Histone deacetylase inhibition reduces hypothyroidism-induced neurodevelopmental defects in rats

Kumar, Praveen; Mohan, Vishwa; Sinha, Rohit Anthony; Chagtoo, Megha; Godbole, Madan M.

doi:10.1530/joe-15-0168

Cited by 12 publications

(8 citation statements)

References 47 publications

(46 reference statements)

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“…A recent report shows that abnormal fetal brain development can be ameliorated by administering an HDAC inhibitor in the rat pups subjected to perinatal hypothyroidism. The HDAC inhibitor could restore TH-regulated genes such as BDNF , MBP , and PCP2 in the cerebellum and also reverse neurocognitive deficits in these rats [171]. In another study a case of pseudohypoparathyroidism in a baby girl was found to be associated with an altered methylation pattern of the GNAS gene, which encodes for an essential signal transduction molecule in various metabolic pathways [172].…”

Section: Maternal Metabolic Disordersmentioning

confidence: 99%

Maternal Factors that Induce Epigenetic Changes Contribute to Neurological Disorders in Offspring

Banik

Kandilya

Ramya

et al. 2017

Genes

102

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It is well established that the regulation of epigenetic factors, including chromatic reorganization, histone modifications, DNA methylation, and miRNA regulation, is critical for the normal development and functioning of the human brain. There are a number of maternal factors influencing epigenetic pathways such as lifestyle, including diet, alcohol consumption, and smoking, as well as age and infections (viral or bacterial). Genetic and metabolic alterations such as obesity, gestational diabetes mellitus (GDM), and thyroidism alter epigenetic mechanisms, thereby contributing to neurodevelopmental disorders (NDs) such as embryonic neural tube defects (NTDs), autism, Down’s syndrome, Rett syndrome, and later onset of neuropsychological deficits. This review comprehensively describes the recent findings in the epigenetic landscape contributing to altered molecular profiles resulting in NDs. Furthermore, we will discuss potential avenues for future research to identify diagnostic markers and therapeutic epi-drugs to reverse these abnormalities in the brain as epigenetic marks are plastic and reversible in nature.

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Section: Maternal Metabolic Disordersmentioning

confidence: 99%

Maternal Factors that Induce Epigenetic Changes Contribute to Neurological Disorders in Offspring

Banik

Kandilya

Ramya

et al. 2017

Genes

102

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“…Histone deacetylase inhibitors can inhibit deacetylation by HDAC. At present, the most well-studied HDAC inhibitors include sodium butyrate (SB) [18, 19], sodium valproate [20], and trichostatin [21], and SB is of great importance for ruminant animals [22, 23].…”

Section: Introductionmentioning

confidence: 99%

Bacterial endotoxin decreased histone H3 acetylation of bovine mammary epithelial cells and the adverse effect was suppressed by sodium butyrate

Sun

Dong

et al. 2019

BMC Vet Res

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Background In practical production, dairy cows are frequently exposed to bacterial endotoxin (lipopolysaccharide, LPS) when they are subjected to high-concentrate diets, poor hygienic environments, as well as mastitis and metritis. Histone acetylation is an important epigenetic control of DNA transcription and a higher histone acetylation is associated with facilitated transcription. LPS might reduce histone acetylation in the mammary epithelial cells, resulting in lower transcription and mRNA expression of lactation-related genes. This study was conducted to investigate the effect of LPS on histone acetylation in bovine mammary epithelial cells and the efficacy of sodium butyrate (SB) in suppressing the endotoxin-induced adverse effect. Firstly, the bovine mammary epithelial cell line MAC-T cells were treated for 48 h with LPS at different doses of 0, 1, 10, 100, and 1000 endotoxin units (EU)/mL (1 EU = 0.1 ng), and the acetylation levels of histones H3 and H4 as well as the histone deacetylase (HDAC) activity were measured. Secondly, the MAC-T cells were treated for 48 h as follows: control, LPS (100 EU/mL), and LPS (100 EU/mL) plus SB (10 mmol/L), and the acetylation levels of histones H3 and H4 as well as milk gene mRNA expressions were determined. Results The results showed that HDAC activity increased linearly with increasing LPS doses ( P < 0.01). The histone H3 acetylation levels were significantly reduced by LPS, while the histone H4 acetylation levels were not affected by LPS ( P > 0.05). Sodium butyrate, an inhibitor of HDAC, effectively suppressed the endotoxin-induced decline of histone H3 acetylation ( P < 0.05). As a result, SB significantly enhanced the mRNA expression of lactation-related genes ( P < 0.05). Conclusions The results suggest one of the adverse effects of LPS on the lactation of bovine mammary gland epithelial cells was due to decreasing histone H3 acetylation through increasing HDAC activity, whereas the endotoxin-induced adverse effects were effectively suppressed by SB. Electronic supplementary material The online version of this article (10.1186/s12917-019-2007-5) contains supplementary material, which is available to authorized users.

