Introduction

Protein methylation, a covalent modification on proteins, is dynamically regulated by protein methyltransferases and demethylases, and S-adenosyl-l-methionine (AdoMet) is the main methyl group donor [1,2,3]. Protein methylation occurs mainly at lysine or arginine residues of histones and non-histones and has been demonstrated to be implicated in the regulation of many biological processes by affecting the activity, subcellular localization, or stability of proteins [4,5,6,7]. In recent years, major advancements in our understanding of protein methylation have been made, including not only its regulatory mechanisms, but also its pathophysiological functions [8,9,10,11].

The SET domain bifurcated histone lysine methyltransferase 1 (SETDB1), also known as lysine N-methyltransferase 1E (KMT1E) or Erg-associated SET domain (ESET), is a family member of the SET domain-containing histone methyltransferases. SETDB1 deposits di- and tri-methyl marks on H3K9 (H3K9me2 and H3K9me3) which are transcriptional repression marks [12,13,14,15,16]. Additionally, SETDB1 has been found to methylate non-histones, such as tri-methylating AKT at K64 and K140 (AKTK64me3 and AKTK140me3), and di-methylating P53 at K370 (P53K370me2) [17,18,19]. SETDB1 has been shown to be involved in maintaining endogenous retroviruses (ERVs) silencing in embryonic stem cells (mESCs) [20,21,22,23], as well as in cell fate determination and tumorigenesis [24,25,26,27,28,29]. In this review, we summarize the structure features of SETDB1, the upstream regulatory mechanisms controlling SETDB1 expression and activity, and the partners of SETDB1, as well as the pivotal roles of SETDB1 in cancer progression, inflammatory bowel disease, ageing, and embryonic stem cells by regulating methylation of H3K9 and non-histone proteins.

Structure of SETDB1

SETDB1 was first identified by Harte et al. in 1999, and they revealed that Setdb1 gene localized to human chromosome band 1q21 [30]. By using the N-terminal region of ERG as a bait to screen a yeast two-hybrid mouse cDNA library, Yang et al. isolated a 4.6 kb full-length mouse cDNA encoding a protein of 1307 amino acids, referred to as ESET [37]. Unsurprisingly, mithramycin inhibits the basal promoter activity of Setdb1 gene in a dose-dependent manner, and in addition, combined treatment with mithramycin and cystamine extends the lifespan of R6/2 mice by 40% and obviously improves the behavioral and neuropathological phenotype [36]. In addition, both mithramycin A and its analog (mithralog) EC-8042 effectively suppress SETDB1 expression in melanoma cells and enhance the efficacy of mitogen-activated protein kinase-inhibitor-based therapies for melanoma [38]. In gastric cancer, transcription factor 4 (TCF4) directly bind to the promoter of Setdb1 gene (binding motif, CAAAG) to enhance the expression of SETDB1, and approximately 90% of patients with gastric cancer (GC) are caused by Helicobacter pylori infection, which promotes SETDB1 expression in a TCF4-dependent manner [39]. Furthermore, elevated SETDB1 interacts with ERG to promote gastric carcinogenesis and metastasis by binding to the promoter regions of matrix metalloproteinase 9 (MMP9) and cyclin D1 (CCND1) to accelerate their transcription [39]. In breast cancer cells, SETDB1 increases the expression of c-MYC to promote cell cycle progression, enhanced growth, and colony formation, and increased c-MYC positive feedback regulates the expression of SETDB1 by directly binding to Setdb1 promoter and enhances its transcription [3) [75].

Fig. 3
figure 3

The mechanisms underlying the role of SETDB1 in cell fate determination and stem cell. SETDB1 trimethylates H3K9 (H3K9me3) to suppress the expression of DPPA2, OTX2, and UTF1 to regulate primordial germ cells (PGC) formation, and to inhibit CEBPβ and CDKN1α, FBP1 and FBP2 expression to affect the hematopoietic stem and progenitor cells (HSPCs), and to repress LINE1 transcript expression to facilitate stem cell self-renewal

Full size image

Although histone methylation and DNA methylation are essential for the repression of ERVs transcription, the genes upregulated after Setdb1 deletion differ from those derepressed genes in mESCs with Dnmt1, Dnmt3a, and Dnmt3b deficient, with the exception of a small number of primarily germline-specific genes [22]. This paradoxical phenotype may be due to an ectopic interaction between SETDB1 and NP95/UHRF1. Under normal conditions, SETDB1 maintains silencing of ERVs, while in the absence of DNMT1, prolonged binding of NP95/UHRF1 to hemimethylated DNA transiently disrupts SETDB1-dependent deposition of H3K9me3 in these regions [76]. In naïve ESCs with SETDB1 deficiency, Tet methylcytosine dioxygenase 2 (TET2) activates IAP elements in a catalytic-dependent manner. Surprisingly, TET2 has no effect on DNA methylation levels at IAPs, but regulates these retrotransposons in a TET2-dependent loss of H4R3me2s manner [77]. In addition, the physically interaction between SETDB1 and methyltransferase-like 3 (METTL3), an RNA N6-methyladenosine (m6A) methyltransferase, is important for the integrity of IAP heterochromatin in mESCs [78,79,80,81].

Hematopoietic stem and progenitor cell

Additionally, Setdb1 has been found to be critical for the maintenance of hematopoietic stem and progenitor cells (HSPCs) in mice, as demonstrated by the rapid depletion of hematopoietic stem, HSPCs, and leukemic stem cells after Setdb1 deletion, which is caused by ectopic activation of nonhematopoietic genes (e.g., gluconeogenic enzyme genes fructose-1,6-bisphosphatase 1 (Fbp1) and Fbp2) (Fig. 3) [82]. Conditional ablation of Setdb1 in pro-B cells (Mb1-Cre) has a significant impact on the pro-B cell compartment, and the B cell populations in the spleen and bone marrow that correspond to later developmental stages are virtually eliminated in mice [83]. Further evidence suggests that these effects of Setdb1 deficiency on B cells may be associated with derepression of endogenous murine leukemia virus (MLV) copies and subsequent activation of the unfolded protein response pathway and apoptosis [84]. In addition, SETDB1 limits the priming of T helper 1 (Th1) cells and maintains the integrity of Th2 cells by repressing a repertoire of ERVs in a H3K9me3-dependent manner [85].

