TY - JOUR
T1 - The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s
AU - Tunbak, Hale
AU - Enriquez-Gasca, Rocio
AU - Tie, Christopher H.C.
AU - Gould, Poppy A.
AU - Mlcochova, Petra
AU - Gupta, Ravindra K.
AU - Fernandes, Liane
AU - Holt, James
AU - van der Veen, Annemarthe G.
AU - Giampazolias, Evangelos
AU - Burns, Kathleen H.
AU - Maillard, Pierre V.
AU - Rowe, Helen M.
N1 - Funding Information:
We thank Jose Garcia-Perez for the engineered L1PA1 construct, Jan Rehwinkel for the ISRE & IFN-β reporter HEK293 cell lines, Matthew Reeves for the primary fibroblasts and Paul Lehner and Caetano Reis e Sousa for advice. We thank the Pathogen Genomics Unit at UCL run by Judy Breuer for total RNA-sequencing runs, and the TCGA and GTEx consortiums for public expression data44,45. This work was funded through a Sir Henry Dale Fellowship through the Wellcome Trust and Royal Society (Grant number 101200/Z/13/Z, supporting H.M.R., H.T., C.H.C.T., and J.H.) and a European Research Council starting grant (678350, TransposonsReprogram, supporting R.E-G., P.G., L.F., and H.M.R.). P.M. and R.G. are funded by a Wellcome Trust Senior Fellowship to R.G. (WT108082AIA). P.V.M. received funding through a Wolfson UCL Excellence Fellowship and is funded through a UKRI Future Leaders Fellowship (MR/S034498/1). This work was also supported through a consumables grant funded by the Rosetrees Trust and Robert Luff Foundation (A2630) and a Barts Charity Lectureship (MMBG1R) awarded to H.M.R. This work is dedicated to the memory of Paul Rowe.
Funding Information:
The cancer genome atlas (TCGA) and GTEx analysis. Phenotype data were downloaded from https://xenabrowser.net/ for the TCGA TARGET GTex cohort78. The phenotype table was manually curated to include only cancer types that had both a matched normal tissue from TCGA and an independent normal tissue from GTex. The TcgaTargetGtex_RSEM_Hugo_norm_count dataset was queried using the xena-Python python API. Differences in expression between cancer and control samples were statistically assessed using a Mann–Whitney U test followed by an FDR multiple test correction in python. The results shown in Fig. 6 are in part based upon data generated by the TCGA research network (https://www.cancer.gov/tcga)44, The Genotype-Tissue Expression (GTEx) Project45 and The TARGET Program (https://ocg.cancer.gov/programs/target)78. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS; the data used for the analyses described in this manuscript were obtained from dbGaP accession number phs000424.vN.pN on 01/09/2019. Raw data from Synapse ICGC-TCGA Whole Genome Pan-Cancer Analysis project (https://www.synapse.org/#!Synapse:syn2351328/wiki/62351, https://www.synapse. org/#!Synapse:syn11288411) was downloaded and visualised using UCSC Xena (https://doi.org/10.1101/326470)78. Immune subtype data were retrieved from https://xenabrowser.net/datapages/?dataset=Subtype_Immune_Model_Based. txt&host=https%3A%2F%2Fpancanatlas.xenahubs.net&addHub=https%3A%2F% 2Fxena.treehouse.gi.ucsc.edu&removeHub=https%3A%2F%2Fpcawg.xenahubs. net. Source data are available with RNA-seq datasets.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-19170-5
DO - 10.1038/s41467-020-19170-5
M3 - Article
C2 - 33144593
AN - SCOPUS:85094964903
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5387
ER -