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Hdac4 regulates proliferation of neural crest-derived osteoblasts during murine craniofacial development

ABSTRACT: Craniofacial development involves regulation of a compendium of transcription factors, signaling molecules and epigenetic regulators. Histone deacetylases (HDACs) are involved in the regulation of cell proliferation, differentiation and homeostasis across a wide range of tissues, such as brain, cardiovascular system, muscular system, and skeletal system. However, functional role of Hdac4 during craniofacial development is still unclear. In this study, we investigated the effects of Hdac4 knockout in craniofacial skeletal development by conditionally disrupting the Hdac4 gene in cranial neural crest cells (CNCCs) using Cre-mediated recombination. Mice deficient in Hdac4 in CNCCs-derived osteoblasts demonstrated a dramatic decrease in bone formation in frontal bone. In vitro pre-osteoblasts (MC3T3-E1 cells) lacking Hdac4 exhibited reduced proliferation activity in association with dysregulation of cell cycle-related genes. These findings suggest that Hdac4 acts partially as a regulator of craniofacial skeletal development by positively regulating proliferation of CNCCs-derived osteoblasts.

ORGANISM(S): Mus musculus

PROVIDER: GSE186707 | GEO | 2022/03/09

REPOSITORIES: GEO

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Hdac4 regulates proliferation of neural crest-derived osteoblasts during murine craniofacial development

Project description:Hdac4 regulates proliferation of neural crest-derived osteoblasts during murine craniofacial development

| PRJNA775618 | ENA

Study of the signaling modulated by HDAC4 in skeletal muscle in ALS

Project description:BACKGROUND: Histone deacetylase 4 (HDAC4) has been proposed as a target for the treatment of Amyotrophic Lateral Sclerosis (ALS) because it mediates nerve-skeletal muscle interaction and since its expression in skeletal muscle correlates with the severity of the disease. However, our recent studies on the skeletal muscle response upon long-term denervation highlighted the importance of HDAC4 in maintaining muscle integrity. METHODS: To fully identify the yet uncharacterized HDAC4 functions in ALS, we genetically deleted HDAC4 in skeletal muscles of a mouse model of ALS. Body weight, skeletal muscle, innervation and spinal cord were analyzed over time by morphological and molecular analyses. A transcriptome analysis was also performed to delineate the signaling modulated by HDAC4 in skeletal muscle of a mouse model of ALS. FINDINGS: HDAC4 deletion in skeletal muscle caused earlier ALS onset, characterized by body weight loss, muscle denervation and atrophy, and compromised muscle performance in ALS mice, although the main catabolic pathways were not activated. A transcriptome analysis identified the gene networks modulated by HDAC4 in ALS, revealing UCP1 as a top regulator that may be implicated in worsening ALS features. INTERPRETATION: HDAC4 plays an important role in preserving innervations and skeletal muscle in ALS, likely by modulating the UCP1 gene network. Our study highlights a possible risk in considering HDAC inhibitors for the treatment of ALS.

2019-01-31 | GSE121789 | GEO

Distinct and redundant roles for zebrafish her genes during osteoblast differentiation and craniofacial patterning.

Project description:The Notch pathway is a cell-cell communication system which is critical for many developmental processes, including craniofacial development. Notch receptor activation induces expression of several well-known canonical targets including those encoded by the hes and her genes in mammals and zebrafish, respectively. The function of these genes, individually and in combination, during craniofacial development is not well understood. Here, we investigated zebrafish her9 and her6 gene function during craniofacial development. We found that her9 is required for osteoblasts to efficiently mineralize bone, while cartilage is largely unaffected. Strikingly, gene expression studies in her9 mutants indicate that although progenitor cells differentiate into osteoblasts at the appropriate time and place, they fail to efficiently lay down mineralized matrix. This mineralization role of her9 is likely independent of Notch activation. In contrast, her9 also functions redundantly with her6 downstream of Jagged1b-induced Notch activation during dorsoventral craniofacial patterning. These studies disentangle distinct and redundant her gene functions during craniofacial development, including an unexpected, Notch independent, requirement during bone mineralization

2022-12-12 | GSE220081 | GEO

Hdac4 interactome in Huntington's Disease

Project description:Hdac4 has been found to modulate symptoms in Huntington's Disease (HD) mouse models through an uknown mechanism unrelated to any enzymatic activity. We investigated the protein-protein interactions to gain insight into the role of Hdac4 in HD.

