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Keep quiet: the HUSH complex in transcriptional silencing and disease

Nature Structural & Molecular Biology volume 31, pages 11–22 (2024)Cite this article

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Abstract

The human silencing hub (HUSH) complex is an epigenetic repressor complex whose role has emerged as an important guardian of genome integrity. It protects the genome from exogenous DNA invasion and regulates endogenous retroelements by recruiting histone methyltransferases catalyzing histone 3 lysine 9 trimethylation (H3K9me3) and additional proteins involved in chromatin compaction. In particular, its regulation of transcriptionally active LINE1 retroelements, by binding to and neutralizing LINE1 transcripts, has been well characterized. HUSH is required for mouse embryogenesis and is associated with disease, in particular cancer. Here we provide insights into the structural and biochemical features of the HUSH complex. Furthermore, we discuss the molecular mechanisms by which the HUSH complex is recruited to specific genomic regions and how it silences transcription. Finally, we discuss the role of HUSH complex members in mammalian development, antiretroviral immunity, and diseases such as cancer.

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Fig. 1: Schematic of the architecture of the HUSH complex.
Fig. 2: Domain structures of the HUSH core complex and associated catalytic subunits.
Fig. 3: Models for HUSH complex recruitment and HUSH-mediated transcriptional repression.
Fig. 4: Biological roles of the HUSH complex.

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References

  1. Tchasovnikarova, I. A. et al. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science 348, 1481–1485 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Eberl, H. C., Spruijt, C. G., Kelstrup, C. D., Vermeulen, M. & Mann, M. A map of general and specialized chromatin readers in mouse tissues generated by label-free interaction proteomics. Mol. Cell 49, 368–378 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Muller, H. J. & Altenburg, E. The frequency of translocations produced by X-rays in Drosophila. Genetics 15, 283–311 (1930).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Blewitt, M. E. et al. An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse. Proc. Natl Acad. Sci. USA 102, 7629–7634 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Matsumoto-Taniura, N., Pirollet, F., Monroe, R., Gerace, L. & Westendorf, J. M. Identification of novel M phase phosphoproteins by expression cloning. Mol. Biol. Cell 7, 1455–1469 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Bua, D. J. et al. Epigenome microarray platform for proteome-wide dissection of chromatin-signaling networks. PLoS ONE 4, e6789 (2009).

    Article  PubMed  Google Scholar 

  7. Kokura, K., Sun, L., Bedford, M. T. & Fang, J. Methyl-H3K9-binding protein MPP8 mediates E-cadherin gene silencing and promotes tumour cell motility and invasion. EMBO J. 29, 3673–3687 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Kazerounian, S. & Aho, S. Characterization of periphilin, a widespread, highly insoluble nuclear protein and potential constituent of the keratinocyte cornified envelope. J. Biol. Chem. 278, 36707–36717 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Kurita, M., Suzuki, H., Kawano, Y., Aiso, S. & Matsuoka, M. CR/periphilin is a transcriptional co-repressor involved in cell cycle progression. Biochem. Biophys. Res. Commun. 364, 930–936 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Garcia-Perez, J. L., Widmann, T. J. & Adams, I. R. The impact of transposable elements on mammalian development. Development 143, 4101–4114 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Min, J., Zhang, Y. & Xu, R. M. Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27. Genes Dev. 17, 1823–1828 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jacobs, S. A. & Khorasanizadeh, S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 295, 2080–2083 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Nielsen, P. R. et al. Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9. Nature 416, 103–107 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Li, J. et al. Structural basis for specific binding of human MPP8 chromodomain to histone H3 methylated at lysine 9. PLoS ONE 6, e25104 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chang, Y. et al. MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a. Nat. Commun. 2, 533 (2011).

