The UHRF1 protein is a key regulator of retrotransposable elements and innate immune response to viral RNA in human cells

References

• Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nat Rev. 2013;14(3):204–18.
   Google Scholar
• Beard C, Li E, Jaenisch R. Loss of methylation activates Xist in somatic but not in embryonic cells. Genes Dev. 1995;9(19):2325–2334.
   PubMed Web of Science ®Google Scholar
• Li E, Beard C, Jaenisch R. Role for DNA methylation in genomic imprinting. Nature. 1993;366(6453):362–365.
   PubMed Web of Science ®Google Scholar
• McClintock TS. Achieving singularity in mammalian odorant receptor gene choice. Chem Senses. 2010;35(6):447–457.
   PubMed Web of Science ®Google Scholar
• Kawaguchi M, Toyama T, Kaneko R, et al. Relationship between DNA methylation states and transcription of individual isoforms encoded by the protocadherin-α gene cluster. J Biol Chem. 2008;283(18):12064–12075. DOI:10.1074/jbc.M709648200
   PubMed Web of Science ®Google Scholar
• Weber M, Hellmann I, Stadler MB, et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet. 2007;39(4):457–466. DOI:10.1038/ng1990
   PubMed Web of Science ®Google Scholar
• Walsh CPP, Chaillet JRR, Bestor THH. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet. 1998;20(2):116–117.
   PubMed Web of Science ®Google Scholar
• Chen T, Hevi S, Gay F, et al. Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells. Nat Genet. 2007;39(3):391–396. DOI:10.1038/ng1982
   PubMed Web of Science ®Google Scholar
• Loughery JEE, Dunne PD, O’Neill KM, et al. DNMT1 deficiency triggers mismatch repair defects in human cells through depletion of repair protein levels in a process involving the DNA damage response. Hum Mol Genet. 2011;20(16):3241–3255. DOI:10.1093/hmg/ddr236
   PubMed Web of Science ®Google Scholar
• Liao J, Karnik R, Gu H, et al. Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nat Genet. 2015;47(5):469–478. DOI:10.1038/ng.3258
   PubMed Web of Science ®Google Scholar
• Chiappinelli KB, Strissel P, Desrichard A, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell. 2015;162(5):974–986. DOI:10.1016/j.cell.2015.07.011
   PubMed Web of Science ®Google Scholar
• Roulois D, Loo Yau H, Singhania R, et al. DNA-Demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell. 2015;162(5):961–973. DOI:10.1016/j.cell.2015.07.056
   PubMed Web of Science ®Google Scholar
• Liu M, Thomas SL, DeWitt AK, et al. Dual Inhibition of DNA and histone methyltransferases increases viral mimicry in ovarian cancer cells. Cancer Res. 2018;78(20):5754–5766. DOI:10.1158/0008-5472.CAN-17-3953
   PubMed Web of Science ®Google Scholar
• Pyeon D, Vu L, Giacobbi NS, et al. The antiviral immune forces awaken in the cancer wars. PLOS Pathog. 2020;16(9):e1008814.
   PubMed Web of Science ®Google Scholar
• Cai Y, Tsai H-C, Yen RWC, et al. Critical threshold levels of DNA methyltransferase 1 are required to maintain DNA methylation across the genome in human cancer cells. Genome Res. 2017;27(4):533–544. DOI:10.1101/gr.208108.116
   PubMed Web of Science ®Google Scholar
• Wozniak RJ, Klimecki WT, Lau SS, et al. 5-Aza-2-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation. Oncogene. 2007;26(1):77–90.
   PubMed Web of Science ®Google Scholar
• Lees-Murdock DJ, De Felici M, Walsh CP, et al. Methylation dynamics of repetitive DNA elements in the mouse germ cell lineage. Genomics. 2003;82(2):230–237.
