The diversity of zinc-finger genes on human chromosome 19 provides an evolutionary mechanism for defense against inherited endogenous retroviruses

Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections of the germ line that can remain capable of replication within the host genome. In the soma, DNA methylation and repressive chromatin keep the majority of this parasitic DNA transcriptionally silent. However, it is unclear how the host organism adapts to recognize and silence novel invading retroviruses that enter the germ line. Krueppel-Associated Box (KRAB)-associated protein 1 (KAP1) is a transcriptional regulatory factor that drives the epigenetic repression of many different loci in mammalian genomes. Here, we use published experimental data to provide evidence that human KAP1 is recruited to endogenous retroviral DNA by KRAB-containing zinc-finger transcription factors (TFs). Many of these zinc-finger genes exist in clusters associated with human chromosome 19. We demonstrate that these clusters are located at hotspots for copy number variation (CNV), generating a large and continuing diversity of zinc-finger TFs with new generations. These zinc-finger genes possess a wide variety of DNA binding affinities, but their role as transcriptional repressors is conserved. We also perform a computational study of the different ERVs that invaded the human genome during primate evolution. We find candidate zinc-finger repressors that arise in the genome for each ERV family that enters the genomes of primates. In particular, we show that those repressors that gained their binding affinity to retrovirus sequences at the same time as their targets invaded the human lineage are preferentially located on chromosome 19 (P-value: 3 × 10−3).

DNA methylation of human endogenous retrovirus in systemic lupus erythematosus : Journal of Human Genetics

Previous studies have reported that T cells from active systemic lupus erythematosus (SLE) patients contained global hypomethylation and demethylation at the promoter of several genes, which may contribute to the pathogenesis of the disease. Currently there are scarce data on methylation of retroelements in patients with SLE. We estimated and compared the methylated levels of human endogenous retroviruses (HERV)-E and HERV-K in normal and SLE CD3+CD4+ T lymphocytes, CD8+ T and B lymphocytes by using combined bisulfite restriction analysis-interspersed repetitive sequences (COBRA-IRS). HERV-E LTR2C methylation level in CD3+CD4+ T lymphocytes of active SLE was significantly lower than inactive SLE and normal controls (P=0.023 and 0.035, respectively). Surprisingly, HERV-K LTR5_Hs hypomethylation was significantly detected in CD3+CD4+ T lymphocytes from patients with inactive SLE when compared with the active SLE and normal controls (P=0.027 and 0.002, respectively). Demethylation of HERV-K LTR5_Hs in B cells was also detected when compared with the normal controls (P=0.048). Furthermore, the hypomethylation of HERV-E LTR2C in CD3+CD4+ T lymphocytes was positively correlated with lymphopenia in active SLE, whereas the hypomethylation of HERV-K LTR5_Hs was significantly correlated with complement activity and Systemic Lupus Erythematosus Disease Activity Index score. In summary, for each lymphocyte subset in patients with SLE, IRS hypomethylation was found to be type specific. Further studies are needed to confirm and explain these observations.

(Thanks Daniel)

Resurrection of endogenous retroviruses in antibody-deficient mice : Nature : Nature Publishing Group

The mammalian host has developed a long-standing symbiotic relationship with a considerable number of microbial species. These include the microbiota on environmental surfaces, such as the respiratory and gastrointestinal tracts¹, and also endogenous retroviruses (ERVs), comprising a substantial fraction of the mammalian genome^2, 3. The long-term consequences for the host of interactions with these microbial species can range from mutualism to parasitism and are not always completely understood. The potential effect of one microbial symbiont on another is even less clear. Here we study the control of ERVs in the commonly used C57BL/6 (B6) mouse strain, which lacks endogenous murine leukaemia viruses (MLVs) able to replicate in murine cells. We demonstrate the spontaneous emergence of fully infectious ecotropic⁴ MLV in B6 mice with a range of distinct immune deficiencies affecting antibody production. These recombinant retroviruses establish infection of immunodeficient mouse colonies, and ultimately result in retrovirus-induced lymphomas. Notably, ERV activation in immunodeficient mice is prevented in husbandry conditions associated with reduced or absent intestinal microbiota. Our results shed light onto a previously unappreciated role for immunity in the control of ERVs and provide a potential mechanistic link between immune activation by microbial triggers and a range of pathologies associated with ERVs, including cancer.