    Article  PubMed  Google Scholar 

  16. Brasher, S. V. et al. The structure of mouse HP1 suggests a unique mode of single peptide recognition by the shadow chromo domain dimer. EMBO J. 19, 1587–1597 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Cruz-Tapias, P., Robin, P., Pontis, J., Maestro, L. D. & Ait-Si-Ali, S. The H3K9 methylation writer SETDB1 and its reader MPP8 cooperate to silence satellite DNA repeats in mouse embryonic stem cells. Genes 10, 750 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Muller, I. et al. MPP8 is essential for sustaining self-renewal of ground-state pluripotent stem cells. Nat. Commun. 12, 3034 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tsusaka, T. et al. Tri-methylation of ATF7IP by G9a/GLP recruits the chromodomain protein MPP8. Epigenetics Chromatin 11, 56 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sun, L. et al. MPP8 and SIRT1 crosstalk in E-cadherin gene silencing and epithelial-mesenchymal transition. EMBO Rep. 16, 689–699 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sedgwick, S. G. & Smerdon, S. J. The ankyrin repeat: a diversity of interactions on a common structural framework. Trends Biochem.Sci. 24, 311–316 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Douse, C. H. et al. TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control. Nat. Commun. 11, 4940 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Prigozhin, D. M. et al. Periphilin self-association underpins epigenetic silencing by the HUSH complex. Nucleic Acids Res. 48, 10313–10328 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Harten, S. K. et al. The first mouse mutants of D14Abb1e (Fam208a) show that it is critical for early development. Mamm. Genome 25, 293–303 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Huh, J. W. et al. Molecular evolution of the periphilin gene in relation to human endogenous retrovirus m element. J. Mol. Evol. 62, 730–737 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Kurita, M. et al. Overexpression of CR/periphilin downregulates Cdc7 expression and induces S-phase arrest. Biochem. Biophys. Res. Commun. 324, 554–561 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Seczynska, M., Bloor, S., Cuesta, S. M. & Lehner, P. J. Genome surveillance by HUSH-mediated silencing of intronless mobile elements. Nature 601, 440–445 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Tchasovnikarova, I. A. et al. Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2. Nat. Genet. 49, 1035–1044 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fukuda, K. & Shinkai, Y. SETDB1-mediated silencing of retroelements. Viruses 12, 596 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Guddeti, R. K., Chutani, N. & Pakala, S. B. MORC2 interactome: its involvement in metabolism and cancer. Biophys. Rev. 13, 507–514 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schultz, D. C., Ayyanathan, K., Negorev, D., Maul, G. G. & Rauscher, F. J. 3rd SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev. 16, 919–932 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Tachibana, M., Sugimoto, K., Fukushima, T. & Shinkai, Y. Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J. Biol. Chem. 276, 25309–25317 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Tachibana, M. et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 16, 1779–1791 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tachibana, M. et al. Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev. 19, 815–826 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stabell, M., Bjorkmo, M., Aalen, R. B. & Lambertsson, A. The Drosophila SET domain encoding gene dEset is essential for proper development. Hereditas 143, 177–188 (2006).

    Article  PubMed  Google Scholar 

  37. Poulin, G., Dong, Y., Fraser, A. G., Hopper, N. A. & Ahringer, J. Chromatin regulation and sumoylation in the inhibition of Ras-induced vulval development in Caenorhabditis elegans. EMBO J. 24, 2613–2623 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Matsumura, Y. et al. H3K4/H3K9me3 bivalent chromatin domains targeted by lineage-specific DNA methylation pauses adipocyte differentiation. Mol. Cell 60, 584–596 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Chen, C., Nott, T. J., Jin, J. & Pawson, T. Deciphering arginine methylation: Tudor tells the tale. Nat. Rev. Mol. Cell Biol. 12, 629–642 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Lu, R. & Wang, G. G. Tudor: a versatile family of histone methylation ‘readers’. Trends Biochem. Sci. 38, 546–555 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Jurkowska, R. Z. et al. H3K14ac is linked to methylation of H3K9 by the triple Tudor domain of SETDB1. Nat. Commun. 8, 2057 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Price, A. J., Manjegowda, M. C., Kain, J., Anandh, S. & Bochkis, I. M. Hdac3, Setdb1 and Kap1 mark H3K9me3/H3K14ac bivalent regions in young and aged liver. Aging Cell 19, e13092 (2020).

    Article  CAS  PubMed  Google Scholar 

  43. Inoue, N. et al. New gene family defined by MORC, a nuclear protein required for mouse spermatogenesis. Hum. Mol. Genet. 8, 1201–1207 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Fukuda, K., Okuda, A., Yusa, K. & Shinkai, Y. A CRISPR knockout screen identifies SETDB1-target retroelement silencing factors in embryonic stem cells. Genome Res. 28, 846–858 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Douse, C. H. et al. Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms. Nat. Commun. 9, 651 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Liu, Y. et al. Family-wide characterization of histone binding abilities of human CW domain-containing proteins. J. Biol. Chem. 291, 9000–9013 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Liu, N. et al. Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. Nature 553, 228–232 (2018).

    Article  CAS  PubMed  Google Scholar 

  48. Robbez-Masson, L. et al. The HUSH complex cooperates with TRIM28 to repress young retrotransposons and new genes. Genome Res. 28, 836–845 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Matsui, T. et al. Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature 464, 927–931 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Rowe, H. M. et al. KAP1 controls endogenous retroviruses in embryonic stem cells. Nature 463, 237–240 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Pastor, W. A. et al. MORC1 represses transposable elements in the mouse male germline. Nat. Commun. 5, 5795 (2014).

