Post-translation modifications of histones modulate the accessibility and transcriptional competence of specific chromatin regions within the eukaryotic genome. Phosphorylation of histone H3 is unique in the sense that it associates on one hand with open chromatin during gene activation and marks on the other hand highly condensed chromatin during mitosis. Phosphorylation of serine residues at histone H3 is a highly dynamic process that creates together with acetylation and methylation marks at neighboring lysine residues specific combinatorial patterns that are read by specific detector proteins. In this review we describe the importance of different histone H3 phosphorylation marks for chromatin condensation during mitosis. In addition, we review the signals that trigger histone H3 phosphorylation and the factors that control this reversible modification during interphase and mediate the biological readout of the signal. Finally, we discuss different models describing the role of histone H3 phosphorylation in the activation of transcription of poised genes or by transient derepression of epigenetically silenced genes. We propose that histone H3 phosphorylation in the context with lysine methylation might temporarily relieve the silencing of specific genes without affecting the epigenetic memory.

Epigenetic memory mediated by Polycomb group (PcG) proteins must be maintained during cell division, but must also be flexible to allow cell fate transitions. Here we quantify dynamic chromatin-binding properties of PH::GFP and PC::GFP in living Drosophila in two cell types that undergo defined differentiation and mitosis events. Quantitative fluorescence recovery after photobleaching (FRAP) analysis demonstrates that PcG binding has a higher plasticity in stem cells than in more determined cells and identifies a fraction of PcG proteins that binds mitotic chromatin with up to 300-fold longer residence times than in interphase. Mathematical modeling examines which parameters best distinguish stem cells from differentiated cells. We identify phosphorylation of histone H3 at Ser 28 as a potential mechanism governing the extent and rate of mitotic PC dissociation in different lineages. We propose that regulation of the kinetic properties of PcG-chromatin binding is an essential factor in the choice between stability and flexibility in the establishment of cell identities.

Traditionally, cancer has been regarded to originate from genetic alterations such as mutations, deletions, rearrangements as well as gene amplifications, leading to abnormal expression of tumor suppressor genes and oncogenes. An increasing body of evidence indicates that in addition to changes in DNA sequence, epigenetic alterations contribute to cancer initiation and progression. In contrast to genetic mutations, epigenetic changes are reversible and therefore an attractive target for cancer therapy. Many epi-drugs such as histone deacetylase (HDAC) inhibitors showed anticancer activity in cell culture and animal models of carcinogenesis. Recently, the two HDAC inhibitors suberoylanilide hydroxamic acid (SAHA, Vorinostat) and Romidepsin (Depsipeptide, FK228) were FDA approved for the treatment of cutaneous T-cell lymphoma (CTCL). Although HDAC inhibitors are potent anticancer agents, these compounds act against several HDAC family members potentially resulting in numerous side effects. This stems from the fact that HDACs play crucial roles in a variety of biological processes including cell cycle progression, proliferation, differentiation, and development. Consistently, mice deficient in single HDACs mostly exhibit severe phenotypes. Therefore, it is necessary to specify the cancer-relevant HDACs in a given tumor type in order to design selective inhibitors that target only cancer cells without affecting normal cells. In this chapter, we summarize the current state of knowledge of individual nuclear HDAC family members in development and tumorigenesis, their contribution to the hallmarks of cancer, and the involvement of HDAC family members in different types of human malignancies.