Similarly, in zebrafishes with Setdb1 or Atf7ip deficiency, excessive myeloid differentiation with impaired HSPC expansion is observed, leading to a decrease in T cell and erythroid lineage [86]. Mechanistically, Setdb1 and Atf7ip interaction facilitates H3K9me3 deposition in cebpβ and cdkn1a to inhibit their expression (Fig. 3) [86]. Concomitantly, deletion of Atf7ip or Setdb1 derepresses retrotransposons, thereby inhibiting human leukemia cell growth and inducing myeloid differentiation and inflammation by activating the viral sensor Mda5/Rig-I like receptor signaling [86].

Other stem cell

Fei et al. demonstrated that SETDB1 works in coordination with Polycomb repressive complex 2 (PRC2) to suppress neural differentiation independently of H3K9me3 [87]. Moreover, ERVs are heavily DNA methylated in both ESCs and differentiated somatic cells, but distinctive sets of ERVs are reactivated in different types of Setdb1-deficient somatic cells in an H3K9me3-dependent or -independent manner [21].

In conclusion, SETDB1 plays an important role in cell fate determination, stem cell differentiation and function, but the regulatory mechanisms are heterogeneous and cell-specific. For example, transcriptomic results showed that Setdb1 deletion significantly induced the expression of ERV families such as the murine leukemia virus (MLV), mouse mammary tumor virus (MMTV) and VL30 in pro-B cells, whereas these ERVs remained silent or expressed at low levels in SETDB1-deficient ESCs and PGCs, which expressed ERV families such as IAPE-z, GLn and ETn/MusD [83]. Thus, further studies are needed to further elucidate the specific mechanisms by which SETDB1 regulates cell fate determination and stem cell differentiation, and how this cell-specific mechanism is achieved, e.g., is it dependent on H3K9me3? and which regulators are involved in determining this cell-specific mechanism.

SETDB1 in tumors

According to Global Cancer Statistics, there were an estimated 19.3 million new cancer cases and 10 million cancer-related deaths worldwide in 2020, with lung cancer being the most commonly diagnosed cancer in both sexes [88]. SETDB1 has been found to be amplified in lung cancer cell lines and primary tumors, resulting in increased mRNA and protein levels, which contributes to tumor growth and invasion [89]. SETDB1 promotes the expression of IGFBP4 (insulin like growth factor binding protein 4), LRP8 (LDL receptor related protein 8), and FZD1 (frizzled class receptor 1), but inhibits APOE (Apolipoprotein E) expression, thereby activating WNT-β-catenin pathway and suppressing P53 expression to enhance NSCLC growth in vitro and in vivo [118, 119]. The expression level of SETDB1 is decreased and rare missense variants of SETDB1 are over-represented in patients with IBD [120, 121]. Moreover, Setdb1 deficiency in mouse intestinal epithelial cells is associated with barrier disruption, defective intestinal epithelial differentiation, inflammation and mortality, indicating that SETDB1 is essential for intestinal epithelial homeostasis [120]. Furthermore, mice with downregulated SETDB1 expression in intestinal stem cells develop spontaneous terminal ileitis and colitis by triggering Z-DNA-binding protein 1 (ZBP1)-dependent necroptosis via de-silencing endogenous retroviruses [121]. Thus, targeting SETDB1 or necroptosis of intestinal stem cells may be potential novel strategies for the treatment of severe IBD in humans. Interestingly, conditional knockout of Setdb1 (Setdb1-NS-cKO) in mouse neural progenitor cells showed that SETDB1 represses 5-hydroxytryptamine receptor 3A (Htr3a) transcription through endogenous retroviral sequence RMER21B-mediated distal chromatin interactions in the embryonic ganglionic eminence, thereby modulating mood behaviors and cortical Htr3a-positive interneurons development [

Availability of data and materials

All the materials will be provided from the corresponding author on reasonable request.

Abbreviations

SETDB1:

SET domain bifurcated histone lysine methyltransferase 1

ERVs:

Endogenous retroviruses

mESCs:

Embryonic stem cells

DNMTs:

DNA methyltransferases

IBD:

Inflammatory bowel disease

AdoMet:

S-Adenosyl-l-methionine

ESET:

Erg-associated SET domain

KMT1E:

Lysine N-methyltransferase 1E

HP1a:

Heterochromatin protein 1a

TUDs:

Tudor domains

MBD:

Methyl-CpG binding domain

Sp1:

Specificity protein 1

MAPK:

Mitogen-activated protein kinase

TCF4:

Transcription factor 4

GC:

Gastric cancer

MMP9:

Matrix metalloproteinase 9

CCND1:

Cyclin D1

HCC:

Hepatocellular carcinoma

NSCLC:

Non-small cell lung cancer

ATF7IP:

Activating transcription factor 7-interacting protein

CAF1:

Chromatin assembly factor 1

KAP-1:

KRAB-ZFP-associated protein 1

IAP:

Intracisternal A-type particles

LTRs:

Long terminal repeats

PGCs:

Primordial germ cells

Dppa2:

Developmental pluripotency associated 2

Otx2:

Orthodenticle homeobox 2

Utf1:

Undifferentiated embryonic cell transcription factor 1

MPP8:

M-phase phosphoprotein 8

TET2:

Tet methylcytosine dioxygenase 2

HSPCs:

Hematopoietic stem and progenitor cells

METTL3:

Methyltransferase-like 3

PRC2:

Polycomb repressive complex 2

IGFBP4:

Insulin like growth factor binding protein 4

LRP8:

LDL receptor related protein 8

FZD1:

Frizzled class receptor 1

APOE:

Apolipoprotein E

FOXA2:

Forkhead box A2

ANXA2:

Annexin A2

EMT:

