<i>Ovol1/2</i> loss‐induced epidermal defects elicit skin immune activation and alter global metabolism

Dragan, Morgan; Chen, Zeyu; Li, Yumei; Le, Junming; Sun, Peng; Haensel, Daniel; Sureshchandra, Suhas; Pham, Alex D.; Lu, Eying; Pham, Kim; Verlande, Amandine; Vu, Remy; Gutierrez, Guadalupe; Li, Wei; Jang, Cholsoon; Masri, Selma; Dai, Xing

doi:10.15252/embr.202256214

Cited by 5 publications

(1 citation statement)

References 168 publications

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“…Our results point towards a gene-regulatory model of Ovo in the female germline piRNA pathway in ovaries where transcription of germline piRNA pathway genes (e.g., aub, ago3 and vas) could be directed by Ovo family TFs, analogous to the model previously suggested for A-MYB in the regulation of the male germline piRNA pathway in mice testes (Figure 7f) 31 . Similar to A-MYB, Ovo and its homologs auto-regulate their own expression [62][63][64] , and as our motif and ChIP-seq results reveal, show strong binding to germline piRNA pathway components. Our experiments show that Ovo is indeed able to activate expression of germline piRNA pathway components when ectopically expressed in fly somatic cells.…”

Section: Discussionsupporting

confidence: 54%

Ovo is a master regulator of the piRNA pathway in animal ovarian germ cells

Alizada,

Hannon,

Nicholson

2024

Preprint

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The gene-regulatory mechanisms controlling the expression of the germline PIWI- interacting RNA (piRNA) pathway components within the gonads of metazoan species remain largely unexplored. In contrast to the male germline piRNA pathway, which in mice is known to be activated by the testis-specific transcription factor A-MYB, the nature of the ovary-specific gene-regulatory network driving the female germline piRNA pathway remains a mystery. Here, using Drosophila as a model, we combine multiple genomics approaches to reveal the transcription factor Ovo as the master regulator of the germline piRNA pathway in ovaries. The enforced expression of Ovo in somatic cells activates germline piRNA pathway components, including the ping- pong factors Aubergine, Argonaute-3, and Vasa, leading to assembly of peri-nuclear cellular structures resembling nuage bodies of germ cells. Cross-species ChIP-seq and motif analyses demonstrate Ovo binding to genomic CCGTTA motifs within the promoters of germline piRNA pathway genes, suggesting a regulation by Ovo in ovaries analogous to that of A-MYB in testes. Our results also show consistent engagement of the Ovo transcription factor family at ovarian piRNA clusters across metazoan species, reflecting a deep evolutionary conservation of this regulatory paradigm from flies to humans.

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Section: Discussionsupporting

confidence: 54%

Ovo is a master regulator of the piRNA pathway in animal ovarian germ cells

Alizada,

Hannon,

Nicholson

2024

Preprint

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Fine-mapping causal tissues and genes at disease-associated loci

Strober,

Zhang,

Amariuta

et al. 2023

Preprint

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Heritable diseases often manifest in a highly tissue-specific manner, with different disease loci mediated by genes in distinct tissues or cell types. We propose Tissue-Gene Fine-Mapping (TGFM), a fine-mapping method that infers the posterior probability (PIP) for each gene-tissue pair to mediate a disease locus by analyzing GWAS summary statistics (and in-sample LD) and leveraging eQTL data from diverse tissues to build cis-predicted expression models; TGFM also assigns PIPs to causal variants that are not mediated by gene expression in assayed genes and tissues. TGFM accounts for both co-regulation across genes and tissues and LD between SNPs (generalizing existing fine-mapping methods), and incorporates genome-wide estimates of each tissue’s contribution to disease as tissue-level priors. TGFM was well-calibrated and moderately well-powered in simulations; unlike previous methods, TGFM was able to attain correct calibration by modeling uncertainty in cis-predicted expression models. We applied TGFM to 45 UK Biobank diseases/traits (averageN= 316K) using eQTL data from 38 GTEx tissues. TGFM identified an average of 147 PIP > 0.5 causal genetic elements per disease/trait, of which 11% were gene-tissue pairs. Implicated gene-tissue pairs were concentrated in known disease-critical tissues, and causal genes were strongly enriched in disease-relevant gene sets. Causal gene-tissue pairs identified by TGFM recapitulated known biology (e.g.,TPO-thyroid for Hypothyroidism), but also included biologically plausible novel findings (e.g.,SLC20A2-artery aorta for Diastolic blood pressure). Further application of TGFM to single-cell eQTL data from 9 cell types in peripheral blood mononuclear cells (PBMC), analyzed jointly with GTEx tissues, identified 30 additional causal gene-PBMC cell type pairs at PIP > 0.5—primarily for autoimmune disease and blood cell traits, including the well-established role ofCTLA4in CD8+T cells for All autoimmune disease. In conclusion, TGFM is a robust and powerful method for fine-mapping causal tissues and genes at disease-associated loci.

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An AhR-Ovol1-Id1 regulatory axis in keratinocytes promotes skin homeostasis against atopic dermatitis

Chen,

Dragan,

Sun

et al. 2024

Preprint

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Skin is our outer permeability and immune defense barrier against myriad external assaults. Aryl hydrocarbon receptor (AhR) senses environmental factors and regulates barrier robustness and immune homeostasis. AhR agonist is in clinical trial for atopic dermatitis (AD) treatment, but the underlying mechanism of action remains ill-defined. Here we reportOVOL1/Ovol1as a conserved and direct transcriptional target of AhR in epidermal keratinocytes. We show that OVOL1/Ovol1 impacts AhR regulation of keratinocyte gene expression, andOvol1deletion in keratinocytes hampers AhR’s barrier promotion function and worsens AD-like inflammation. Mechanistically, we identify Ovol1’s direct downstream targets genome-wide, and providein vivoevidence for Id1’s critical role in barrier maintenance and disease suppression. Furthermore, our findings reveal an IL-1/dermal γδT cell axis exacerbating both type 2 and type 3 immune responses downstream of barrier perturbation inOvol1-deficient AD skin. Finally, we present data suggesting the clinical relevance of OVOL1 and ID1 function in human AD. Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis against AD-like inflammation, implicating new therapeutic targets for AD.

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Ovol1/2 loss‐induced epidermal defects elicit skin immune activation and alter global metabolism

Cited by 5 publications

References 168 publications

Ovo is a master regulator of the piRNA pathway in animal ovarian germ cells

Ovo is a master regulator of the piRNA pathway in animal ovarian germ cells

Fine-mapping causal tissues and genes at disease-associated loci

An AhR-Ovol1-Id1 regulatory axis in keratinocytes promotes skin homeostasis against atopic dermatitis

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