eviction. Dr Schneider’s studies show that the list of discovered histone modifications is far from complete. He also highlighted the possibility of histones directly altering nucleosome structure through modifications of the nucleosomal core. Histones are essential for viability. In an elegant genetic and biochemical approach, the groups of Jürg Müller (MPI of Biochemistry, Germany) and Alf Herzig (MPI of Biophysical Chemistry, Göttingen) further characterized the function of histones and their modifications in vivo. Using a conditional knockout of the histone cluster and a transgenic recovery sys- tem, they were able to investigate the importance of histones and their modifications and the role of histone variants in the fruit fly Drosophila melanogaster.19 Due to its genetics, Drosophila is an excellent model organism for this study. Specifically, the develop- ing wing disc offered a good system to analyze viability and divi- sion of cells with altered histones during development. With this assay system, Müller, Herzig and colleagues showed that histone variants are unable to compensate for the loss of S-phase synthe- sized core histones. However, despite showing somewhat reduced proliferation rates, loss of the linker histone H1 permitted cells to continue to proliferate possibly because the lack of H1 was com- pensated for by non-histone chromosomal proteins. This assay system also enabled the investigation of the importance of spe- cific histone modifications. It was found that mutation of histone residues that are subject to particular modifications cause pheno- typic alterations due to perturbed gene expression. Together, this study provided novel insights into the role of histones and their modifications during development. Natural and Synthetic “Histone Mimics” Alexander Tarakhovsky (Rockefeller University) discussed how pathogenic or synthetic proteins with histone-like sequences (his- tone mimics) can function as potent inhibitors of inflammatory gene expression. Histone mimics, such as the H3N2 influenza non-structural protein 1 (NS1) that is important for viral infec- tion, can interfere with the human antiviral response via inhibit- ing the transcription elongation complex hPAF1C. This discovery also identified hPAF1 as a potential target for treatment in thera- peutic applications. Upon viral infection, mammalian cells recruit chromatin remodeling complexes that open up the chromatin of antiviral gene promoters. This response specifically facilitates the expression of antiviral genes. Like the synthetic histone mimic I-BET,20 the C-terminal tail of NS1 contains a sequence motif that mimics the N terminus of histone H3. The histone-like sequence (ARSK) can be methylated at lysine 229, by the histone modifying enzymes Set1C and Set7/9 or acetylated, by histone acetyltransfer- ase TIP60. Biochemical analysis showed that NS1 interacts with the hPAF1C and the hCHD1 chromatin remodeling complex. This interaction may facilitate NS1 positioning in proximity to viral induced promoters. NS1 interferes with the transcription of virus-induced genes, while the transcription of housekeeping genes is not affected. Repression of virus-induced transcription of anti- viral genes was hPAF1C-dependent. Moreover, depletion of the histone mimic of NS1 in recombinant H3N2 influenza greatly enhanced transcription of antiviral genes and reduced the viral infection titer. This suggests that the histone mimic in the tail of NS1 interferes with hPAF1C-dependent transcriptional elongation of antiviral response genes.21 Transcriptional Control by Nucleotide Biosynthetic Enzymes Metabolic enzymes are usually thought to be downstream of regulatory networks. Peter Verrijzer (Erasmus University Medical Centre, Netherlands), however, showed that GMP synthetase (GMPS) can function as a gene specific transcriptional co-repres- sor.22,23 GMPS is required for deubiquitination of histone H2B by USP7. Dr Verrijzer demonstrated that, in humans, GMPS stabi- lizes p53 by stimulating its deubiquitination by USP7. Knockdown of GMPS and USP7 affected the expression of p53 target genes. GMPS localizes mostly to the cytoplasm, where it maintains the pool of nucleotides. Upon stress induction, GMPS accumulates in the nucleus. However, depletion of the guanidine nucleotide pool causes a GMPS-mediated p53 response. GMPS retention in the cytoplasm is mediated by a ubiquitylation dependent mechanism, thus preventing p53 induction. When deubiquitinated, GMPS is imported to the nucleus and pairs with USP7 to stabilize p53. Heterochromatin Regulation Hypoacetylation and H3K9me enrichment are key features of heterochromatin. Yet, the requirements for establishing and maintaining a heterochromatic region are not well understood. Gunnar Schotta (LMU Munich, Germany) identified chromatin compaction by Suv4-20h2 to be essential for cohesin recruitment to heterochromatin.24 Suv4-20h2 is stabilized at heterochroma- tin loci through multiple HP1 interactions. Cells with depleted Suv4-20h2 levels exhibits increased DNA accessibility and wider centromere distances. After a detailed analysis, Dr Schotta found that Suv4-20h2 condenses chromatin via cohesin recruitment, identifying a molecular cascade between H3K9me3/H4K20me3 and chromatin compaction. Oliver Bell, from Gerald Crabtree’s lab (HHMI and Stanford University), discussed the kinetics of H3K9me propagation and epigenetic inheritance. Dr Bell and colleagues found that direct targeting of HP1α could nucleate the formation of a heterochro- matic H3K9me3 domain that propagated at rates of approxi- mately 5.7 h per nucleosome in pluripotent cells and 6.9 h per nucleosome in mouse embryonic fibroblast cells. The research- ers demonstrated that heterochromatic domains could be stably inherited through cell divisions even after removal of the HP1α stimulus. However, heterochromatin does not present a static barrier to transcription as strong activation could overcome HP1 dependent gene repression.25 Higher Order Chromatin Structure and Long Range Interactions Wouter de Laat, from the Hubrecht Institute (Netherlands), pre- sented a novel 3D analysis of the genome of pluripotent ESCs and showed that it undergoes major structural changes during 1214 Epigenetics Volume 7 issue 10