Epithelial–mesenchymal transition

Snai1:

Snail family transcriptional repressor 1

EZH2:

Enhancer of zeste homolog 2

RUNX3:

RUNX Family Transcription Factor 3

PDACs:

Pancreatic ductal adenocarcinomas

THBS1:

Thrombospondin 1

CRC:

Colorectal cancer

AML:

Acute myeloid leukemia

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed cell death ligand 1

cGAS:

Cyclic GMP-AMP synthase

STING:

Stimulator of interferon genes

KDM5B:

Lysine demethylase 5B

ALT:

Alternative lengthening of telomeres

ZBP1:

Z-DNA-binding protein 1

Htr3a:

5-Hydroxytryptamine receptor 3A

Macrod2:

Mono-ADP Ribosylhydrolase 2

KDM4B:

Lysine demethylase 4B

JMJD2A:

Jumonji Domain-Containing Protein 2A

References

  1. Biggar KK, Li SS. Non-histone protein methylation as a regulator of cellular signalling and function. Nat Rev Mol Cell Biol. 2015;16(1):5–17.

    Article  CAS  PubMed  Google Scholar 

  2. Li R, Wei X, Jiang DS. Protein methylation functions as the posttranslational modification switch to regulate autophagy. Cell Mol Life Sci. 2019;76(19):3711–22.

    Article  CAS  PubMed  Google Scholar 

  3. Yi X, Jiang XJ, Fang ZM. Histone methyltransferase SMYD2: ubiquitous regulator of disease. Clin Epigenet. 2019;11(1):112.

    Article  Google Scholar 

  4. Wu Q, Schapira M, Arrowsmith CH, Barsyte-Lovejoy D. Protein arginine methylation: from enigmatic functions to therapeutic targeting. Nat Rev Drug Discov. 2021;20(7):509–30.

    Article  CAS  PubMed  Google Scholar 

  5. Feldman D, Ziv C, Gorovits R, Efrat M, Yarden O. Neurospora crassa protein arginine methyl transferases are involved in growth and development and interact with the NDR kinase COT1. PLoS ONE. 2013;8(11): e80756.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Dilworth D, Barsyte-Lovejoy D. Targeting protein methylation: from chemical tools to precision medicines. Cell Mol Life Sci. 2019;76(15):2967–85.

    Article  CAS  PubMed  Google Scholar 

  7. Li R, Yi X, Wei X, Huo B, Guo X, Cheng C, Fang ZM, Wang J, Feng X, Zheng P, et al. EZH2 inhibits autophagic cell death of aortic vascular smooth muscle cells to affect aortic dissection. Cell Death Dis. 2018;9(2):180.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Yi X, Jiang XJ, Li XY, Jiang DS. Histone methyltransferases: novel targets for tumor and developmental defects. Am J Transl Res. 2015;7(11):2159–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Yi X, Jiang X, Li X, Jiang DS. Histone lysine methylation and congenital heart disease: from bench to bedside (Review). Int J Mol Med. 2017;40(4):953–64.

    Article  CAS  PubMed  Google Scholar 

  10. Jiang DS, Yi X, Li R, Su YS, Wang J, Chen ML, Liu LG, Hu M, Cheng C, Zheng P, et al. The histone methyltransferase mixed lineage leukemia (MLL) 3 may play a potential role on clinical dilated cardiomyopathy. Mol Med. 2017;23:196–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wei X, Yi X, Zhu XH, Jiang DS. Histone methylation and vascular biology. Clin Epigenet. 2020;12(1):30.

    Article  CAS  Google Scholar 

  12. Markouli M, Strepkos D, Chlamydas S, Piperi C. Histone lysine methyltransferase SETDB1 as a novel target for central nervous system diseases. Prog Neurobiol. 2021;200: 101968.

    Article  CAS  PubMed  Google Scholar 

  13. Fukuda K, Shinkai Y. SETDB1-mediated silencing of retroelements. Viruses. 2020;12(6):596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fukuda K, Shimura C, Miura H, Tanigawa A, Suzuki T, Dohmae N, Hiratani I, Shinkai Y. Regulation of mammalian 3D genome organization and histone H3K9 dimethylation by H3K9 methyltransferases. Commun Biol. 2021;4(1):571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zeller P, Padeken J, van Schendel R, Kalck V, Tijsterman M, Gasser SM. Histone H3K9 methylation is dispensable for caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability. Nat Genet. 2016;48(11):1385–95.

    Article  CAS  PubMed  Google Scholar 

  16. Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ 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. 2002;16(8):919–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang G, Long J, Gao Y, Zhang W, Han F, Xu C, Sun L, Yang SC, Lan J, Hou Z, et al. SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis. Nat Cell Biol. 2019;21(2):214–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Guo J, Dai X, Laurent B, Zheng N, Gan W, Zhang J, Guo A, Yuan M, Liu P, Asara JM, et al. AKT methylation by SETDB1 promotes AKT kinase activity and oncogenic functions. Nat Cell Biol. 2019;21(2):226–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fei Q, Shang K, Zhang J, Chuai S, Kong D, Zhou T, Fu S, Liang Y, Li C, Chen Z, et al. Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53. Nat Commun. 2015;6:8651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Barral A, Pozo G, Ducrot L, Papadopoulos GL, Sauzet S, Oldfield AJ, Cavalli G, Dejardin J. SETDB1/NSD-dependent H3K9me3/H3K36me3 dual heterochromatin maintains gene expression profiles by bookmarking poised enhancers. Mol Cell. 2022;82(4):816-832.e812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kato M, Takemoto K, Shinkai Y. A somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing. Nat Commun. 2018;9(1):1683.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Karimi MM, Goyal P, Maksakova IA, Bilenky M, Leung D, Tang JX, Shinkai Y, Mager DL, Jones S, Hirst M, 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):676–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Matsui T, Leung D, Miyashita H, Maksakova IA, Miyachi H, Kimura H, Tachibana M, Lorincz MC, Shinkai Y. Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature. 2010;464(7290):927–31.