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“…THs play an essential role in the growth and metabolic homeostasis in humans as well as in animals ( Prezioso et al, 2018 ). Triiodothyronine (T3), the active form of thyroid hormone, acts on its nuclear receptor and modulates target gene transcription ( Kumar et al, 2015 ). Even a 25% reduction in DDX3X levels strongly perturbs neurogenesis, suggesting the high dose-dependency of embryonic cortical development to DDX3X ( Lennox et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Expansion of Clinical and Genetic Spectrum of DDX3X Neurodevelopmental Disorder in 23 Chinese Patients

Dai

Yang

Guo

et al. 2022

Front. Mol. Neurosci.

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AimDe novo DDX3X variants account for 1–3% of unexplained intellectual disability cases in females and very rarely in males. Yet, the clinical and genetic features of DDX3X neurodevelopmental disorder in the Chinese cohort have not been characterized.MethodA total of 23 Chinese patients (i.e., 22 female and 1 male) with 22 de novo DDX3X deleterious variants were detected among 2,317 probands with unexplained intellectual disability (ID) undertaking whole exome sequencing (WES). The age, sex, genetic data, feeding situation, growth, developmental conditions, and auxiliary examinations of the cohort were collected. The Chinese version of the Gesell Development Diagnosis Scale (GDDS-C) was used to evaluate neurodevelopment of DDX3X patients. The Social Communication Questionnaire (SCQ)-Lifetime version was applied as a primary screener to assess risk for autism spectrum disorder (ASD).ResultA total of 17 DDX3X variants were novel and 22 were de novo. Missense variants overall were only slightly more common than loss-of-function variants and were mainly located in two functional subdomains. The average age of this cohort was 2.67 (±1.42) years old. The overlapping phenotypic spectrum between this cohort and previously described reports includes intellectual disability (23/23, 100%) with varying degrees of severity, muscle tone abnormalities (17/23, 73.9%), feeding difficulties (13/23, 56.5%), ophthalmologic problems (11/23, 47.8%), and seizures (6/23, 26.1%). A total of 15 individuals had notable brain anatomical disruption (15/23, 65.2%), including lateral ventricle enlargement, corpus callosum abnormalities, and delayed myelination. Furthermore, 9 patients showed abnormal electroencephalogram results (9/23, 39.1%). Hypothyroidism was first noted as a novel clinical feature (6/23, 26.1%). The five primary neurodevelopmental domains of GDDS-C in 21 patients were impaired severely, and 13 individuals were above the “at-risk” threshold for ASD.InterpretationAlthough a certain degree of phenotypic overlap with previously reported cohorts, our study described the phenotypic and variation spectrum of 23 additional individuals carrying DDX3X variants in the Chinese population, adding hypothyroidism as a novel finding. We confirmed the importance of DDX3X as a pathogenic gene in unexplained intellectual disability, supporting the necessity of the application of WES in patients with unexplained intellectual disability.

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Histone deacetylase inhibition reduces hypothyroidism-induced neurodevelopmental defects in rats

Cited by 12 publications

References 47 publications

Maternal Factors that Induce Epigenetic Changes Contribute to Neurological Disorders in Offspring

Maternal Factors that Induce Epigenetic Changes Contribute to Neurological Disorders in Offspring

Bacterial endotoxin decreased histone H3 acetylation of bovine mammary epithelial cells and the adverse effect was suppressed by sodium butyrate

Expansion of Clinical and Genetic Spectrum of DDX3X Neurodevelopmental Disorder in 23 Chinese Patients

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