    Article  CAS  PubMed  Google Scholar 

  53. Moissiard, G. et al. MORC family ATPases required for heterochromatin condensation and gene silencing. Science 336, 1448–1451 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Marnef, A. et al. A cohesin/HUSH- and LINC-dependent pathway controls ribosomal DNA double-strand break repair. Genes Dev. 33, 1175–1190 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yurkovetskiy, L. et al. Primate immunodeficiency virus proteins Vpx and Vpr counteract transcriptional repression of proviruses by the HUSH complex. Nat. Microbiol. 3, 1354–1361 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chougui, G. et al. HIV-2/SIV viral protein X counteracts HUSH repressor complex. Nat. Microbiol. 3, 891–897 (2018).

    Article  CAS  PubMed  Google Scholar 

  57. Zhu, Y., Wang, G. Z., Cingoz, O. & Goff, S. P. NP220 mediates silencing of unintegrated retroviral DNA. Nature 564, 278–282 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Castello, A. et al. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149, 1393–1406 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Queiroz, R. M. L. et al. Comprehensive identification of RNA–protein interactions in any organism using orthogonal organic phase separation (OOPS). Nat. Biotechnol. 37, 169–178 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Fujita, N. et al. MCAF mediates MBD1-dependent transcriptional repression. Mol. Cell Biol. 23, 2834–2843 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang, H. et al. mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression. Mol. Cell 12, 475–487 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Timms, R. T., Tchasovnikarova, I. A., Antrobus, R., Dougan, G. & Lehner, P. J. ATF7IP-mediated stabilization of the histone methyltransferase SETDB1 is essential for heterochromatin formation by the HUSH complex. Cell Rep. 17, 653–659 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tsusaka, T., Shimura, C. & Shinkai, Y. ATF7IP regulates SETDB1 nuclear localization and increases its ubiquitination. EMBO Rep. 20, e48297 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang, Q. et al. By recruiting HDAC1, MORC2 suppresses p21 Waf1/Cip1 in gastric cancer. Oncotarget 6, 16461–16470 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Shao, Y. et al. Involvement of histone deacetylation in MORC2-mediated down-regulation of carbonic anhydrase IX. Nucleic Acids Res. 38, 2813–2824 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Garland, W. et al. Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression. Mol. Cell 82, 1691–1707.e8 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lubas, M. et al. The human nuclear exosome targeting complex is loaded onto newly synthesized RNA to direct early ribonucleolysis. Cell Rep. 10, 178–192 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Lubas, M. et al. Interaction profiling identifies the human nuclear exosome targeting complex. Mol. Cell 43, 624–637 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Wu, G. et al. A two-layered targeting mechanism underlies nuclear RNA sorting by the human exosome. Cell Rep. 30, 2387–2401 (2020).

    Article  CAS  PubMed  Google Scholar 

  70. Matkovic, R. et al. TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV. Nat. Commun. 13, 66 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Soehn, A. S. et al. Periphilin is strongly expressed in the murine nervous system and is indispensable for murine development. Genesis 47, 697–707 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Bhargava, S. et al. The epigenetic modifier Fam208a is required to maintain epiblast cell fitness. Sci. Rep. 7, 9322 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Arand, J. et al. In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet. 8, e1002750 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Habibi, E. et al. Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells. Cell Stem Cell 13, 360–369 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. Gu, Z. et al. Silencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia. Nat. Genet. 53, 672–682 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hagelkruys, A. et al. The HUSH complex controls brain architecture and protocadherin fidelity. Sci. Adv. 8, eabo7247 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Dodge, J. E., Kang, Y. K., Beppu, H., Lei, H. & Li, E. Histone H3-K9 methyltransferase ESET is essential for early development. Mol. Cell Biol. 24, 2478–2486 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Karimi, M. M. et al. DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements and chimeric transcripts in mESCs. Cell Stem Cell 8, 676–687 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Liu, S. et al. Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells. Genes Dev. 28, 2041–2055 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Luo, C., Hajkova, P. & Ecker, J. R. Dynamic DNA methylation: in the right place at the right time. Science 361, 1336–1340 (2018).

    Article  CAS  PubMed  Google Scholar 

  81. Crichton, J. H., Dunican, D. S., Maclennan, M., Meehan, R. R. & Adams, I. R. Defending the genome from the enemy within: mechanisms of retrotransposon suppression in the mouse germline. Cell Mol. Life Sci. 71, 1581–1605 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Liu, L. et al. A whole genome screen for HIV restriction factors. Retrovirology 8, 94 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Greenwood, E. J. D. et al. Promiscuous targeting of cellular proteins by Vpr drives systems-level proteomic remodeling in HIV-1 infection. Cell Rep. 27, 1579–1596 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Chougui, G. & Margottin-Goguet, F. HUSH, a link between intrinsic immunity and HIV latency. Front. Microbiol. 10, 224 (2019).

