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Endogenous retroviruses act as enhancers to drive species-specific germline transcriptomes in mammals

ABSTRACT: Gene regulation in the germline ensures the production of high-quality gametes, long-term maintenance of the species, and speciation. Germline transcriptomes undergo dynamic changes after the mitosis-to-meiosis transition in males and have been subject to evolutionary divergence among mammals. However, the mechanism that underlies germline regulatory divergence remains undetermined. Here, we show that endogenous retroviruses influence species-specific germline transcriptomes in mammals. We show that the endogenous retroviruses function as active enhancers to drive evolutionarily young (mouse or rodent specific) spermatogenesis-specific genes after the mitosis-to-meiosis transition in male mice. These ERV loci bear binding motifs for critical regulators of spermatogenesis such as A-MYB. The genome-wide transposition of ERVs might have rewired germline gene expression in a species-specific manner. Notably, these features are present in human spermatogenesis, but independently evolved ERVs are associated with expression of germline genes, demonstrating the prevalence of ERV-driven mechanisms in mammals. Together, we propose a model whereby species-specific transcriptomes are fine-tuned by endogenous retroviruses in the mammalian germline.

ORGANISM(S): Mus musculus

PROVIDER: GSE142173 | GEO | 2020/05/28

REPOSITORIES: GEO

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Project description:The genome of vertebrates contains endogenous retroviruses (ERVs) that have resulted from ancestral infections by exogenous retroviruses. ERVs are germline encoded, transmitted in a Mendelian fashion and account for about 8% of the human and 9.9% of the murine genome, respectively1, 2. By spontaneous activation and reintegration ERVs may cause insertional mutagenesis and thus participate in the process of malignant transformation or progression of tumor growth3, 4. However, if the innate immune system is able to recognize and control ERVs has not yet been elucidated. Here we report that, in vitro, nucleic-acid sensing TLRs on dendritic cells are activated by retroviral RNA and DNA from infected cells in vitro. Infection of TLR competent wild type mice with murine leukemia virus (MuLV)-like ERV isolates results in non-canonical gene upregulation, independent of type I IFN. In vivo, TLR3, -7 and -9 triple deficient mice (TLR379-/-) and mice with non functional TLR3, 7 and 9 signaling due to a mutation in UNC93B develop spontaneous ERV-induced viremia. More importantly, in TLR379-/- mice ERV-induced viremia correlates with acute T cell lymphoblastic leukemia (T-ALL). Multiple independent TLR379-/- T cell leukemia lines produce infectious MuLV of endogenous origin. These cell lines display de novo retroviral integration into the Nup214 or Notch1 gene locus leading to gene dysregulation that is reminiscent of aberrant Nup214 and Notch1 expression in human T-ALLs5. Overall, our results demonstrate that in addition to their role in innate immune defense against exogenous pathogens, TLR3,-7, and -9 may be essential for the control of endogenous retroviral mediated T-cell lymphomagenesis. The data covers two data sets. The data set covers two comparisons of the expression profile from old and young TLR379-/- knockout. Spleen was taken from and old wild type (C57BL/6 background) to compare it against an old TLR379-/- knockout and also from an young wild type (C57BL/6 background) to compare it against a young TLR379-/- knockout. The second experiment includes three replicates of the wild type, the Baki-1MuLV infected C57BL/6, and the Sendai infected C57BL/6.

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Endogenous retroviruses act as enhancers to drive species-specific germline transcriptomes in mammals

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