Novel Interaction of Class IIb Histone Deacetylase 6 (HDAC6) with Class IIa HDAC9 Controls Gonadotropin Releasing Hormone (GnRH) Neuronal Cell Survival and Movement

Salian-Mehta, Smita; Xu, Mei; McKinsey, Timothy A.; Tobet, Stuart A.; Wierman, Margaret E.

doi:10.1074/jbc.m115.640482

Cited by 15 publications

(10 citation statements)

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“…These findings are consistent with our observation that HDAC9 expression is reduced in subjects with AD and in the subjects with HDAC9 SNP alleles associated with higher NFT and CAA. Decreased HDAC9 expression has also been linked to increased neuronal apoptosis [ 44 , 45 ]. Collectively, findings from our and other studies indicate that MEF2C and HDAC9 may participate in a pathway leading to NFT formation and brain atrophy.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease

et al. 2018

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BackgroundSimultaneous consideration of two neuropathological traits related to Alzheimer’s disease (AD) has not been attempted in a genome-wide association study.MethodsWe conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data.ResultsGenome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10−8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10−8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10−6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10−3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10−3) and visual (P = 5.6 × 10−4) cortices.ConclusionsOur findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0349-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease

et al. 2018

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“…Moreover interaction of class IIa and class IIb HDACs is possible. This was shown for HDCA6 and HDAC9 in GnRH neuronal cells for modulating cell movement and survival [40]. Therefore, it is possible that HDAC5 and HDAC6 act in concert for positively regulating the expression of Icer via an indirect mechanism involving similar nuclear or cytoplasmic targets in adipocyte.…”

Section: Discussionmentioning

confidence: 86%

Impaired histone deacetylases 5 and 6 expression mimics the effects of obesity and hypoxia on adipocyte function

Bricambert

Favre

Brajkovic

et al. 2016

Molecular Metabolism

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ObjectiveThe goal of the study was to investigate the role of histone deacetylases (HDACs) in adipocyte function associated with obesity and hypoxia.MethodsTotal proteins and RNA were prepared from human visceral adipose tissues (VAT) of human obese and normal weight subjects and from white adipose tissue (WAT) of C57Bl6-Rj mice fed a normal or high fat diet (HFD) for 16 weeks. HDAC activity was measured by colorimetric assay whereas the gene and protein expression were monitored by real-time PCR and by western blotting, respectively. RNA interference (RNAi) was used to silence the expression of genes in 3T3-L1 adipocytes.ResultsTotal HDAC activity was decreased in VAT and WAT from obese individuals and from mice fed a HFD, respectively. The HDAC activity reduction was associated with decreased HDAC5/Hdac5 and HDAC6/Hdac6 expression in human and mice adipocyte fraction. Similarly, hypoxia hampered total Hdac activity and reduced the expression of Hdac5 and Hdac6 in 3T3-L1 adipocytes. The decrease of both Hdac5 and Hdac6 by hypoxia was associated with altered expression of adipokines and of the inducible cAMP early repressor (Icer), a key repressor that is defective in human and mice obesity. Silencing of Icer in adipocytes reproduced the changes in adipokine levels under hypoxia and obesity, suggesting a causative effect. Finally, modeling the defect of the two Hdacs in adipocytes by RNAi or selective inhibitors mimicked the effects of hypoxia on the expression of Icer, leading to impairment of insulin-induced glucose uptake.ConclusionHdac5 and Hdac6 expression are required for the adequate expression of Icer and adipocyte function. Altered adipose expression of the two Hdacs in obesity by hypoxia may contribute to the development of metabolic abnormalities.

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“…The interaction of HDAC6 and HDAC9 has been recently demonstrated. It is dependent on the second catalytic domain of HDAC6 [11], which is thought to use α-tubulin as substrate since its mutation lowers the catalytic rate of the enzyme 5000-fold [12]. In our study, HDAC6-deficient CTLs show impaired cytotoxic activity in vitro and in vivo concomitant with the decreased secretion of their lytic content upon T Cell Receptor (TCR) activation.…”

Section: Introductionmentioning

confidence: 73%

HDAC6 is a Regulator of CTL Function through Control of Lytic Granule Dynamics

2016

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Novel Interaction of Class IIb Histone Deacetylase 6 (HDAC6) with Class IIa HDAC9 Controls Gonadotropin Releasing Hormone (GnRH) Neuronal Cell Survival and Movement

Cited by 15 publications

References 47 publications

Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease

Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease

Impaired histone deacetylases 5 and 6 expression mimics the effects of obesity and hypoxia on adipocyte function

HDAC6 is a Regulator of CTL Function through Control of Lytic Granule Dynamics

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