   PubMed Web of Science ®Google Scholar
• Hajkova P, Erhardt S, Lane N, et al. Epigenetic reprogramming in mouse primordial germ cells. Mech Dev. 2002;117(1–2):15. DOI:10.1016/S0925-4773(02)00181-8
   PubMed Web of Science ®Google Scholar
• Hill PWS, Leitch HG, Requena CE, et al. Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. Nature. 2018;555(7696):392–396. DOI:10.1038/nature25964
   PubMed Web of Science ®Google Scholar
• Karimi MM, Goyal P, Maksakova I, et al. DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mEscs. Cell Stem Cell. 2011;8(6):676–687. DOI:10.1016/j.stem.2011.04.004
   PubMed Web of Science ®Google Scholar
• Cuellar L, Herzner A-M, Zhang X, et al. Silencing of retrotransposons by SET DB1 inhibits the interferon response in acute myeloid leukemia. J Cell Bio. 2017;216(11):3535–3549. DOI:10.1083/jcb.201612160
   PubMed Web of Science ®Google Scholar
• Kassiotis G, Stoye JP. Immune responses to endogenous retroelements: taking the bad with the good. Nat Rev Immunol. 2016;16(4):207–219.
   PubMed Web of Science ®Google Scholar
• Mikkelsen TS, Ku M, Jaffe DB, et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007;448(7153):553–560. DOI:10.1038/nature06008
   PubMed Web of Science ®Google Scholar
• Sharif J, Muto M, Takebayashi S-I, et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature. 2007;450(7171):908–912. DOI:10.1038/nature06397
   PubMed Web of Science ®Google Scholar
• Bostick M, Kim JK, Esteve P-O, et al. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science. 2007;317(5845):1760–1764. DOI:10.1126/science.1147939
   PubMed Web of Science ®Google Scholar
• Rothbart SB, Krajewski K, Nady N, et al. Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation. Nat Struct Mol Biol. 2012;19(11):1155–1160. DOI:10.1038/nsmb.2391
   PubMed Web of Science ®Google Scholar
• Rothbart SB, Dickson BM, Ong MS, et al. Multivalent histone engagement by the linked tandem tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation. Genes Dev. 2013;27(11):1288–1298. DOI:10.1101/gad.220467.113
   PubMed Web of Science ®Google Scholar
• Zhao Q, Zhang J, Chen R, et al. Dissecting the precise role of H3K9 methylation in crosstalk with DNA maintenance methylation in mammals. Nat Commun. 2016;7(1).
   Google Scholar
• Sharif J, Endo T, Nakayama M, et al. Activation of endogenous retroviruses in dnmt1−/− ESCs involves disruption of SETDB1-Mediated repression by NP95 binding to hemimethylated DNA. Cell Stem Cell. 2016;19(1):81–94. DOI:10.1016/j.stem.2016.03.013
   PubMed Web of Science ®Google Scholar
• Haggerty C, Kretzmer H, Riemenschneider C, et al. Dnmt1 has de novo activity targeted to transposable elements. Nat Struct Mol Biol. 2021;28(7):594–603. DOI:10.1038/s41594-021-00603-8
   PubMed Web of Science ®Google Scholar
• Chernyavskaya Y, Mudbhary R, Tokarz D, et al. Loss of DNA methylation in zebrafish embryos activates retrotransposons to trigger antiviral signaling. Development. 2017;144:2925–2939.
   PubMed Web of Science ®Google Scholar
• Magnani E, Macchi F, Madakashira BP, et al. Uhrf1 and Dnmt1 loss induces an immune response in zebrafish livers due to viral mimicry by transposable elements. Front Immunol. 2021;12. doi:10.3389/fimmu.2021.627926.
   Web of Science ®Google Scholar
• Wang S, Zhang C, Hasson D, et al. Epigenetic compensation promotes liver regeneration. Dev Cell. 2019;50(1):43–56.e6. DOI:10.1016/j.devcel.2019.05.034
   PubMed Web of Science ®Google Scholar
• McDaid JRR, Loughery J, Dunne P, et al. MLH1 mediates PARP-dependent cell death in response to the methylating agent N-methyl-N-nitrosourea. Br J Cancer. 2009;101(3):441–451. DOI:10.1038/sj.bjc.6605186
   PubMed Web of Science ®Google Scholar
• Ouellette MM, McDaniel LD, Wright WE, et al. The establishment of telomerase-immortalized cell lines representing human chromosome instability syndromes. Hum Mol Genet. 2000;9(3):403–411.
   PubMed Web of Science ®Google Scholar
• O’Neill KM, Irwin RE, Mackin S-J, et al. Depletion of DNMT1 in differentiated human cells highlights key classes of sensitive genes and an interplay with polycomb repression. Epigenet Chromatin. 2018;11(1).