2019-05-01 | PXD011845 | Pride

STAT3 regulates osteogenesis, making it critical for skeletal development and bone homeostasis

Project description:Skeletal deformities are typical clinical manifestations of autosomal dominant hyper-immunoglobulin E syndrome (AD-HIES), but the treatment is still limited. AD-HIES is mainly caused by dominant-negative mutations in signal transducer and activator of transcription 3 (STAT3). Clarifying the mechanisms by which STAT3 inactivation destructs bone metabolism is, therefore, important. Although, a few lines of data indicate osteoporosis induced by STAT3 inactivation may be related to increased osteoclast activity, here, we firstly report that deletion of Stat3 in osteoblasts, but not in osteoclasts, induced AD-HIES-like bone defects, including craniofacial malformation, osteoporosis, and spontaneous bone fracture in mice, and these defects were resulted from impaired osteogenesis induced by STAT3 inactivation in osteoblasts, but not increased osteoclast activity. Mechanistic analysis revealed a novel regulatory model in which STAT3 drove osteoblast differentiation via promoting distal-less homeobox 5 transcription in cooperation with MSX1. Furthermore, inducible deletion of Stat3 in osteoblasts also inhibited osteogenesis and induced bone loss in adult mice. Meaningfully, pharmacological inhibition of STAT3 induced bone loss, while activation of STAT3 partially prevent bone loss due to tail sus-pension. Taken together, STAT3 is critical for both modulating skeletal development and maintaining bone homeostasis, and inactivation of STAT3 in osteoblasts, but not in osteoclasts, induced AD-HIES-related skeletal deformities by impairing osteogenesis, providing new insights for their treatment.

2021-07-28 | GSE173711 | GEO

Effects of Citalopram Exposure on Osteogenesis in Mouse Calvarial Pre-Osteoblasts

Project description:Recently, serotonin and serotonin reuptake inhibitor (SSRI) drugs have been shown to have an effect on the development and maintenance of bone. However, little is known about its role in craniofacial development. We used microarray as one tool to determine the gene expression profile of intramembranous (calvarial) derived murine pre-osteoblasts after citalopram (SSRI) exposure. We isolated whole RNA from MC3T3-E1 cells treated with proliferation media or proliferation media with SSRI at a dose of 10^-4 mol./liter for 3 or 7 days in culture. We then used an Affymetrix array and compared expression profiles between control and experimental treatments.

2013-06-19 | E-GEOD-48057 | biostudies-arrayexpress

Nociceptor HDAC4 regulates inflammatory pain

Project description:Transcriptional alterations are characteristic of persistent pain states but the key regulators remain elusive. Using a conditional knockout (cKO) strategy in mice we sought to determine whether loss of the transcriptional co-repressor histone deacetylase four (HDAC4) would have implications for sensory neuron transcription and nociception. HDAC4 was found to be largely dispensable for transcriptional regulation of naïve sensory neurons but was required for transcriptional responses after injury, with Calca and Trpv1 expression consistently downregulated in HDAC4 cKO compared to littermate controls (0.2-0.44 fold). This downregulation corresponded to reduced sensitivity to capsaicin in vitro (76% +/- 4.4% wildtype capsaicin responders vs 56.9% +/- 4.7% cKO responders) and to reduced thermal hypersensitivity in the complete Freund’s adjuvant model of inflammatory pain (1.3-1.4 fold improvement). These data indicate that HDAC4 is a novel inflammatory pain mediator and may be a good therapeutic target, capable of orchestrating the regulation of multiple downstream effectors. Total RNA was extracted from HDAC4 cKO and HDAC4 fl/fl naïve adult lumbar dorsal root ganglia (n=3/group). mRNA expression was compared using Affymetrix Mouse Gene Arrays (Mouse Gene 2.0ST) run on a GeneChip Fluidics Station 450. Chips were scanned on an Affymetrix GeneChip Scanner.