    Article  PubMed  Google Scholar 

  85. Palella, F. J. Jr. et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient study investigators. N. Engl. J. Med. 338, 853–860 (1998).

    Article  PubMed  Google Scholar 

  86. Chomont, N. et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat. Med. 15, 893–900 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Archin, N. M. et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 487, 482–485 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Tunbak, H. et al. The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s. Nat. Commun. 11, 5387 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wang, Y. et al. M-phase phosphoprotein 8 promotes gastric cancer growth and metastasis via p53/Bcl-2 and EMT-related signaling pathways. J. Cell. Biochem. 121, 2330–2342 (2020).

    Article  CAS  PubMed  Google Scholar 

  90. Li, T., Li, N., Wang, L., Li, J. & Zhang, X. MPP8 promotes proliferation and restrains apoptosis in osteosarcoma by regulating p38αMAPK pathway. Technol. Cancer Res. Treat. 20, 1533033821995272 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Yuan, B. et al. Repression of M-phase phosphoprotein 8 inhibits melanoma growth and metastasis in vitro and in vivo. Int. J. Clin. Exp. Pathol. 10, 12003–12009 (2017).

    PubMed  PubMed Central  Google Scholar 

  92. Gao, X. Y. et al. Knockdown of MPP8 suppresses cell proliferation via regulation of HOXA5 in non-small cell lung cancer cells. Cell. Mol. Biol. 64, 27–31 (2018).

    Article  PubMed  Google Scholar 

  93. Liang, X. et al. Lentivirus-mediated knockdown of M-phase phosphoprotein 8 inhibits proliferation of colon cancer cells. Biotechnol. Appl. Biochem. 64, 911–917 (2017).

    Article  CAS  PubMed  Google Scholar 

  94. Sia, D. et al. Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nat. Commun. 6, 6087 (2015).

    Article  CAS  PubMed  Google Scholar 

  95. Huang, K. C. et al. The clinical relevance of frequent germline genetic variants detected by targeted sequencing in patients with rectal adenocarcinoma (READ). Cancer Genomics Proteomics 17, 291–299 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Goerner-Potvin, P. & Bourque, G. Computational tools to unmask transposable elements. Nat. Rev. Genet. 19, 688–704 (2018).

    Article  CAS  PubMed  Google Scholar 

  97. Griffin, G. K. et al. Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity. Nature 595, 309–314 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Vafaei, S. et al. Combination therapy with immune checkpoint inhibitors (ICIs); a new frontier. Cancer Cell Int. 22, 2 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sato, T., Issa, J. J. & Kropf, P. DNA hypomethylating drugs in cancer therapy. Cold Spring Harb. Perspect. Med 7, a026948 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Lazaro-Camp, V. J., Salari, K., Meng, X. & Yang, S. SETDB1 in cancer: overexpression and its therapeutic implications. Am. J. Cancer Res. 11, 1803–1827 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Sevilla, T. et al. Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease. Brain 139, 62–72 (2016).

    Article  PubMed  Google Scholar 

  102. Albulym, O. M. et al. MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs. Ann. Neurol. 79, 419–427 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lassuthova, P. et al. Severe axonal Charcot-Marie-Tooth disease with proximal weakness caused by de novo mutation in the MORC2 gene. Brain 139, e26 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Hyun, Y. S., Hong, Y. B., Choi, B. O. & Chung, K. W. Clinico-genetics in Korean Charcot-Marie-Tooth disease type 2Z with MORC2 mutations. Brain 139, e40 (2016).

    Article  PubMed  Google Scholar 

  105. Schottmann, G., Wagner, C., Seifert, F., Stenzel, W. & Schuelke, M. MORC2 mutation causes severe spinal muscular atrophy-phenotype, cerebellar atrophy and diaphragmatic paralysis. Brain 139, e70 (2016).

    Article  PubMed  Google Scholar 

  106. Zanni, G. et al. De novo p.T362R mutation in MORC2 causes early onset cerebellar ataxia, axonal polyneuropathy and nocturnal hypoventilation. Brain 140, e34 (2017).

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a Memorial Sloan Kettering Cancer Center support grant (no. NIH P30 CA008748) and by The Institute of Cancer Research.

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  1. Cell Biology Program and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Iris Müller & Kristian Helin

  2. The Institute of Cancer Research, London, UK

    Kristian Helin

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Correspondence to Kristian Helin.

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K.H. is a co-founder of Dania Therapeutics and a scientific advisor for Hannibal Innovation. He was recently a consultant for Inthera Bioscience AG and a scientific advisor for MetaboMed Inc. I.M. declares no competing interests.

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Müller, I., Helin, K. Keep quiet: the HUSH complex in transcriptional silencing and disease. Nat Struct Mol Biol 31, 11–22 (2024). https://doi.org/10.1038/s41594-023-01173-7

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