   PubMedGoogle Scholar
• Mackin S-J, O’Neill KM, Walsh CP. Comparison of DNMT1 inhibitors by methylome profiling identifies unique signature of 5-aza-2 deoxycytidine. Epigenomics. 2018;10(8):1085–1101.
   PubMed Web of Science ®Google Scholar
• Bibikova M, Barnes B, Tsan C, et al. High density DNA methylation array with single CpG site resolution. Genomics. 2011;98(4):288–295. DOI:10.1016/j.ygeno.2011.07.007
   PubMed Web of Science ®Google Scholar
• Assenov Y, Müller F, Lutsik P, et al. Comprehensive analysis of DNA methylation data with RnBeads. Nat Methods. 2014;11(11):1138–1140. DOI:10.1038/nmeth.3115
   PubMed Web of Science ®Google Scholar
• Kent WJ, Sugnet CW, Furey TS, et al. The human genome browser at UCSC. Genome Res. 2002;12(6):996–1006.
   PubMed Web of Science ®Google Scholar
• Thursby SJ, Lobo DK, Pentieva K, et al. CandiMeth: powerful yet simple visualization and quantification of DNA methylation at candidate genes. Gigascience. 2020;9(6).
   PubMed Web of Science ®Google Scholar
• Giardine B, Riemer C, Hardison RC, et al. Galaxy: a platform for interactive large-scale genome analysis. Genome Res. 2005;15(10):1451–1455. DOI:10.1101/gr.4086505
   PubMed Web of Science ®Google Scholar
• Huang WBD, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57.
   PubMed Web of Science ®Google Scholar
• Jensen S, Thomsen AR. Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion. J Virol. 2012;86(6):2900–2910.
   PubMed Web of Science ®Google Scholar
• Weber F, Wagner V, Rasmussen SB, et al. Double-Stranded RNA is produced by positive-strand RNA Viruses and DNA viruses but not in detectable amounts by negative-strand RNA Viruses. J Virol. 2006;80(10):5059–5064.
   PubMed Web of Science ®Google Scholar
• Ramesh V, Bayam E, Cernilogar FM, et al. Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration. Genes Dev. 2016;30(19):2199–2212. DOI:10.1101/gad.284992.116
   PubMed Web of Science ®Google Scholar
• Barlow DP, Randle BJ, Burke DC. Interferon synthesis in the early post-implantation mouse embryo. Differentiation. 1984;27(1–3):229–235.
   PubMed Web of Science ®Google Scholar
• Mehdiphour P, Marhon SA, Ettayebi I, et al. Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency. Nature. 2020;588(7896):169–173. DOI:10.1038/s41586-020-2844-1
   PubMedGoogle Scholar
• Arita K, Ariyoshi M, Tochio H, et al. Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature. 2008;455(7214):818–821.
   PubMed Web of Science ®Google Scholar
• Hashimoto H, Horton JR, Zhang X, et al. The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature. 2008;455(7214):826–829. DOI:10.1038/nature07280
   PubMed Web of Science ®Google Scholar
• DaRosa PA, Harrison JS, Zelter A, et al. A bifunctional role for the UHRF1 UBL domain in the control of hemi-methylated DNA-Dependent Histone Ubiquitylation. Mol Cell. 2018;72(4):753–765.e6. DOI:10.1016/j.molcel.2018.09.029
   PubMed Web of Science ®Google Scholar
• Foster BM, Stolz P, Mulholland CB, et al. Critical role of the UBL domain in stimulating the E3 Ubiquitin Ligase Activity of UHRF1 toward Chromatin. Mol Cell. 2018;72(4):739–752.e9. DOI:10.1016/j.molcel.2018.09.028
   PubMed Web of Science ®Google Scholar
• Xie S, Jakoncic J, Qian C. UHRF1 double Tudor domain and the adjacent PHD finger Act together to recognize K9me3-containing histone H3 tail. J Mol Biol. 2012;415(2):318–328.
   PubMed Web of Science ®Google Scholar
• Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992;69(6):915–926.
   PubMed Web of Science ®Google Scholar
• Lei H, Oh SP, Okano M, et al. De Novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development. 1996;122(10):3195–3205. DOI:10.1242/dev.122.10.3195
   PubMed Web of Science ®Google Scholar
• Tie CHC, Fernandes L, Conde L, et al. KAP1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control. EMBO Rep. 2018;19(10).
   PubMed Web of Science ®Google Scholar