdistani et al, 2004 ). Global as well as gene specific histone hypoacetylation at promoters of down-regulated genes were shown in various HD models ( Sadri-Vakili et al, 2007 ; Yildirim et al, 2019 ). Mutant HTT leads to hypoacetylation by directly binding HATs such as CBP, reducing their activity and resulting in gene repression ( Steffan et al, 2000 ; NuciforaJr., Sasaki et al, 2001 ; Cong et al, 2005 ; Jiang et al, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

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The Effects of Selective Inhibition of Histone Deacetylase 1 and 3 in Huntington’s Disease Mice

Hecklau

Mueller

Koch

et al. 2021

Front. Mol. Neurosci.

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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 alleviated transcriptional dysregulation of a number of genes, including the transcription factor genes Neurod2 and Nr4a2, and gene sets and programs, especially those that are associated to insulin-like growth factor pathway, in the striatum of R6/1 mice. RGFP109 treatment led to a modest improvement of the motor skill learning and coordination deficit on the RotaRod test, while it did not alter the locomotor and anxiety-like phenotypes in R6/1 animals. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed no significant effects. Collectively, our combined work suggests that specific HDAC1 and HDAC3 inhibition may offer benefits for alleviating the motor phenotypic deficits and transcriptional dysregulation in HD.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Effects of Selective Inhibition of Histone Deacetylase 1 and 3 in Huntington’s Disease Mice

Hecklau

Mueller

Koch

et al. 2021

Front. Mol. Neurosci.

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“…in R6/1 mice R6/1 transgenic mice faithfully recapitulate many of the disease features of human HD, such as transcriptional dysregulation, progressive impairments of both motor and cognitive functions (Brooks et al, 2012;Hodges et al, 2008;Naver et al, 2003;Yildirim et al, 2019), brain atrophy and mutant HTT accumulation (Bayram-Weston et al, 2012). In our study, to evaluate if the specific HDAC inhibitor RGFP109 could alleviate the transcriptional dysregulation in HD in vivo and improve the characteristic neuroanatomical HD features and behavioral deficits, we treated R6/1 mice (11 to 14 weeks of age) with 30 mg/kg (i.p.)…”

Section: Hdac1 and Hdac3 Inhibition By Rgfp109 Ameliorates Motor Learmentioning

confidence: 98%

“…Arc and Syp) (Seredenina and Luthi-Carter, 2012;Vashishtha et al, 2013;Yildirim et al, 2019). To examine the impact of RGFP109 treatment on transcriptional dysregulation, we conducted transcriptome analysis of the striatum by RNA-sequencing (RNA-seq) (n=5 for WT-vehicle, n=6 for R6/1-vehicle, n=6 for WT-RGFP109, n=7 for R6/1-RGFP109).…”

Section: Rgfp109 Treatment Alleviates In Part the Global Gene Exprementioning

confidence: 99%

“…Histone hyperacetylation by histone acetyltransferases (HATs) is generally associated with gene expression and histone hypoacetylation by histone deacetylases (HDACs) with gene repression (Kurdistani et al, 2004). Global as well as gene specific histone hypoacetylation at promoters of down-regulated genes were shown in various HD models (Sadri-Vakili et al, 2007;Yildirim et al, 2019). Mutant HTT leads to hypoacetylation by directly binding HATs such as CBP, reducing their activity and resulting in gene repression (Cong et al, 2005;Jiang et al, 2006;Nucifora et al, 2001;Steffan et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Selective inhibition of histone deacetylase 1 and 3 improves motor phenotype and alleviates transcriptional dysregulation in Huntington’s disease mice

Hecklau

Mueller

Koch

et al. 2020

Preprint

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Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 repaired the expression of a number of genes, including the transcription factor genes Neurod2 and Nr4a2, and 43% of the gene sets that were dysregulated by mutant Huntingtin expression in the striatum and improved motor skill learning deficit in the R6/1 mouse model of HD. RGFP109-treated R6/1 mice showed improved coordination on the RotaRod over four consecutive trials, while vehicle-treated R6/1 animals displayed no improvement in coordination skills and fell 50 seconds earlier off the rod in the fourth trial. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed a modest effect. Collectively, our combined work presents new evidence for specific HDAC1 and HDAC3 inhibition as a therapeutic strategy for alleviating the phenotypic and molecular features of HD.

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Altered m6A RNA methylation contributes to hippocampal memory deficits in Huntington’s disease mice

Pupak

Singh

Sancho-Balsells

et al. 2022

Cell. Mol. Life Sci.

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N6-methyladenosine (m6A) regulates many aspects of RNA metabolism and is involved in learning and memory processes. Yet, the impact of a dysregulation of post-transcriptional m6A editing on synaptic impairments in neurodegenerative disorders remains unknown. Here we investigated the m6A methylation pattern in the hippocampus of Huntington’s disease (HD) mice and the potential role of the m6A RNA modification in HD cognitive symptomatology. m6A modifications were evaluated in HD mice subjected to a hippocampal cognitive training task through m6A immunoprecipitation sequencing (MeRIP-seq) and the relative levels of m6A-modifying proteins (FTO and METTL14) by subcellular fractionation and Western blot analysis. Stereotaxic CA1 hippocampal delivery of AAV-shFTO was performed to investigate the effect of RNA m6A dysregulation in HD memory deficits. Our results reveal a m6A hypermethylation in relevant HD and synaptic related genes in the hippocampal transcriptome of Hdh+/Q111 mice. Conversely, m6A is aberrantly regulated in an experience-dependent manner in the HD hippocampus leading to demethylation of important components of synapse organization. Notably, the levels of RNA demethylase (FTO) and methyltransferase (METTL14) were modulated after training in the hippocampus of WT mice but not in Hdh+/Q111 mice. Finally, inhibition of FTO expression in the hippocampal CA1 region restored memory disturbances in symptomatic Hdh+/Q111 mice. Altogether, our results suggest that a differential RNA methylation landscape contributes to HD cognitive symptoms and uncover a role of m6A as a novel hallmark of HD.

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Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington’s disease

Cited by 36 publications

References 61 publications

The Effects of Selective Inhibition of Histone Deacetylase 1 and 3 in Huntington’s Disease Mice

The Effects of Selective Inhibition of Histone Deacetylase 1 and 3 in Huntington’s Disease Mice

Selective inhibition of histone deacetylase 1 and 3 improves motor phenotype and alleviates transcriptional dysregulation in Huntington’s disease mice

Altered m6A RNA methylation contributes to hippocampal memory deficits in Huntington’s disease mice

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