    Article  CAS  PubMed  Google Scholar 

  24. Wu K, Liu H, Wang Y, He J, Xu S, Chen Y, Kuang J, Liu J, Guo L, Li D, et al. SETDB1-mediated cell fate transition between 2C-like and pluripotent states. Cell Rep. 2020;30(1):25-36.e26.

    Article  CAS  PubMed  Google Scholar 

  25. Warrier T, El Farran C, Zeng Y, Ho BSQ, Bao Q, Zheng ZH, Bi X, Ng HH, Ong DST, Chu JJH, et al. SETDB1 acts as a topological accessory to Cohesin via an H3K9me3-independent, genomic shunt for regulating cell fates. Nucleic Acids Res. 2022;50(13):7326–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Strepkos D, Markouli M, Klonou A, Papavassiliou AG, Piperi C. Histone methyltransferase SETDB1: a common denominator of tumorigenesis with therapeutic potential. Cancer Res. 2021;81(3):525–34.

    Article  CAS  PubMed  Google Scholar 

  27. Zhao Z, Feng L, Peng X, Ma T, Tong R, Zhong L. Role of histone methyltransferase SETDB1 in regulation of tumourigenesis and immune response. Front Pharmacol. 2022;13:1073713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Torrano J, Al Emran A, Hammerlindl H, Schaider H. Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming. Clin Epigenet. 2019;11(1):43.

    Article  Google Scholar 

  29. Vural S, Palmisano A, Reinhold WC, Pommier Y, Teicher BA, Krushkal J. Association of expression of epigenetic molecular factors with DNA methylation and sensitivity to chemotherapeutic agents in cancer cell lines. Clin Epigenet. 2021;13(1):49.

    Article  CAS  Google Scholar 

  30. Harte PJ, Wu W, Carrasquillo MM, Matera AG. Assignment of a novel bifurcated SET domain gene, SETDB1, to human chromosome band 1q21 by in situ hybridization and radiation hybrids. Cytogenet Cell Genet. 1999;84(1–2):83–6.

    Article  CAS  PubMed  Google Scholar 

  31. Yang L, **a L, Wu DY, Wang H, Chansky HA, Schubach WH, Hickstein DD, Zhang Y. Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor. Oncogene. 2002;21(1):148–52.

    Article  CAS  PubMed  Google Scholar 

  32. Blackburn ML, Chansky HA, Zielinska-Kwiatkowska A, Matsui Y, Yang L. Genomic structure and expression of the mouse ESET gene encoding an ERG-associated histone methyltransferase with a SET domain. Biochim Biophys Acta. 2003;1629(1–3):8–14.

    Article  CAS  PubMed  Google Scholar 

  33. Karanth AV, Maniswami RR, Prashanth S, Govindaraj H, Padmavathy R, Jegatheesan SK, Mullangi R, Rajagopal S. Emerging role of SETDB1 as a therapeutic target. Expert Opin Ther Targets. 2017;21(3):319–31.

    Article  CAS  PubMed  Google Scholar 

  34. Li H, Rauch T, Chen ZX, Szabo PE, Riggs AD, Pfeifer GP. The histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells. J Biol Chem. 2006;281(28):19489–500.

    Article  CAS  PubMed  Google Scholar 

  35. Markouli M, Strepkos D, Piperi C. Structure, activity and function of the SETDB1 protein methyltransferase. Life (Basel). 2021;11(8):817.

    CAS  PubMed  Google Scholar 

  36. Ryu H, Lee J, Hagerty SW, Soh BY, McAlpin SE, Cormier KA, Smith KM, Ferrante RJ. ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington’s disease. Proc Natl Acad Sci USA. 2006;103(50):19176–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Osada N, Kosuge Y, Ishige K, Ito Y. Mithramycin, an agent for develo** new therapeutic drugs for neurodegenerative diseases. J Pharmacol Sci. 2013;122(4):251–6.

    Article  CAS  PubMed  Google Scholar 

  38. Federico A, Steinfass T, Larribere L, Novak D, Moris F, Nunez LE, Umansky V, Utikal J. Mithramycin A and mithralog EC-8042 inhibit SETDB1 expression and its oncogenic activity in malignant melanoma. Mol Ther Oncolytics. 2020;18:83–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shang W, Wang Y, Liang X, Li T, Shao W, Liu F, Cui X, Wang Y, Lv L, Chai L, et al. SETDB1 promotes gastric carcinogenesis and metastasis via upregulation of CCND1 and MMP9 expression. J Pathol. 2021;253(2):148–59.

    Article  CAS  PubMed  Google Scholar 

  40. **ao JF, Sun QY, Ding LW, Chien W, Liu XY, Mayakonda A, Jiang YY, Loh XY, Ran XB, Doan NB, et al. The c-MYC-BMI1 axis is essential for SETDB1-mediated breast tumourigenesis. J Pathol. 2018;246(1):89–102.

    Article  CAS  PubMed  Google Scholar 

  41. Kim WR, Park EG, Lee HE, Park SJ, Huh JW, Kim JN, Kim HS. Hsa-miR-422a originated from short interspersed nuclear element increases ARID5B expression by collaborating with NF-E2. Mol Cells. 2022;45(7):465–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shao Y, Song X, Jiang W, Chen Y, Ning Z, Gu W, Jiang J. MicroRNA-621 acts as a tumor radiosensitizer by directly targeting SETDB1 in hepatocellular carcinoma. Mol Ther. 2019;27(2):355–64.

