A New Family of “H3L-Like” Histone Genes

The H3L histone variant gene in Paracentrotus lividus (sea urchin) shows almost all typical features of the replication-dependent histone genes, but it codes for the H3.3 histone protein with the S.//. A.IG amino acid motif, which is typical of the variants synthesized in a replication-independent manner. H3L-like histone genes have been found in several unrelated organisms. These genes are intronless and encode for the typical H3.3 histone proteins. The newly described family of H3L-like variants, nearly ubiquitous within the animal kingdom, could represent the common ancestor of H3 and H3.3 histone genes.     

Structural Mechanism of TAF-Iβ Chaperone Function on Linker Histone H1.10

Linker histone H1, facilitated by its chaperones, plays an essential role in regulating gene expression by maintaining chromatin’s higher-order structure and epigenetic state. However, we know little about the structural mechanism of how the chaperones recognize linker histones and conduct their function. Here, we used biophysical and biochemical methods to investigate the recognition of human linker histone isoform H1.10 by the TAF-Iβ chaperone. Both H1.10 and TAF-Iβ proteins consist of folded cores and disordered tails. We found that H1.10 formed a complex with TAF-Iβ in a 2:2 stoichiometry. Using distance restraints obtained from methyl-TROSY NMR and spin labels, we built a structural model for the core region of the complex. In the model, the TAF-Iβ core interacts with the globular domain of H1.10 mainly through electrostatic interactions. We confirmed the interactions by measuring the effects of mutations on the binding affinity. A comparison of our structural model with the chromatosome structure shows that TAF-Iβ blocks the DNA binding sites of H1.10. Our study provides insights into the structural mechanism whereby TAF-Iβ functions as a chaperone by preventing H1.10 from interacting with DNA directly.     

Histone deacetylases – a new target for suppression of cartilage degradation?

Increased expression of metalloproteinases is a fundamental aspect of arthritispathology and its control is a major therapeutic objective. In cartilage cultured in the presence of the cytokines interleukin-1 and oncostatin M, chondrocytes produce enhanced levels of metalloproteinases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and MMP (matrix metalloproteinase) families, resulting in the degradation of aggrecan and collagen. The histone deacetylase inhibitors trichostatin A and butyrate were shown to drastically reduce expression of these enzymes relatively selectively, with concomitant inhibition of breakdown of matrix components. This family of enzymes is therefore a promising target for therapeutic intervention.     

Histone methyltransferases: a new class of therapeutic targets in cancer treatment?

Epigenetic gene regulation contributes, together with genetic alterations, to cancer development and progression. In contrast to genetic disorders, the possibility of reversing epigenetic alterations has provided original targets for therapeutic application. In the last years, work has been focused on the pharmacological restoration of epigenetic regulation balance using epidrugs which yield hopes for novel strategy in cancer therapy. Histone acetylation and DNA methylation are epigenetic modifications which have been closely linked to the pathology of human cancers, and inhibitors of both enzyme classes for clinical use are at hands. Novel findings accumulated during the last years both in chemistry and biomedical applications give rise to new targeted treatments against cancer. Since their links with pathogenesis and progression of cancer were recognized, histone methyltransferases emerge as promising therapeutic targets in cancer treatment.     

Apoptotic Phosphorylation of Histone H3 on Ser-10 by Protein Kinase C��

Phosphorylation of histone H3 on Ser-10 is regarded as an epigenetic mitotic marker and is tightly correlated with chromosome condensation during both mitosis and meiosis. However, it was also reported that histone H3 Ser-10 phosphorylation occurs when cells are exposed to various death stimuli, suggesting a potential role in the regulation of apoptosis. Here we report that histone H3 Ser-10 phosphorylation is mediated by the pro-apoptotic kinase protein kinase C (PKC) δ during apoptosis. We observed that PKCδ robustly phosphorylates histone H3 on Ser-10 both in vitro and in vivo. Ectopic expression of catalytically active PKCδ efficiently induces condensed chromatin structure in the nucleus. We also discovered that activation of PKCδ is required for histone H3 Ser-10 phosphorylation after treatment with DNA damaging agents during apoptosis. Collectively, these findings suggest that PKCδ is the kinase responsible for histone H3 Ser-10 phosphoryation during apoptosis and thus contributes to chromatin condensation together with other apoptosis-related histone modifications. As a result, histone H3 Ser-10 phosphorylation can be designated a new ‘apoptotic histone code’ mediated by PKCδ.     

Histone variants: are they functionally heterogeneous?

In most eukaryotes, histones, which are the major structural components of chromatin, are expressed as a family of sequence variants encoded by multiple genes. Because different histone variants can contribute to a distinct or unique nucleosomal architecture, this heterogeneity can be exploited to regulate a wide range of nuclear functions, and evidence is accumulating that histone variants do indeed have distinct functions.     

Regulation of the Nuclear–Cytoplasmic Traffic of Class IIa Histone Deacethylases in Rat Soleus Muscle at the Early Stage of Gravitational Unloading

The negative regulation of expression of genes involved in various metabolic pathways in a skeletal muscle is the main function of histone deacetylases 4 and 5 (HDAC4/HDAC5). HDAC4 and HDAC5 seem to be the targets of the AMP-activated protein kinase (AMPK). Earlier, an essential decrease in the level of Thr172-phosphorylated-AMPK in a rat soleus muscle at the first day of gravitational unloading was shown. Possibility of a protein kinase D (PKD) to phosphorylate histone deacetylases 4/5 has been shown, too. We supposed that under the conditions of gravitational unloading, alterations in AMPK phosphorylation level can affect regulation of nuclear-cytoplasmic traffic of class II histone deacetylases and of various skeletal muscle genes expression. To verify the hypothesis, we used administration of an AMPK activator, AICAR, before and during a day-long hindlimb suspension. It was shown that at an early stage of gravitational unloading, HDAC4 is not a PKD target, and its nuclear import is realized due to decrease in AMPK activity. We were the first to show reciprocal relations between AMPK and PKD in a skeletal muscle at early gravitational unloading.