RESUMO
The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We show that HUSH-depletion in human cell lines and primary fibroblasts leads to induction of interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect is mainly attributed to MDA5 and RIG-I sensing of double-stranded RNAs (dsRNAs). This coincides with upregulation of primate-conserved LINE-1s, as well as increased expression of full-length hominid-specific LINE-1s that produce bidirectional RNAs, which may form dsRNA. Notably, LTRs nearby ISGs are derepressed likely rendering these genes more responsive to interferon. LINE-1 shRNAs can abrogate the HUSH-dependent response, while overexpression of an engineered LINE-1 construct activates interferon signaling. Finally, we show that the HUSH component, MPP8 is frequently downregulated in diverse cancers and that its depletion leads to DNA damage. These results suggest that LINE-1s may drive physiological or autoinflammatory responses through dsRNA sensing and gene-regulatory roles and are controlled by the HUSH complex.
Assuntos
Epigênese Genética/fisiologia , Regulação Neoplásica da Expressão Gênica , Inativação Gênica/fisiologia , Interferon Tipo I/metabolismo , Elementos Nucleotídeos Longos e Dispersos/fisiologia , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/metabolismo , Dano ao DNA , Regulação para Baixo , Técnicas de Inativação de Genes , Células HEK293 , Células HeLa , Humanos , Inflamação , Helicase IFIH1 Induzida por Interferon/metabolismo , Elementos Nucleotídeos Longos e Dispersos/genética , Fosfoproteínas/metabolismo , RNA de Cadeia Dupla , Receptores Imunológicos , Análise de Sequência de RNA , Transdução de SinaisRESUMO
Retrotransposons encompass half of the human genome and contribute to the formation of heterochromatin, which provides nuclear structure and regulates gene expression. Here, we asked if the human silencing hub (HUSH) complex is necessary to silence retrotransposons and whether it collaborates with TRIM28 and the chromatin remodeler ATRX at specific genomic loci. We show that the HUSH complex contributes to de novo repression and DNA methylation of an SVA retrotransposon reporter. By using naïve versus primed mouse pluripotent stem cells, we reveal a critical role for the HUSH complex in naïve cells, implicating it in programming epigenetic marks in development. Although the HUSH component FAM208A binds to endogenous retroviruses (ERVs) and long interspersed element-1s (LINE-1s or L1s), it is mainly required to repress evolutionarily young L1s (mouse-specific lineages <5 million years old). TRIM28, in contrast, is necessary to repress both ERVs and young L1s. Genes co-repressed by TRIM28 and FAM208A are evolutionarily young, or exhibit tissue-specific expression, are enriched in young L1s, and display evidence for regulation through LTR promoters. Finally, we demonstrate that the HUSH complex is also required to repress L1 elements in human cells. Overall, these data indicate that the HUSH complex and TRIM28 co-repress young retrotransposons and new genes rewired by retrotransposon noncoding DNA.
Assuntos
Genoma Humano , Proteínas Nucleares/genética , Retroelementos/genética , Proteína 28 com Motivo Tripartido/genética , Animais , Metilação de DNA/genética , Retrovirus Endógenos/genética , Heterocromatina/genética , Humanos , Elementos Nucleotídeos Longos e Dispersos/genética , Camundongos , Regiões Promotoras GenéticasRESUMO
Cancer cells thrive on genetic and epigenetic changes that confer a selective advantage but also need strategies to avoid immune recognition. In this issue, Cuellar et al. (2017. J. Cell Biol https://doi.org/10.1083/jcb.201612160) find that the histone methyltransferase SETDB1 enables acute myeloid leukemia cells to evade sensing of retrotransposons by innate immune receptors.