    Article  CAS  PubMed  Google Scholar 

  43. Liu S, Li B, Xu J, Hu S, Zhan N, Wang H, Gao C, Li J, Xu X. SOD1 promotes cell proliferation and metastasis in non-small cell lung cancer via an miR-409-3p/SOD1/SETDB1 epigenetic regulatory feedforward loop. Front Cell Dev Biol. 2020;8:213.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Beyer S, Pontis J, Schirwis E, Battisti V, Rudolf A, Le Grand F, Ait-Si-Ali S. Canonical Wnt signalling regulates nuclear export of Setdb1 during skeletal muscle terminal differentiation. Cell Discov. 2016;2:16037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tsusaka T, Shimura C, Shinkai Y. ATF7IP regulates SETDB1 nuclear localization and increases its ubiquitination. EMBO Rep. 2019;20(12): e48297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Timms RT, Tchasovnikarova IA, Antrobus R, Dougan G, Lehner PJ. ATF7IP-mediated stabilization of the histone methyltransferase SETDB1 is essential for heterochromatin formation by the HUSH complex. Cell Rep. 2016;17(3):653–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hu H, Khodadadi-Jamayran A, Dolgalev I, Cho H, Badri S, Chiriboga LA, Zeck B, Lopez De Rodas Gregorio M, Dowling CM, Labbe K, et al. Targeting the Atf7ip-Setdb1 complex augments antitumor immunity by boosting tumor immunogenicity. Cancer Immunol Res. 2021;9(11):1298–315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sun L, Fang J. E3-independent constitutive monoubiquitination complements histone methyltransferase activity of SETDB1. Mol Cell. 2016;62(6):958–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Osumi K, Sato K, Murano K, Siomi H, Siomi MC. Essential roles of Windei and nuclear monoubiquitination of Eggless/SETDB1 in transposon silencing. EMBO Rep. 2019;20(12): e48296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Montavon T, Shukeir N, Erikson G, Engist B, Onishi-Seebacher M, Ryan D, Musa Y, Mittler G, Meyer AG, Genoud C, et al. Complete loss of H3K9 methylation dissolves mouse heterochromatin organization. Nat Commun. 2021;12(1):4359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Padeken J, Methot S, Zeller P, Delaney CE, Kalck V, Gasser SM. Argonaute NRDE-3 and MBT domain protein LIN-61 redundantly recruit an H3K9me3 HMT to prevent embryonic lethality and transposon expression. Genes Dev. 2021;35(1–2):82–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fritsch L, Robin P, Mathieu JR, Souidi M, Hinaux H, Rougeulle C, Harel-Bellan A, Ameyar-Zazoua M, Ait-Si-Ali S. A subset of the histone H3 lysine 9 methyltransferases Suv39h1, G9a, GLP, and SETDB1 participate in a multimeric complex. Mol Cell. 2010;37(1):46–56.

    Article  CAS  PubMed  Google Scholar 

  53. Lundberg LE, Stenberg P, Larsson J. HP1a, Su(var)3–9, SETDB1 and POF stimulate or repress gene expression depending on genomic position, gene length and expression pattern in Drosophila melanogaster. Nucleic Acids Res. 2013;41(8):4481–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ayyanathan K, Lechner MS, Bell P, Maul GG, Schultz DC, Yamada Y, Tanaka K, Torigoe K, Rauscher FJ 3rd. Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation. Genes Dev. 2003;17(15):1855–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dong L, Liao H, Zhao L, Wang J, Wang C, Wang B, Sun Y, Xu L, **a Y, Ling S, et al. A functional crosstalk between the H3K9 methylation writers and their reader HP1 in safeguarding embryonic stem cell identity. Stem Cell Rep. 2023;18(9):1775–92.

    Article  CAS  Google Scholar 

  56. Maeda R, Tachibana M. HP1 maintains protein stability of H3K9 methyltransferases and demethylases. EMBO Rep. 2022;23(4): e53581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tzeng TY, Lee CH, Chan LW, Shen CK. Epigenetic regulation of the Drosophila chromosome 4 by the histone H3K9 methyltransferase dSETDB1. Proc Natl Acad Sci USA. 2007;104(31):12691–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Maksimov DA, Koryakov DE. Binding of SU(VAR)3–9 partially depends on SETDB1 in the chromosomes of Drosophila melanogaster. Cells. 2019;8(9):1030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Seller CA, Cho CY, O’Farrell PH. Rapid embryonic cell cycles defer the establishment of heterochromatin by eggless/SetDB1 in Drosophila. Genes Dev. 2019;33(7–8):403–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Loyola A, Tagami H, Bonaldi T, Roche D, Quivy JP, Imhof A, Nakatani Y, Dent SY, Almouzni G. The HP1alpha-CAF1-SetDB1-containing complex provides H3K9me1 for Suv39-mediated K9me3 in pericentric heterochromatin. EMBO Rep. 2009;10(7):769–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rauwel B, Jang SM, Cassano M, Kapopoulou A, Barde I, Trono D. Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch. Elife. 2015;4: e06068.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Muller I, Moroni AS, Shlyueva D, Sahadevan S, Schoof EM, Radzisheuskaya A, Hojfeldt JW, Tatar T, Koche RP, Huang C, et al. MPP8 is essential for sustaining self-renewal of ground-state pluripotent stem cells. Nat Commun. 2021;12(1):3034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Leung D, Du T, Wagner U, **e W, Lee AY, Goyal P, Li Y, Szulwach KE, ** P, Lorincz MC, et al. Regulation of DNA methylation turnover at LTR retrotransposons and imprinted loci by the histone methyltransferase Setdb1. Proc Natl Acad Sci USA. 2014;111(18):6690–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mochizuki K, Sharif J, Shirane K, Uranishi K, Bogutz AB, Janssen SM, Suzuki A, Okuda A, Koseki H, Lorincz MC. Repression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing. Nat Commun. 2021;12(1):7020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang Z, Fan R, Russo A, Cernilogar FM, Nuber A, Schirge S, Shcherbakova I, Dzhilyanova I, Ugur E, Anton T, et al. Dominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm. Nat Commun. 2022;13(1):5447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wenger A, Biran A, Alcaraz N, Redo-Riveiro A, Sell AC, Krautz R, Flury V, Reveron-Gomez N, Solis-Mezarino V, Volker-Albert M, et al. Symmetric inheritance of parental histones governs epigenome maintenance and embryonic stem cell identity. Nat Genet. 2023;55(9):1567–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wen Q, Zhou J, Tian C, Li X, Song G, Gao Y, Sun Y, Ma C, Yao S, Liang X, et al. Symmetric inheritance of parental histones contributes to safeguarding the fate of mouse embryonic stem cells during differentiation. Nat Genet. 2023;55(9):1555–66.

