Depletion of Histone Deacetylase I Protein: A Common Consequence of Inflammatory Cytokine Signaling?

The dynamics of histone acetylation and deacetylation have long been known to influence gene expression by cellular signaling pathways. However, the mechanisms that regulate histone acetyl transferases (HATs) and histone deacetylases (HDACs) by these pathways have only recently become the focus of scientific investigation, spurred by increasing knowledge that HDACs can promote cancer growth. We recently reported that pro-inflammatory signals such as tumor necrosis factor α (TNFα) induce HDAC1 ubiquitination and proteasomal degradation through the IκB kinase IKKβ. The resulting depletion of cellular HDAC1 levels lead to a consequent depletion of HDAC1 associated with the CDKN1A gene promoter and increased expression of its protein product, p^21WAF1/CIP1. This phenomenon heralds a unique mechanism of HDAC regulation that modulates the pro-inflammatory activity of TNFα and other cytokines at the level of gene expression. Here we discuss the current knowledge of pro-inflammatory cytokine-induced regulation of gene expression, emphasizing the involvement of HDAC1, and its possible implications in inflammation, cancer, and their therapy.     

HDACs, histone deacetylation and gene transcription： from molecular biology to cancer therapeutics

Histone deacetylases （HDACs） and histone acetyl transferases （HATs） are two counteracting enzyme families whose enzymatic activity controls the acetylation state of protein lysine residues, notably those contained in the N-terminal extensions of the core histones. Acetylation of histones affects gene expression through its influence on chromatin conformation. In addition, several non-histone proteins are regulated in their stability or biological function by the acetylation state of specific lysine residues. HDACs intervene in a multitude of biological processes and are part of a multiprotein family in which each member has its specialized functions. In addition, HDAC activity is tightly controlled through targeted recruitment, protein-protein interactions and post-translational modifications. Control of cell cycle progression, cell survival and differentiation are among the most important roles of these enzymes. Since these processes are affected by malignant transformation, HDAC inhibitors were developed as antineoplastic drugs and are showing encouraging efficacy in cancer patients.     

Complementary roles for histone deacetylases 1, 2, and 3 in differentiation of pluripotent stem cells

Abstract In eukaryotic cells, covalent modifications to core histones contribute to the establishment and maintenance of cellular phenotype via regulation of gene expression. Histone acetyltransferases (HATs) cooperate with histone deacetylases (HDACs) to establish and maintain specific patterns of histone acetylation. HDAC inhibitors can cause pluripotent stem cells to cease proliferating and enter terminal differentiation pathways in culture. To better define the roles of individual HDACs in stem cell differentiation, we have constructed "dominant-negative" stem cell lines expressing mutant, Flag-tagged HDACs with reduced enzymatic activity. Replacement of a single residue (His→Ala) in the catalytic center reduced the activity of HDACs 1 and 2 by 80%, and abolished HDAC3 activity; the mutant HDACs were expressed at similar levels and in the same multiprotein complexes as wild-type HDACs. Hexamethylene bisacetamide-induced MEL cell differentiation was potentiated by the individual mutant HDACs, but only to 2%, versus 60% for an HDAC inhibitor, sodium butyrate, suggesting that inhibition of multiple HDACs is required for full potentiation. Cultured E14.5 cortical stem cells differentiate to neurons, astrocytes, and oligodendrocytes upon withdrawal of basic fibroblast growth factor. Transduction of stem cells with mutant HDACs 1, 2, or 3 shifted cell fate choice toward oligodendrocytes. Mutant HDAC2 also increased differentiation to astrocytes, while mutant HDAC1 reduced differentiation to neurons by 50%. These results indicate that HDAC activity inhibits differentiation to oligodendrocytes, and that HDAC2 activity specifically inhibits differentiation to astrocytes, while HDAC1 activity is required for differentiation to neurons.     

Inhibition of histone acetylation and deacetylation enzymes affects longevity,development, and fecundity in the pea aphid (Acyrthosiphon pisum)

Histone acetylation is an evolutionarily conserved epigenetic mechanism of eukaryotic gene regulation which is tightly controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). In insects, life-history traits such as longevity and fecundity are severely affected by the suppression of HAT/HDAC activity, which can be achieved by RNA-mediated gene silencing or the application of chemical inhibitors. We used both experimental approaches to investigate the effect of HAT/HDAC inhibition in the pea aphid (Acyrthosiphon pisum) a model insect often used to study complex life-history traits. The silencing of HAT genes (kat6b, kat7, and kat14) promoted survival or increased the number of offspring, whereas targeting rpd3 (HDAC) reduced the number of viviparous offspring but increased the number of premature nymphs, suggesting a role in embryogenesis and eclosion. Specific chemical inhibitors of HATs/HDACs showed a remarkably severe impact on life-history traits, reducing survival, delaying development, and limiting the number of offspring. The selective inhibition of HATs and HDACs also had opposing effects on aphid body weight. The suppression of HAT/HDAC activity in aphids by RNA interference or chemical inhibition revealed similarities and differences compared to the reported role of these enzymes in other insects. Our data suggest that gene expression in A. pisum is regulated by multiple HATs/HDACs, as indicated by the fitness costs triggered by inhibitors that suppress several of these enzymes simultaneously. Targeting multiple HATs or HDACs with combined effects on gene regulation could, therefore, be a promising approach to discover novel targets for the management of aphid pests.     

Excessive HDAC activation is critical for neurodegeneration in the rd1 mouse

Inherited retinal degenerations, collectively termed retinitis pigmentosa (RP), constitute one of the leading causes of blindness in the developed world. RP is at present untreatable and the underlying neurodegenerative mechanisms are unknown, even though the genetic causes are often established. Acetylation and deacetylation of histones, carried out by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively, affects cellular division, differentiation, death and survival. We found acetylation of histones and probably other proteins to be dramatically reduced in degenerating photoreceptors in the rd1 human homologous mouse model for RP. Using a custom developed in situ HDAC activity assay, we show that overactivation of HDAC classes I/II temporally precedes photoreceptor degeneration. Moreover, pharmacological inhibition of HDACs I/II activity in rd1 organotypic retinal explants decreased activity of poly-ADP-ribose-polymerase and strongly reduced photoreceptor cell death. These findings highlight the importance of protein acetylation for photoreceptor cell death and survival and propose certain HDAC classes as novel targets for the pharmacological intervention in RP.     

Recent advances in class IIa histone deacetylases research

Epigenetic control plays an important role in gene regulation through chemical modifications of DNA and post-translational modifications of histones. An essential post-translational modification is the histone acetylation/deacetylation-process which is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The mammalian zinc dependent HDAC family is subdivided into three classes: class I (HDACs 1-3, 8), class II (IIa: HDACs 4, 5, 7, 9; IIb: HDACs 6, 10) and class IV (HDAC 11). In this review, recent studies on the biological role and regulation of class IIa HDACs as well as their contribution in neurodegenerative diseases, immune disorders and cancer will be presented. Furthermore, the development, synthesis, and future perspectives of selective class IIa inhibitors will be highlighted.