Drosophila Enhancer of Polycomb, E(Pc), is a suppressor of position-effect variegation and an enhancer of both Polycomb and trithorax mutations. A homologous yeast protein, Epl1, is a subunit of the NuA4 histone acetyltransferase complex. Epl1 depletion causes cells to accumulate in G2/M and global loss of acetylated histones H4 and H2A. In relation to the Drosophila protein, mutation of Epl1 suppresses gene silencing by telomere position effect. Epl1 protein is found in the NuA4 complex and a novel highly active smaller complex named Piccolo NuA4 (picNuA4). The picNuA4 complex contains Esa1, Epl1, and Yng2 as subunits and strongly prefers chromatin over free histones as substrate. Epl1 conserved N-terminal domain bridges Esa1 and Yng2 together, stimulating Esa1 catalytic activity and enabling acetylation of chromatin substrates. A recombinant picNuA4 complex shows characteristics similar to the native complex, including strong chromatin preference. Cells expressing only the N-terminal half of Epl1 lack NuA4 HAT activity, but possess picNuA4 complex and activity. These results indicate that the essential aspect of Esa1 and Epl1 resides in picNuA4 function. We propose that picNuA4 represents a nontargeted histone H4/H2A acetyltransferase activity responsible for global acetylation, whereas the NuA4 complex is recruited to specific genomic loci to perturb locally the dynamic acetylation/deacetylation equilibrium.

NuA4 is an essential histone H4/H2A acetyltransferase complex that interacts with activators and stimulates transcription in vitro. We have identified three novel NuA4 subunits: Act3/Arp4, an actin-related protein implicated in epigenetic control of transcription, Act1, and Epl1, a protein homologous to Drosophila Enhancer of Polycomb. Act3/Arp4 binds nucleosomes in vitro and is required for NuA4 integrity in vivo. Mutations in ACT3 and acetyltransferase-encoding ESA1 cause gene-specific transcription defects. Accordingly, NuA4 is localized in precise loci within the nucleus and does not overlap with the silent chromatin marker Sir3. These data along with the known epigenetic roles of Act3/Arp4 and homologs of Epl1 and Esa1 strongly support an essential role for chromatin structure modification by NuA4 in transcription regulation in vivo.

It is not known whether pandemic 2009 influenza A/H1N1 (2009 H1N1) leads to more serious disease than seasonal influenza in hematopoietic cell transplant (HCT) recipients. In a retrospective study in HCT recipients with virologically proven influenza virus infection, a total of 161 HCT recipients (18 2009 H1N1, 103 seasonal influenza A, and 40 seasonal influenza B) were analyzed. In multivariable analyses, more patients with 2009 H1N1 had lower respiratory tract disease (LRD), hypoxemia, and prolonged viral shedding compared with seasonal influenza A. Seasonal influenza A and B outcomes were similar. There was no difference in overall and influenza-associated mortality among influenza virus types. Both early and delayed administration of antiviral therapy was shown to be beneficial in terms of decreased rates of development of LRD, although earlier intervention appeared to be more effective. Profound lymphopenia and lack of early antiviral therapy were associated significantly with LRD, hypoxemia, and death. High-dose corticosteroid treatment (≥ 1 mg/kg) given at the time of influenza diagnosis was associated with a reduced risk for mechanical ventilation. Thus, our data suggest that infection with 2009 influenza A/H1N1 resulted in more severe respiratory disease in HCT recipients compared with seasonal influenza.