4 research outputs found
Transcriptome dynamics of CD4âș T cells during malaria maps gradual transit from effector to memory
The dynamics of CD4âș T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4âș T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (T_H1) and follicular helper T (T_(FH)) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated T_H1 and T_(FH) trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between T_(FH) and central memory were revealed, with antimalarials modulating these responses and boosting T_H1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4âș T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and geneâgene correlations (http://haquelab.mdhs.unimelb.edu.au/cd4_memory/)
Transcriptome dynamics of CD4âș T cells during malaria maps gradual transit from effector to memory
The dynamics of CD4âș T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4âș T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (T_H1) and follicular helper T (T_(FH)) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated T_H1 and T_(FH) trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between T_(FH) and central memory were revealed, with antimalarials modulating these responses and boosting T_H1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4âș T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and geneâgene correlations (http://haquelab.mdhs.unimelb.edu.au/cd4_memory/)
Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have
fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in
25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16
regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of
correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP,
while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in
Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium
(LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region.
Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant
enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the
refined data for existing association signals, we estimate that these loci now explain âŒ38.9% of the familial relative risk of PrCa,
an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of
PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent
signals within the same regio
Transcriptome dynamics of CD4+ T cells during malaria maps gradual transit from effector to memory
The dynamics of CD4 T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4 T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (T1) and follicular helper T (T) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated T1 and T trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between T and central memory were revealed, with antimalarials modulating these responses and boosting T1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4 T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and geneâgene correlations (http://haquelab.mdhs.unimelb.edu.au/cd4_memory/)