    Article  CAS  PubMed  Google Scholar 

  68. Cheng EC, Hsieh CL, Liu N, Wang J, Zhong M, Chen T, Li E, Lin H. The essential function of SETDB1 in homologous chromosome pairing and synapsis during meiosis. Cell Rep. 2021;34(1): 108575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hirota T, Blakeley P, Sangrithi MN, Mahadevaiah SK, Encheva V, Snijders AP, ElInati E, Ojarikre OA, de Rooij DG, Niakan KK, et al. SETDB1 links the meiotic DNA damage response to sex chromosome silencing in mice. Dev Cell. 2018;47(5):645-659.e646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Eymery A, Liu Z, Ozonov EA, Stadler MB, Peters AH. The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos. Development. 2016;143(15):2767–79.

    CAS  PubMed  Google Scholar 

  71. Smolko AE, Shapiro-Kulnane L, Salz HK. The H3K9 methyltransferase SETDB1 maintains female identity in Drosophila germ cells. Nat Commun. 2018;9(1):4155.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Gualdrini F, Polletti S, Simonatto M, Prosperini E, Pileri F, Natoli G. H3K9 trimethylation in active chromatin restricts the usage of functional CTCF sites in SINE B2 repeats. Genes Dev. 2022;36(7–8):414–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Liu S, Brind’Amour J, Karimi MM, Shirane K, Bogutz A, Lefebvre L, Sasaki H, Shinkai Y, Lorincz MC. Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells. Genes Dev. 2014;28(18):2041–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Rowe HM, Jakobsson J, Mesnard D, Rougemont J, Reynard S, Aktas T, Maillard PV, Layard-Liesching H, Verp S, Marquis J, et al. KAP1 controls endogenous retroviruses in embryonic stem cells. Nature. 2010;463(7278):237–40.

    Article  CAS  PubMed  Google Scholar 

  75. Mochizuki K, Tando Y, Sekinaka T, Otsuka K, Hayashi Y, Kobayashi H, Kamio A, Ito-Matsuoka Y, Takehara A, Kono T, et al. SETDB1 is essential for mouse primordial germ cell fate determination by ensuring BMP signaling. Development. 2018;145(23):dev164160.

    Article  PubMed  Google Scholar 

  76. Sharif J, Endo TA, Nakayama M, Karimi MM, Shimada M, Katsuyama K, Goyal P, Brind’Amour J, Sun MA, Sun Z, 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.

    Article  CAS  PubMed  Google Scholar 

  77. Deniz O, de la Rica L, Cheng KCL, Spensberger D, Branco MR. SETDB1 prevents TET2-dependent activation of IAP retroelements in naive embryonic stem cells. Genome Biol. 2018;19(1):6.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Xu W, Li J, He C, Wen J, Ma H, Rong B, Diao J, Wang L, Wang J, Wu F, et al. METTL3 regulates heterochromatin in mouse embryonic stem cells. Nature. 2021;591(7849):317–21.

    Article  CAS  PubMed  Google Scholar 

  79. Fang ZM, Zhang SM, Luo H, Jiang DS, Huo B, Zhong X, Feng X, Cheng W, Chen Y, Feng G, et al. Methyltransferase-like 3 suppresses phenotypic switching of vascular smooth muscle cells by activating autophagosome formation. Cell Prolif. 2022;56: e13386.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Li N, Yi X, He Y, Huo B, Chen Y, Zhang Z, Wang Q, Li Y, Zhong X, Li R, et al. Targeting ferroptosis as a novel approach to alleviate aortic dissection. Int J Biol Sci. 2022;18(10):4118–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chen J, Wei X, Yi X, Jiang DS. RNA modification by m(6)A methylation in cardiovascular disease. Oxid Med Cell Longev. 2021;2021:8813909.

    PubMed  PubMed Central  Google Scholar 

  82. Koide S, Oshima M, Takubo K, Yamazaki S, Nitta E, Saraya A, Aoyama K, Kato Y, Miyagi S, Nakajima-Takagi Y, et al. Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of nonhematopoietic genes. Blood. 2016;128(5):638–49.

    Article  CAS  PubMed  Google Scholar 

  83. Collins PL, Kyle KE, Egawa T, Shinkai Y, Oltz EM. The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes. Proc Natl Acad Sci USA. 2015;112(27):8367–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Pasquarella A, Ebert A, Pereira de Almeida G, Hinterberger M, Kazerani M, Nuber A, Ellwart J, Klein L, Busslinger M, Schotta G. Retrotransposon derepression leads to activation of the unfolded protein response and apoptosis in pro-B cells. Development. 2016;143(10):1788–99.

    CAS  PubMed  Google Scholar 

  85. Adoue V, Binet B, Malbec A, Fourquet J, Romagnoli P, van Meerwijk JPM, Amigorena S, Joffre OP. The histone methyltransferase SETDB1 controls T helper cell lineage integrity by repressing endogenous retroviruses. Immunity. 2019;50(3):629-644.e628.

    Article  CAS  PubMed  Google Scholar 

  86. Wu J, Li J, Chen K, Liu G, Zhou Y, Chen W, Zhu X, Ni TT, Zhang B, ** D, et al. Atf7ip and Setdb1 interaction orchestrates the hematopoietic stem and progenitor cell state with diverse lineage differentiation. Proc Natl Acad Sci USA. 2023;120(1): e2209062120.

    Article  CAS  PubMed  Google Scholar 

  87. Fei Q, Yang X, Jiang H, Wang Q, Yu Y, Yu Y, Yi W, Zhou S, Chen T, Lu C, et al. SETDB1 modulates PRC2 activity at developmental genes independently of H3K9 trimethylation in mouse ES cells. Genome Res. 2015;25(9):1325–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.

