Susceptibility variants on chromosome 7p21.1 suggest HDAC9 as a new candidate gene for male-pattern baldness

Histone Deacetylase 9 Deficiency Protects against Effector T Cell-mediated Systemic Autoimmunity*


Abstract

Co-repressor histone deacetylase 9 (HDAC9) plays a key role in the development and differentiation of many types of cells, including regulatory T cells. However, the biological function of HDAC9 in T effector cells is unknown. Systemic autoimmune diseases like lupus, diabetes, and rheumatoid arthritis have dysfunctional effector T cells. To determine the role of HDAC9 in systemic autoimmunity, we created MRL/lpr mice with HDAC9 deficiency that have aberrant effector T cell function. HDAC9 deficiency led to decreased lympho-proliferation, inflammation, autoantibody production, and increased survival in MRL/lpr mice. HDAC9-deficient mice manifested Th2 polarization, decreased T effector follicular cells positive for inducible co-stimulator, and activated T cells in vivo compared with HDAC9-intact MRL/lpr mice. HDAC9 deficiency also resulted in increased GATA3 and roquin and decreased BCL6 gene expression. HDAC9 deficiency was associated with increased site-specific lysine histone acetylation at H3 (H3K9, H3K14, and H3K18) globally that was localized to IL-4, roquin, and peroxisome proliferator-activated receptor-γ promoters with increased gene expression, respectively. In kidney and spleen, HDAC9 deficiency decreased inflammation and cytokine and chemokine production due to peroxisome proliferator-activated receptor γ overexpression. These findings suggest that HDAC9 acts as an epigenetic switch in effector T cell-mediated systemic autoimmunity.

Sulforaphane may inhibit histone deacetylase (HDAC) activity.[10][11]

Preliminary experiments indicate sulforaphane may protect the heart from vascular inflammation and atherosclerosis.[12]

Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection


+ Author Affiliations

1Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland;
2Service of Infectious Diseases, Genomic Research Laboratory, Geneva University Hospitals, Geneva, Switzerland; and
3Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

Abstract

Regulated by histone acetyltransferases and deacetylases (HDACs), histone acetylation is a key epigenetic mechanism controlling chromatin structure, DNA accessibility, and gene expression. HDAC inhibitors induce growth arrest, differentiation, and apoptosis of tumor cells and are used as anticancer agents. Here we describe the effects of HDAC inhibitors on microbial sensing by macrophages and dendritic cells in vitro and host defenses against infection in vivo. HDAC inhibitors down-regulated the expression of numerous host defense genes, including pattern recognition receptors, kinases, transcription regulators, cytokines, chemokines, growth factors, and costimulatory molecules as assessed by genome-wide microarray analyses or innate immune responses of macrophages and dendritic cells stimulated with Toll-like receptor agonists. HDAC inhibitors induced the expression of Mi-2β and enhanced the DNA-binding activity of the Mi-2/NuRD complex that acts as a transcriptional repressor of macrophage cytokine production. In vivo, HDAC inhibitors increased the susceptibility to bacterial and fungal infections but conferred protection against toxic and septic shock. Thus, these data identify an essential role for HDAC inhibitors in the regulation of the expression of innate immune genes and host defenses against microbial pathogens.

aAny idea what purpouse these genes serve or is it a flaw?

LPS regulates proinflammatory gene expression in macrophages by altering histone deacetylase expression
Hnin Thanda Aung*,,†,1, Kate Schroder*,,†,1, Stewart R. Himes*,,†, Kristian Brion*,,†, Wendy van Zuylen*,,†, Angela Trieu*,,†, Harukazu Suzuki‡, Yoshihide Hayashizaki‡, David A. Hume*,,†, Matthew J. Sweet*,,† and Timothy Ravasi*,,†,‡,2

* Cooperative Research Centre for Chronic inflammatory Diseases and

† Australian Research Council Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, Australia;

‡ Laboratory for Genome Exploration Research Group, RIKEN Genomic Sciences Center, RIKEN Yokohama Institute, Tsurumi-ku, Yokohama, Japan; and

† Department of Bioengineering, University of California, San Diego, California, USA

2Correspondence: Department of Bioengineering, University of California, San Diego, CA, USA. E-mail: travasi@bioeng.ucsd.edu

ABSTRACT

Bacterial LPS triggers dramatic changes in gene expression in macrophages. We show here that LPS regulated several members of the histone deacetylase (HDAC) family at the mRNA level in murine bone marrow-derived macrophages (BMM). LPS transiently repressed, then induced a number of HDACs (Hdac-4, 5, 7) in BMM, whereas Hdac-1 mRNA was induced more rapidly. Treatment of BMM with trichostatin A (TSA), an inhibitor of HDACs, enhanced LPS-induced expression of the Cox-2, Cxcl2, and Ifit2 genes. In the case of Cox-2, this effect was also apparent at the promoter level. Overexpression of Hdac-8 in RAW264 murine macrophages blocked the ability of LPS to induce Cox-2 mRNA. Another class of LPS-inducible genes, which included Ccl2, Ccl7, and Edn1, was suppressed by TSA, an effect most likely mediated by PU.1 degradation. Hence, HDACs act as potent and selective negative regulators of proinflammatory gene expression and act to prevent excessive inflammatory responses in macrophages.

aTaken from Wikipedia.

Sulforaphane may inhibit histone deacetylase (HDAC) activity.[10][11]

Preliminary experiments indicate sulforaphane may protect the heart from vascular inflammation and atherosclerosis.[12]

Probiotic metabolites such as butyrate are therefore an important class of therapeutic compounds. These SCFAs are also a well-known class of epigenetic drugs known as histone deacetylase inhibitors (HDACi) that have a central role as anti-cancer agents with strong anti-proliferative effects on tumour cells [28,29]. This activity of SCFAs may explain the anti-inflammatory effects observed for probiotic bacteria. Intriguingly, the principal HDACi compound is butyric acid (sodium butyrate) which inhibits most HDAC enzymes except class III and class II HDACs 6 and 10 [30]. Butyrate is one of the most potent HDACi in human colon cancer cell lines suggesting an integral role as anti-inflammatory derivatives of microbial fermentation in the colon [24]. Studies using fecal fermentation supernatants were found to be rich in butyrate and exhibited strong HDAC inhibitory properties in several colon cancer cell lines [31]. The HDACi activity of butyrate and propionate was associated with blockade of DC development primarily through the Na+ coupled monocarboxylate transporter Slc5a8 [32].

imprisoned-radical Yesterday at 4:19 am

a<="" cite="">Taken from Wikipedia.

Sulforaphane may inhibit histone deacetylase (HDAC) activity.[10][11]

Preliminary experiments indicate sulforaphane may protect the heart from vascular inflammation and atherosclerosis.[12]



Time to get some broccoli sprouts.

The most significant association signal was obtained for rs756853 (P=1.64x10(-7) ), which is located intronically in the histone deacetylase 9 (HDAC9) gene. Fine-mapping and a family-based analysis revealed that rs756853 and the 6kb distal rs2249817 were the most highly associated SNPs.