C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line

Zoch, Ansgar; Konieczny, Gabriela; Auchynnikava, Tania; Stallmeyer, Birgit; Rotte, Nadja; Heep, Madeleine; Berrens, Rebecca V.; Schito, Martina; Kabayama, Yuka; Schöpp, Theresa; Kliesch, Sabine; Houston, Brendan; Nagirnaja, Liina; O’Bryan, Moira K.; Aston, Kenneth I.; Conrad, Donald F.; Rappsilber, Juri; Allshire, Robin C.; Cook, Atlanta G.; Tüttelmann, Frank; O’Carroll, Dónal

doi:10.1016/j.molcel.2024.01.014

Cited by 2 publications

References 88 publications

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Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility

Stallmeyer,

Bühlmann,

Stakaitis

et al. 2024

Nat Commun

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AbstractpiRNAs are crucial for transposon silencing, germ cell maturation, and fertility in male mice. Here, we report on the genetic landscape of piRNA dysfunction in humans and present 39 infertile men carrying biallelic variants in 14 different piRNA pathway genes, including PIWIL1, GTSF1, GPAT2, MAEL, TDRD1, and DDX4. In some affected men, the testicular phenotypes differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal sperm. A reduced number of pachytene piRNAs was detected in the testicular tissue of variant carriers, demonstrating impaired piRNA biogenesis. Furthermore, LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. These results establish the disrupted piRNA pathway as a major cause of human spermatogenic failure and provide insights into transposon silencing in human male germ cells.

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Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility

Stallmeyer,

Bühlmann,

Stakaitis

et al. 2024

Nat Commun

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IFNγ regulates ferroptosis in KFs by inhibiting the expression of SPOCD1 through DNMT3A

Wang,

Yang,

Zhou

et al. 2024

Preprint

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Keloid is benign skin tumor, and their curing is relatively difficult due to the unclear mechanism of formation. Inducing ferroptosis of keloid fibroblasts (KFs) may become a new method for treating keloid. Here, we discover interferon (IFN)γ could induce KFs ferroptosis through inhibiting SPOC domain-containing protein 1 (SPOCD1), serving as a mode of action for CD8+T cell (CTL)-mediated keloid killing. Mechanistically, keloid IFNγ deficiency in combination with reduced DNMT3A increase the expression of SPOCD1, thereby promoting KFs’ proliferation and inhibiting its ferroptosis. Moreover, keloid SPOCD1 deficiency attenuates KFs progression and extracellular matrix (ECM) deposition. Reducing IFNγ and SPOCD1 simultaneously can increase the positive rate of reactive oxygen species (ROS) and promote mitochondrial shrinkage. Ex-vivo explant keloid culture has also confirmed that the reduction of SPOCD1 helps to reduce the proliferation rate of KFs, inhibit the angiogenesis of keloid scars, and thus inhibit keloid formation. Thus, IFNγ signaling paired with SPOCD1 is a natural keloid ferroptosis promoting mechanism and a mode of action of CTLs. Targeting SPOCD1 pathway is a potential anti-keloid approach.

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C19ORF84 connects piRNA and DNA methylation machineries to defend the mammalian germ line

Cited by 2 publications

References 88 publications

Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility

Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility

IFNγ regulates ferroptosis in KFs by inhibiting the expression of SPOCD1 through DNMT3A

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