    Article  PubMed  Google Scholar 

  89. Rodriguez-Paredes M, Martinez de Paz A, Simo-Riudalbas L, Sayols S, Moutinho C, Moran S, Villanueva A, Vazquez-Cedeira M, Lazo PA, Carneiro F, et al. Gene amplification of the histone methyltransferase SETDB1 contributes to human lung tumorigenesis. Oncogene. 2014;33(21):2807–13.

    Article  CAS  PubMed  Google Scholar 

  90. Sun QY, Ding LW, **ao JF, Chien W, Lim SL, Hattori N, Goodglick L, Chia D, Mah V, Alavi M, et al. SETDB1 accelerates tumourigenesis by regulating the WNT signalling pathway. J Pathol. 2015;235(4):559–70.

    Article  CAS  PubMed  Google Scholar 

  91. Zakharova VV, Magnitov MD, Del Maestro L, Ulianov SV, Glentis A, Uyanik B, Williart A, Karpukhina A, Demidov O, Joliot V, et al. SETDB1 fuels the lung cancer phenotype by modulating epigenome, 3D genome organization and chromatin mechanical properties. Nucleic Acids Res. 2022;50(8):4389–413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cruz-Tapias P, Zakharova V, Perez-Fernandez OM, Mantilla W, Ram I-CS, Ait-Si-Ali S. Expression of the major and pro-oncogenic H3K9 lysine methyltransferase SETDB1 in non-small cell lung cancer. Cancers (Basel). 2019;11(8):1134.

    Article  CAS  PubMed  Google Scholar 

  93. Ueshima S, Fang J. Histone H3K9 methyltransferase SETDB1 augments invadopodia formation to promote tumor metastasis. Oncogene. 2022;41(24):3370–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wu PC, Lu JW, Yang JY, Lin IH, Ou DL, Lin YH, Chou KH, Huang WF, Wang WP, Huang YL, et al. H3K9 histone methyltransferase, KMT1E/SETDB1, cooperates with the SMAD2/3 pathway to suppress lung cancer metastasis. Cancer Res. 2014;74(24):7333–43.

    Article  CAS  PubMed  Google Scholar 

  95. Du D, Katsuno Y, Meyer D, Budi EH, Chen SH, Koeppen H, Wang H, Akhurst RJ, Derynck R. Smad3-mediated recruitment of the methyltransferase SETDB1/ESET controls Snail1 expression and epithelial–mesenchymal transition. EMBO Rep. 2018;19(1):135–55.

    Article  CAS  PubMed  Google Scholar 

  96. Tang X, Sui X, Weng L, Liu Y. SNAIL1: linking tumor metastasis to immune evasion. Front Immunol. 2021;12: 724200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Balinth S, Fisher ML, Hwangbo Y, Wu C, Ballon C, Sun X, Mills AA. EZH2 regulates a SETDB1/DeltaNp63alpha axis via RUNX3 to drive a cancer stem cell phenotype in squamous cell carcinoma. Oncogene. 2022;41(35):4130–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wong CM, Wei L, Law CT, Ho DW, Tsang FH, Au SL, Sze KM, Lee JM, Wong CC, Ng IO. Up-regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis. Hepatology. 2016;63(2):474–87.

    Article  CAS  PubMed  Google Scholar 

  99. Ogawa S, Fukuda A, Matsumoto Y, Hanyu Y, Sono M, Fukunaga Y, Masuda T, Araki O, Nagao M, Yoshikawa T, et al. SETDB1 inhibits p53-mediated apoptosis and is required for formation of pancreatic ductal adenocarcinomas in mice. Gastroenterology. 2020;159(2):682-696.e613.

    Article  CAS  PubMed  Google Scholar 

  100. Orouji E, Federico A, Larribere L, Novak D, Lipka DB, Assenov Y, Sachindra S, Huser L, Granados K, Gebhardt C, et al. Histone methyltransferase SETDB1 contributes to melanoma tumorigenesis and serves as a new potential therapeutic target. Int J Cancer. 2019;145(12):3462–77.

    Article  CAS  PubMed  Google Scholar 

  101. Ceol CJ, Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA, Battisti V, Fritsch L, Lin WM, Hollmann TJ, Ferre F, et al. The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature. 2011;471(7339):513–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cao N, Yu Y, Zhu H, Chen M, Chen P, Zhuo M, Mao Y, Li L, Zhao Q, Wu M, et al. SETDB1 promotes the progression of colorectal cancer via epigenetically silencing p21 expression. Cell Death Dis. 2020;11(5):351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Huang Z, Li X, Tang B, Li H, Zhang J, Sun R, Ma J, Pan Y, Yan B, Zhou Y, et al. SETDB1 modulates degradation of phosphorylated RB and anti-cancer efficacy of CDK4/6 inhibitors. Cancer Res. 2023;83(6):875–89.

    Article  CAS  PubMed  Google Scholar 

  104. Ropa J, Saha N, Hu H, Peterson LF, Talpaz M, Muntean AG. SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation. Haematologica. 2020;105(9):2273–85.

    Article  CAS  PubMed  Google Scholar 

  105. Klonou A, Korkolopoulou P, Giannopoulou AI, Kanakoglou DS, Pampalou A, Gargalionis AN, Sarantis P, Mitsios A, Sgouros S, Papavassiliou AG, et al. Histone H3K9 methyltransferase SETDB1 overexpression correlates with pediatric high-grade gliomas progression and prognosis. J Mol Med (Berl). 2023;101(4):387–401.

    Article  CAS  PubMed  Google Scholar 

  106. Spyropoulou A, Gargalionis A, Dalagiorgou G, Adamopoulos C, Papavassiliou KA, Lea RW, Piperi C, Papavassiliou AG. Role of histone lysine methyltransferases SUV39H1 and SETDB1 in gliomagenesis: modulation of cell proliferation, migration, and colony formation. Neuromol Med. 2014;16(1):70–82.

