Proximal and Distal Regions of Pathogenic Th17 Related Chromatin Loci Are Sequentially Accessible During Pathogenicity of Th17

Abstract

Pathogenic Th17, featured by their production of pro-inflammatory cytokines, are considered as a key player in most autoimmune diseases. The transcriptome of them is obviously distinct from that of conventional regulatory Th17. However, chromatin accessibility of the two Th17 groups have not been comprehensively compared yet. Here, we found that their chromatin-accessible regions(ChARs) significantly correlated with the expression of related genes, indicating that they might engage in the regulation of these genes. Indeed, pathogenic Th17 specific ChARs (patho-ChARs) exhibited a significant distribution preference in TSS-proximal region. We further filtered the patho-ChARs based on their conservation among mammalians or their concordance with the expression of their related genes. In either situation, the filtered patho-ChARs also showed a preference for TSS-proximal region. Enrichment of expression concordant patho-ChARs related genes suggested that they might involve in the pathogenicity of Th17. Thus, we also examined all ChARs of patho-ChARs related genes, and defined an opening ChAR set according to their changes in the Th17 to Th1 conversion. Interestingly, these opening ChARs displayed a sequential accessibility change from TSS-proximal region to TSS-distal region. Meanwhile, a group of patho-TFs (transcription factors) were identified based on the appearance of their binding motifs in the opening ChARs. Consistently, some of them also displayed a similar preference for binding the TSS-proximal region. Single-cell transcriptome analysis further confirmed that these patho-TFs were involved in the generation of pathogenic Th17. Therefore, our results shed light on a new regulatory mechanism underlying the generation of pathogenic Th17, which is worth to be considered for autoimmune disease therapy.

Distinct regulatory machineries underlying divergent chromatin landscapes distinguish innate lymphoid cells from T helper cells

“…Therefore, we also investigated the genomic distribution of these ILC and Th concordant and non-concordant OCRs. Consistent with the previous studies (39)(40)(41), ILC concordant OCRs demonstrated a preferential distribution within 1 kilobase pair (kb) around TSSs compared with the Th concordant OCRs (Figure 3H). However, the distribution of ILC non-concordant OCRs did not show such a tendency (Supplementary Figure 4F).…”

Genetic distinction between functional tissue-resident and conventional natural killer cells

“…Among them, the concordant ChARs were further defined, based on two criteria: (1) ChARs related to the upregulated genes showed the highest accessibility or likewise ChARs related to the downregulated genes showed the lowest accessibility and (2) accessibility of these ChARs displayed at least 1.25-fold changes between the additional IL-21-stimulated trNK and the unstimulated or PMA/ionomycin-stimulated trNK ( Figures 7 B and S7 A). 40 Accordingly, we identified 294 concordant ChARs for the additional IL-21 stimulation-upregulated genes and 433 concordant ChARs for the additional IL-21 stimulation-downregulated genes ( Figure 7 C). Although their related genes did not account for a large proportion of the total upregulated or downregulated genes by the additional IL-21 stimulation, their enriched features recapitulated the additional IL-21 stimulation-induced changes in trNK, suggesting that the regulation of these genes might be still important ( Figure 7 D and 7E).…”

IKK1 aggravates ischemia–reperfusion kidney injury by promoting the differentiation of effector T cells

“…The pathogenetic role of Th17-cells in immune-mediated glomerular diseases and ischemia- reperfusion injury has been demonstrated recently by us and others [ 15 , 22 , 46 – 49 ]. The exact molecular mechanisms how Th17-cells are regulated once infiltrating into the kidney and how Th17-cells induce kidney injury by attacking endogenous renal glomerular, tubular epithelial and vascular endothelial cells or kidney fibroblasts remains to be defined [ 50 – 52 ].…”