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ABSTRACT Background Aim Methods Results Conclusion Blocking IL‐13 is highly efficacious in patients with Th2‐biased atopic dermatitis (AD), and recent clinical data have highlighted that targeting the T cell costimulatory molecules OX40 and OX40L (TNFSF4) holds promise for future treatment of AD.We asked whether targeting another T cell costimulatory molecule, CD30L (TNFSF8), might also be a possible treatment option in AD.Single‐cell RNA‐seq data from human AD skin lesions was analyzed to identify pathogenic IL‐13‐ or IL‐22‐producing T cells and assess expression of CD30 and its ligand in comparison to OX40 and its ligand. Additionally, a murine model of AD with repetitive exposure to house dust mite allergen was used to compare neutralizing antibodies against CD30L with those against IL‐13 or OX40L.Analysis of several scRNA‐seq datasets from skin lesions of AD patients showed that transcripts for CD30 or CD30L were found expressed with OX40 or OX40L in the primary T cell populations that also expressed mRNA for IL13 and/or IL22. Suggesting that this could be therapeutically relevant, mice treated prophylactically with a blocking CD30L antibody were protected from developing maximal allergen‐induced AD features, including epidermal and dermal thickening, immune cell infiltration, and expression of AD‐related genes, similar to mice treated with a blocking IL‐13 antibody. Moreover, therapeutic neutralization of CD30L in mice with experimental AD also reduced all of the pathological skin lesion features to a comparable extent as blocking OX40L.These data suggest that targeting the CD30–CD30L axis might hold promise as a future therapeutic intervention in human AD, similar to targeting the OX40–OX40L axis. [ABSTRACT FROM AUTHOR]

TNF and IL-17 are two cytokines that drive dysregulated keratinocyte activity, and their targeting is highly efficacious in patients with psoriasis, but whether these molecules act with other inflammatory factors is not clear. Here, we show that mice having a keratinocyte-specific deletion of Fn14 (Tnfrsf12a), the receptor for the TNF superfamily cytokine TWEAK (Tnfsf12), displayed reduced imiquimod-induced skin inflammation, including diminished epidermal hyperplasia and less expression of psoriasis signature genes. This corresponded with Fn14 being expressed in keratinocytes in human psoriasis lesions and TWEAK being found in several subsets of skin cells. Transcriptomic studies in human keratinocytes revealed that TWEAK strongly overlaps with IL-17A and TNF in up-regulating the expression of CXC chemokines, along with cytokines such as IL-23 and inflammation-associated proteins like S100A8/9 and SERPINB1/B9, all previously found to be highly expressed in the lesional skin of patients with psoriasis. TWEAK displayed strong synergism with TNF or IL-17A in up-regulating messenger RNA for many psoriasis-associated genes in human keratinocytes, including IL23A, IL36G, and multiple chemokines, implying that TWEAK acts with TNF and IL-17 to enhance feedback inflammatory activity. Correspondingly, therapeutic treatment of mice with anti-TWEAK was equally as effective as antibodies to IL-17A or TNF in reducing clinical and immunological features of psoriasis-like skin inflammation and combination targeting of TWEAK with either cytokine had no greater inhibitory effect, reinforcing the conclusion that all three cytokines function together. Thus, blocking TWEAK could be comparable to targeting TNF or IL-17 and might be considered as an alternate therapeutic treatment for psoriasis. [ABSTRACT FROM AUTHOR]

HiChIP enables cost-effective and high-resolution profiling of regulatory and structural loops. To leverage the increasing number of publicly available HiChIP datasets from diverse cell lines and primary cells, we developed the Loop Catalog (https://loopcatalog.lji.org), a web-based database featuring HiChIP loop calls for 1319 samples across 133 studies and 44 high-resolution Hi-C loop calls. We demonstrate its utility in interpreting fine-mapped GWAS variants (SNP-to-gene linking), in identifying enriched sequence motifs and motif pairs at loop anchors, and in network-level analysis of loops connecting regulatory elements (community detection). Our comprehensive catalog, spanning over 4M unique 5kb loops, along with the accompanying analysis modalities constitutes an important resource for studies in gene regulation and genome organization., Competing Interests: Competing interests: None

The molecular circuitry that causes stem cells to exit from pluripotency remains largely uncharacterized. Using chromatin RNA in situ reverse transcription sequencing, we identified Peln1 as a novel chromatin RNA component in the promoter complex of Oct4, a stem cell master transcription factor gene. Peln1 was negatively associated with pluripotent status during somatic reprogramming. Peln1 overexpression caused E14 cells to exit from pluripotency, while Peln1 downregulation induced robust reprogramming. Mechanistically, we discovered that Peln1 interacted with the Oct4 promoter and recruited the DNA methyltransferase DNMT3A. By de novo altering the epigenotype in the Oct4 promoter, Peln1 dismantled the intrachromosomal loop that is required for the maintenance of pluripotency. Using RNA reverse transcription-associated trap sequencing, we showed that Peln1 targets multiple pathway genes that are associated with stem cell self-renewal. These findings demonstrate that Peln1 can act as a new epigenetic player and use a trans mechanism to induce an exit from the pluripotent state in stem cells., (© 2022 Wang et al.)