Reduced Expression of Foxp1 as a Contributing Factor in Huntington's Disease

Titus, Anto Sam Crosslee Louis Sam; Yusuff, Tanzeen; Cassar, Marlène; Thomas, Elizabeth A.; Kretzschmar, Doris; D’Mello, Santosh R.

doi:10.1523/jneurosci.3612-16.2017

Cited by 21 publications

(20 citation statements)

References 59 publications

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“…The HDAC3 adenovirus was generated using ViraPower Adenovirus Expression Kit (Invitrogen) as previously described [44]. Briefly, crude viral lysate was purified by CsCl ultracentrifugation and the titer of the adenovirus was in the range of 10 10 –10 11 pfu/ml.…”

Section: Methodsmentioning

confidence: 99%

“…For infecting neurons with adenovirus, the conditioned media was collected and saved and the neurons were incubated with fresh media sufficient to cover the cell layer along with the virus. The plates were gently swirled every 15 min for 2 h after which the viral media was removed and the conditioned media was returned to the neurons [44]. The gene and protein expression analysis was performed after 28 h.…”

Section: Methodsmentioning

confidence: 99%

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The Bdnf and Npas4 genes are targets of HDAC3-mediated transcriptional repression

et al. 2019

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BackgroundHistone deacetylase-3 (HDAC3) promotes neurodegeneration in various cell culture and in vivo models of neurodegeneration but the mechanism by which HDAC3 exerts neurotoxicity is not known. HDAC3 is known to be a transcriptional co-repressor. The goal of this study was to identify transcriptional targets of HDAC3 in an attempt to understand how it promotes neurodegeneration.ResultsWe used chromatin immunoprecipitation analysis coupled with deep sequencing (ChIP-Seq) to identify potential targets of HDAC3 in cerebellar granule neurons. One of the genes identified was the activity-dependent and neuroprotective transcription factor, Neuronal PAS Domain Protein 4 (Npas4). We confirmed using ChIP that in healthy neurons HDAC3 associates weakly with the Npas4 promoter, however, this association is robustly increased in neurons primed to die. We find that HDAC3 also associates differentially with the brain-derived neurotrophic factor (Bdnf) gene promoter, with higher association in dying neurons. In contrast, association of HDAC3 with the promoters of other neuroprotective genes, including those encoding c-Fos, FoxP1 and Stat3, was barely detectable in both healthy and dying neurons. Overexpression of HDAC3 leads to a suppression of Npas4 and Bdnf expression in cortical neurons and treatment with RGFP966, a chemical inhibitor of HDAC3, resulted in upregulation of their expression. Expression of HDAC3 also repressed Npas4 and Bdnf promoter activity.ConclusionOur results suggest that Bdnf and Npas4 are transcriptional targets of Hdac3-mediated repression. HDAC3 inhibitors have been shown to protect against behavioral deficits and neuronal loss in mouse models of neurodegeneration and it is possible that these inhibitors work by upregulating neuroprotective genes like Bdnf and Npas4.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The Bdnf and Npas4 genes are targets of HDAC3-mediated transcriptional repression

et al. 2019

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“…Given an increasing appreciation that transcription dysregulation (transcriptionally and epigenetically) is a prominent facet of HD pathogenesis (58), our identification of a dysregulated transcriptional network containing the forkhead box protein p1 transcription factor (Foxp1), and a three-member network involving histone acetylation activity is noteworthy. Foxp1 has striatal selective expression and likely serves a neuroprotective role in HD (59). The cluster of proteins involved in histone acetylation (Yeats4, Brd8, and Dr1) can be members of the NuA4 and ATAC histone acetyltransferase (HAT) complexes (60,61).…”

Section: S102mentioning

confidence: 99%

Hdac4 Interactions in Huntington's Disease Viewed Through the Prism of Multiomics

Federspiel

Greco

Lum

et al. 2019

Molecular & Cellular Proteomics

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The histone deacetylase Hdac4 is known to contribute to the progression of Huntington's Disease (HD), but the underlying mechanisms remain unknown. Here, we defined the endogenous interactome of Hdac4 in the brain of HD mouse models, characterizing their polyQ-and age-dependence in affected tissues. Further integration with proteome and transcriptome data sets reveals the diseaseinduced enhancement of Hdac4 interactions with vesicular sorting proteins, including the WASH complex. This may contribute to the known decreased synaptic functions in Huntington's Disease.

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“…The generation of GFP-encoding adenovirus (Ad-GFP) was described previously 72 . HSF1-FLAG adenovirus (Ad-HSF1) and HSF1-AB-FLAG adenovirus (Ad-HSF1-AB) were made using ViraPower adenoviral expression system (Thermo Fisher Scientific) following manufacturer’s instruction.…”

Section: Methodsmentioning

confidence: 99%

Neuroprotection by Heat Shock Factor-1 (HSF1) and Trimerization-Deficient Mutant Identifies Novel Alterations in Gene Expression

Titus

Xuan

et al. 2018

Sci Rep

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Heat shock factor-1 (HSF1) protects neurons from death caused by the accumulation of misfolded proteins by stimulating the transcription of genes encoding heat shock proteins (HSPs). This stimulatory action depends on the association of trimeric HSF1 to sequences within HSP gene promoters. However, we recently described that HSF-AB, a mutant form of HSF1 that is incapable of either homo-trimerization, association with HSP gene promoters, or stimulation of HSP expression, protects neurons just as efficiently as wild-type HSF1 suggesting an alternative neuroprotective mechanism that is activated by HSF1. To gain insight into the mechanism by which HSF1 and HSF1-AB protect neurons, we used RNA-Seq technology to identify transcriptional alterations induced by these proteins in either healthy cerebellar granule neurons (CGNs) or neurons primed to die. When HSF1 was ectopically-expressed in healthy neurons, 1,211 differentially expressed genes (DEGs) were identified with 1,075 being upregulated. When HSF1 was expressed in neurons primed to die, 393 genes were upregulated and 32 genes were downregulated. In sharp contrast, HSF1-AB altered expression of 13 genes in healthy neurons and only 6 genes in neurons under apoptotic conditions, suggesting that the neuroprotective effect of HSF1-AB may be mediated by a non-transcriptional mechanism. We validated the altered expression of 15 genes by QPCR. Although other studies have conducted RNA-Seq analyses to identify HSF1 targets, our study performed using primary neurons has identified a number of novel targets that may play a special role in brain maintenance and function.

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Reduced Expression of Foxp1 as a Contributing Factor in Huntington's Disease

Cited by 21 publications

References 59 publications

The Bdnf and Npas4 genes are targets of HDAC3-mediated transcriptional repression

The Bdnf and Npas4 genes are targets of HDAC3-mediated transcriptional repression

Hdac4 Interactions in Huntington's Disease Viewed Through the Prism of Multiomics

Neuroprotection by Heat Shock Factor-1 (HSF1) and Trimerization-Deficient Mutant Identifies Novel Alterations in Gene Expression

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