Biology subjects

Danielli, S.

Publications and source records attributed to Danielli, S..

3 recordsLinked to original sources

bioRxiv2023

Characterisation of the genetic determinants of context specific DNA methylation in primary monocytes

DNA methylation (DNAm) has pervasive effects on gene expression and associations with ageing-related traits. Here we describe monocyte DNAm responses to inflammatory stimuli across 192 individuals. We find that, unlike the similarly widespread changes in gene expression elicited by LPS and IFN{gamma}, DNAm is markedly more sensitive to LPS. Exposure to LPS caused differential methylation at 20,858 immune-modulated CpGs (imCpGs) which display distinct genomic localisation and transcription factor usage, dependent upon whether methylation is lost or gained. Demethylated imCpGs are profoundly enriched for enhancers, and are over-represented by genes implicated in human diseases, most notably cancer. We find LPS-induced demethylation follows hydroxymethylation and for most sites the degree of demethylation correlates with baseline signal. Notably, we find LPS exposure triggers gain in epigenetic age by approximately 6 months, identifying a potential cause of accelerated epigentic aging which has diverse negative health associations. Finally, we explore the effect of genetic variation on LPS-induced changes in DNAm, identifying 209 imCpGs under genetic control. Exploring shared causal loci between LPS-induced DNAm responses and human disease traits highlights examples of human disease associated loci that also modulate imCpG formation. In summary, our findings suggest innate immune activity continually remodels DNAm in a highly punctate, enhancerenriched fashion that is under tight genetic control and predominantly involves genes commonly mutated in cancer.

genetics↗

bioRxiv2021

Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity

Natural Killer (NK) cells are innate lymphocytes with central roles in immunosurveillance and are implicated in autoimmune pathogenesis. The degree to which regulatory variants affect NK gene expression is poorly understood. We performed expression quantitative trait locus (eQTL) mapping of negatively selected NK cells from a population of healthy Europeans (n=245). We find a significant subset of genes demonstrate eQTL specific to NK cells and these are highly informative of human disease, in particular autoimmunity. An NK cell transcriptome-wide association study (TWAS) across five common autoimmune diseases identified further novel associations at 27 genes. In addition to these cis observations, we find novel master-regulatory regions impacting expression of trans gene networks at regions including 19q13.4, the Killer cell Immunoglobulin-like Receptor (KIR) Region, GNLY and MC1R. Our findings provide new insights into the unique biology of NK cells, demonstrating markedly different eQTL from other immune cells, with implications for disease mechanisms.

genetics↗

bioRxiv2018

The Autoimmune Disease Risk Allele rs6897932 Modulates Monocyte IL7R Surface and Soluble Receptor Levels in a Context-Specific Manner

IL-7 is a key factor in T-cell immunity and IL7R polymorphisms are implicated in autoimmune pathogenesis. IL7R mRNA is induced in stimulated monocytes in a genetically determined manner, yet a role for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level across multiple cell subsets and conditions in healthy individuals. We find monocyte surface and soluble IL7R (sIL7R) protein are markedly expressed in response to lipopolysaccharide (LPS). We further demonstrate alleles of rs6897932, a non-synonymous IL7R polymorphism associated with susceptibility to Multiple Sclerosis, Ankylosing Spondylitis and Primary Biliary Cirrhosis, form the key determinant of both surface IL7R and sIL7R in the context of inflammation. No effect of this allele was observed in unstimulated monocytes or across lymphoid subsets. Production of sIL7R by monocytes greatly exceeded that of CD4+ T-cells, and was strongly associated with both rs6897932 genotype and expression of the splicing factor gene DDX39A. Stimulated monocytes were sensitive to exogenous IL-7, which elicits a defined transcriptional signature. Flow cytometry and single-cell sequencing of synovial fluid derived monocytes from patients with spondyloarthritis showed an enlarged subset of IL7R+ monocytes with a unique transcriptional profile that markedly overlaps that induced by IL-7 in-vitro and shows similarity to the previously described Mono4 subset. These data demonstrate disease-associated genetic variants at IL7R specifically impact monocyte surface IL7R and sIL7R following innate immune stimulation, suggesting a previously unappreciated key role for monocytes in IL-7 pathway biology and IL7R-associated diseases.

immunology↗