In the conventional model of transcriptional activation, transcription factors bind to response elements and recruit co-factors, including histone acetyltransferases. Contrary to this model, we show ...that the histone acetyltransferase KAT7 (HBO1/MYST2) is required genome wide for histone H3 lysine 14 acetylation (H3K14ac). Examining neural stem cells, we find that KAT7 and H3K14ac are present not only at transcribed genes but also at inactive genes, intergenic regions, and in heterochromatin. KAT7 and H3K14ac were not required for the continued transcription of genes that were actively transcribed at the time of loss of KAT7 but indispensable for the activation of repressed genes. The absence of KAT7 abrogates neural stem cell plasticity, diverse differentiation pathways, and cerebral cortex development. Re-expression of KAT7 restored stem cell developmental potential. Overexpression of KAT7 enhanced neuron and oligodendrocyte differentiation. Our data suggest that KAT7 prepares chromatin for transcriptional activation and is a prerequisite for gene activation.
Display omitted
•KAT7 is essential for H3K14 acetylation, neuron, and oligodendrocyte differentiation•KAT7 and H3K14ac are distributed widely in the genome, including in H3K9me3+ domains•Neuronal gene expression program fails to be activated in the absence of KAT7•KAT7 creates a permissive chromatin state for transcriptional activation
The role of acetylation of specific histone lysine residues remains unclear. Kueh et al. find that the absence of the lysine acetyltransferase KAT7 in neural stem cells causes loss of H3K14 acetylation, a failure to activate the neuron differentiation gene expression program, and neuronal differentiation.
IFN-γ-driven responses to malaria have been shown to modulate the development and function of T follicular helper (TFH) cells and memory B cells (MBCs), with conflicting evidence of their involvement ...in the induction of antibody responses required to achieve clinical immunity and their association with disease outcomes. Using high-dimensional single-cell mass cytometry, we identified distinct populations of TH1-polarized CD4+ T cells and MBCs expressing the TH1-defining transcription factor T-bet, associated with either increased or reduced risk of Plasmodium vivax (P. vivax) malaria, demonstrating that inflammatory responses to malaria are not universally detrimental for infection. Furthermore, we found that, whereas class-switched but not IgM+ MBCs were associated with a reduced risk of symptomatic malaria, populations of TH1 cells with a stem central memory phenotype, TH17 cells, and T regulatory cells were associated with protection from asymptomatic infection, suggesting that activation of cell-mediated immunity might also be required to control persistent P. vivax infection with low parasite burden.
Sensitivity of eigenvectors and eigenvalues of symmetric matrix estimates to the removal of a single observation have been well documented in the literature. However, a complicating factor can exist ...in that the rank of the eigenvalues may change due to the removal of an observation, and with that so too does the perceived importance of the corresponding eigenvector. We refer to this problem as "switching of eigenvalues". Since there is not enough information in the new eigenvalues post observation removal to indicate that this has happened, how do we know that this switching has occurred? In this paper, we show that approximations to the eigenvalues can be used to help determine when switching may have occurred. We then discuss possible actions researchers can take based on this knowledge, for example making better choices when it comes to deciding how many principal components should be retained and adjustments to approximate influence diagnostics that perform poorly when switching has occurred. Our results are easily applied to any eigenvalue problem involving symmetric matrix estimators. We highlight our approach with application to a real data example.
Emerging evidence suggests that antibodies against merozoite proteins involved in P. falciparum invasion into the red blood cell (RBC) play an important role in clinical immunity to malaria. The ...protein family of parasite antigens known as P. falciparum Reticulocyte Binding Protein Homologue (PfRh) is required for RBC invasion. PfRh5 is the only member within the PfRh family that cannot be genetically deleted, suggesting it plays an essential role in parasite survival. This antigen forms a complex with the cysteine-rich P. falciparum Rh5 interacting protein (PfRipr), on the merozoite surface during RBC invasion. The PfRh5 ectodomain sequence and a C-terminal fragment of PfRipr were cloned and expressed in E. coli and baculovirus-infected cells respectively. Immunization of rabbits with these recombinant proteins induced antibodies able to inhibit growth of various P. falciparum strains. Antibody responses to these proteins were investigated in a treatment-re-infection study conducted in an endemic area of Papua New Guinea (PNG) to determine their contribution to naturally acquired immunity. Antibody titres to PfRh5 but not PfRipr showed strong association with protection against P. falciparum clinical episodes. When associations with time to first infection were analysed, high antibody levels against PfRh5 were also found to be associated with protection from high-density infections but not from re-infection. Together these results indicate that PfRh5 is an important target of protective immunity and constitutes a promising vaccine candidate.
PDF