2015-04-23 | E-GEOD-62405 | biostudies-arrayexpress

SMAD4 regulated through HDAC4 is associated with chemoresistance in MCF-7 cells

Project description:HDACs play crucial role in epigenetic modulation through deacetylation of histone and non-histone substrates in critical process of normal development and cancer. Moreover, HDAC inhibitors have been considered as new agent by effects such as cell cycle arrest, apoptosis, anti-angiogenic effects and autophagy and utilized in clinical applications for chemotherapy. we previously reported that HDAC 1, 4, 6 and 8 were higly expressed in MDA-MB-231 than MCF-7 cells and HDAC1, 6 and 8 excepting HDAC4 were associated with invasion that is very important factor in cancer progression. However, HDAC4 did not affect in invasion. To investigate interaction between chemoresistance and HDAC4 expression, we establish stable cells overexpressing HDAC4 in MCF-7 cells. Cells overexpressed HDAC4 were increased cytotoxicity about 5-FU and identified 356 differentially expressed genes using Ilumina array. Based on array result, we selected SMAD4 as a candidate gene related with chemoresistance because SMAD4 was previously reported evaluation of chemoresistance to 5-FU. We purpose that HDAC4 regulated with SMAD4 expression through acetylation in SMAD4 promoter region. HDAC4 directly bound a part of SMAD4 promoter. Total RNA obtained from cells overexpressed HDAC4 cDNA in MCF-7 compared to control cells.

2013-11-01 | E-GEOD-42242 | biostudies-arrayexpress

ChIP-seq analysis about Hdac4/5 samples

Project description:To identify whether Hdac4/5 were enriched in MuERVL directly, we performed Hdac4/5 ChIP-seq with anti-Hdac4/5 antibody in wildtype ESCs. we conclude that Hdac4/5 binding were enriched on MuERVL-int region and weakly enriched on MT2, suggesting a direct regulatory role of Hdac4/5 on MuERVL expression.

2022-09-05 | GSE178130 | GEO

Control of Th17 Cell Development Through Cooperative Transcriptional Activities of Class IIa HDAC4 and HDAC7

Project description:Histone deacetylases (HDACs) are long recognized for important functions in regulating gene transcription in biology and diseases. However, unlike for ubiquitously expressed class I HDACs, we have little mechanistic understanding of class II HDACs that have postulated tissue specific functions. Here we report that class IIa Hdac4 and Hdac7 are up-regulated in transcription through IL-6-Stat3 signaling selectively in mouse T-helper 17 (Th17) cells during lineage-specific differentiation, but not in Th1, Th2, and Treg subtypes. Genetic knockout of Hdac4 or Hdac7 established their importance for Th17 differentiation with different functional mechanisms. Hdac4 works with Th17 transcription factors JunB-Irf4-Batf for transcriptional activation of Th17 signature genes Il17a/f, whereas Hdac7 acts distinctively in concert with Aiolos/Ncor1/Hdac3 co-repressor complex for transcriptional repression of Th17 negative regulators including Il2. Pharmacological inhibition or gene knockout of Hdac4 and Hdac7 ameliorates development of T-cell transfer induced colitis and experimental autoimmune encephalomyelitis (EAE) in mice through blockage of Th17 cell development in colon and central nervous system that recapitulate inflammatory bowel diseases and multiple sclerosis in humans, respectively. Our study highlights a previously unknown distinct mechanisms of Hdac4 and Hdac7 in transcriptional control of Th17 cell development, and rationalizes a new therapeutic strategy of targeting class IIa HDAC4/7 for the treatment of Th17-related inflammatory and autoimmune diseases.

2023-02-03 | GSE144830 | GEO

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