Anti-IKZF2 (aa 25-75) polyclonal antibody

We investigated how one calcitriol dose plus vitamin D3 reverses experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model. This protocol rapidly increased CD4(+) T cell Ikzf2 transcripts, Helios protein, and CD4(+) Helios(+) FoxP3 T regulatory cells. It also rapidly increased CD4(+) T cell Bhmtl transcripts, betaine:homocysteine methyltransferase-1 (BHMT1) enzyme activity, and global DNA methylation. BHMT1 transmethylates homocysteine to replenish methionine. Targeting the Vdr gene in T cells decreased Ikzf2 and Bhmtl gene expression, reduced DNA methylation, and elevated systemic homocysteine in mice with EAE. We hypothesize that calcitriol drives a transition from encephalitogenic CD4(+) T cell to Treg cell dominance by upregulating Ikzf2 and Bhmtl, recycling homocysteine to methionine, reducing homocysteine toxicity, maintaining DNA methylation, and stabilizing CD4(+) Helios(+) FoxP3(+) Tregulatory cells. Conserved vitamin D-responsive element (VDRE)-type sequences in the Bhmtl and Ikzf2 promoters, the universal need for methionine in epigenetic regulation, and betaine's protective effects in MTHFR-deficiency suggest similar regulatory mechanisms exist in humans.

Genome-wide association studies have identified hundreds of risk loci for autoimmune disease, yet only a minority (similar to 25%) share genetic effects with changes to gene expression (eQTLs) in immune cells. RNA-Seq based quantification at whole-gene resolution, where abundance is estimated by culminating expression of all transcripts or exons of the same gene, is likely to account for this observed lack of colocalisation as subtle isoform switches and expression variation in independent exons can be concealed. We performed integrative cis-eQTL analysis using association statistics from twenty autoimmune diseases (560 independent loci) and RNA-Seq data from 373 individuals of the Geuvadis cohort profiled at gene-, isoform-, exon-, junction-, and intron-level resolution in lymphoblastoid cell lines. After stringently testing for a shared causal variant using both the Joint Likelihood Mapping and Regulatory Trait Concordance frameworks, we found that gene-level quantification significantly underestimated the number of causal cis-eQTLs. Only 5.0-5.3% of loci were found to share a causal cis-eQTL at gene-level compared to 12.9-18.4% at exon-level and 9.6-10.5% at junction-level. More than a fifth of autoimmune loci shared an underlying causal variant in a single cell type by combining all five quantification types; a marked increase over current estimates of steady-state causal cis-eQTLs. Causal cis-eQTLs detected at different quantification types localised to discrete epigenetic annotations. We applied a linear mixed-effects model to distinguish cis-eQTLs modulating all expression elements of a gene from those where the signal is only evident in a subset of elements. Exonlevel analysis detected disease-associated cis-eQTLs that subtly altered transcription globally across the target gene. We dissected in detail the genetic associations of systemic lupus erythematosus and functionally annotated the candidate genes. Many of the known and novel genes were concealed at gene-level (e.g. IKZF2, TYK2, LYST). Our findings are provided as a web resource.