    Article  CAS  Google Scholar 

  107. Sepsa A, Levidou G, Gargalionis A, Adamopoulos C, Spyropoulou A, Dalagiorgou G, Thymara I, Boviatsis E, Themistocleous MS, Petraki K, et al. Emerging role of linker histone variant H1x as a biomarker with prognostic value in astrocytic gliomas. A multivariate analysis including trimethylation of H3K9 and H4K20. PLoS ONE. 2015;10(1): e0115101.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Lin J, Guo D, Liu H, Zhou W, Wang C, Muller I, Kossenkov AV, Drapkin R, Bitler BG, Helin K, et al. The SETDB1-TRIM28 complex suppresses antitumor immunity. Cancer Immunol Res. 2021;9(12):1413–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J, Davis T, Dele-Oni D, Du PP, Halawi AG, Ishizuka JJ, et al. Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity. Nature. 2021;595(7866):309–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wu M, Huang Q, **e Y, Wu X, Ma H, Zhang Y, **a Y. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation. J Hematol Oncol. 2022;15(1):24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Cuellar TL, Herzner AM, Zhang X, Goyal Y, Watanabe C, Friedman BA, Janakiraman V, Durinck S, Stinson J, Arnott D, et al. Silencing of retrotransposons by SETDB1 inhibits the interferon response in acute myeloid leukemia. J Cell Biol. 2017;216(11):3535–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Pan D, Bao X, Hu M, Jiao M, Li F, Li CY. SETDB1 restrains endogenous retrovirus expression and antitumor immunity during radiotherapy. Cancer Res. 2022;82(15):2748–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Wang C, Songyang Z, Huang Y. TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation. Cell Biosci. 2021;11(1):149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gauchier M, Kan S, Barral A, Sauzet S, Agirre E, Bonnell E, Saksouk N, Barth TK, Ide S, Urbach S, et al. SETDB1-dependent heterochromatin stimulates alternative lengthening of telomeres. Sci Adv. 2019;5(5): eaav3673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lee JH, Demarest TG, Babbar M, Kim EW, Okur MN, De S, Croteau DL, Bohr VA. Cockayne syndrome group B deficiency reduces H3K9me3 chromatin remodeler SETDB1 and exacerbates cellular aging. Nucleic Acids Res. 2019;47(16):8548–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Liu R, Liu Z, Guo M, Zeng W, Zheng Y. SETDB1 regulates porcine spermatogonial adhesion and proliferation through modulating MMP3/10 transcription. Cells. 2022;11(3):370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Liu D, Saikam V, Skrada KA, Merlin D, Iyer SS. Inflammatory bowel disease biomarkers. Med Res Rev. 2022;42(5):1856–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shah SC, Itzkowitz SH. Colorectal cancer in inflammatory bowel disease: mechanisms and management. Gastroenterology. 2022;162(3):715-730.e713.

    Article  PubMed  Google Scholar 

  120. Juznic L, Peuker K, Strigli A, Brosch M, Herrmann A, Hasler R, Koch M, Matthiesen L, Zeissig Y, Loscher BS, et al. SETDB1 is required for intestinal epithelial differentiation and the prevention of intestinal inflammation. Gut. 2021;70(3):485–98.

    Article  CAS  PubMed  Google Scholar 

  121. Wang R, Li H, Wu J, Cai ZY, Li B, Ni H, Qiu X, Chen H, Liu W, Yang ZH, et al. Gut stem cell necroptosis by genome instability triggers bowel inflammation. Nature. 2020;580(7803):386–90.

    Article  CAS  PubMed  Google Scholar 

  122. Li J, Zheng S, Dong Y, Xu H, Zhu Y, Weng J, Sun D, Wang S, **ao L, Jiang Y. Histone methyltransferase SETDB1 regulates the development of cortical Htr3a-positive interneurons and mood behaviors. Biol Psychiatry. 2023;93(3):279–90.

    Article  CAS  PubMed  Google Scholar 

  123. Tan SL, Nishi M, Ohtsuka T, Matsui T, Takemoto K, Kamio-Miura A, Aburatani H, Shinkai Y, Kageyama R. Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development. Development. 2012;139(20):3806–16.

    Article  CAS  PubMed  Google Scholar 

  124. Zhang L, Xu L, Zhang X, Wang K, Tan Y, Li G, Wang Y, Xue T, Sun Q, Cao X, et al. Methyltransferase Setdb1 promotes osteoblast proliferation by epigenetically silencing Macrod2 with the assistance of Atf7ip. Cells. 2022;11(16):2580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. He Y, Yi X, Zhang Z, Luo H, Li R, Feng X, Fang ZM, Zhu XH, Cheng W, Jiang DS, et al. JIB-04, a histone demethylase Jumonji C domain inhibitor, regulates phenotypic switching of vascular smooth muscle cells. Clin Epigenet. 2022;14(1):101.

    Article  CAS  Google Scholar 

  126. Chen Y, Yi X, Huo B, He Y, Guo X, Zhang Z, Zhong X, Feng X, Fang ZM, Zhu XH, et al. BRD4770 functions as a novel ferroptosis inhibitor to protect against aortic dissection. Pharmacol Res. 2022;177: 106122.

    Article  CAS  PubMed  Google Scholar 

  127. Hou Z, Sun L, Xu F, Hu F, Lan J, Song D, Feng Y, Wang J, Luo X, Hu J, et al. Blocking histone methyltransferase SETDB1 inhibits tumorigenesis and enhances cetuximab sensitivity in colorectal cancer. Cancer Lett. 2020;487:63–73.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize to authors whose papers could not be cited due to space restrictions.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82070306, No. 81873456, and No. 82170502).

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  1. Hanshen Luo and **ngliang Wu contributed equally to this work.

Authors and Affiliations

  1. Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China

    Hanshen Luo, Xue-Hai Zhu & Ding-Sheng Jiang

  2. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China

    **ngliang Wu & **n Yi

  3. Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China

    Xue-Hai Zhu, Dunfeng Du & Ding-Sheng Jiang

  4. Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Dunfeng Du

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DSJ and DD supervised the general concept of this review. HL and XW wrote the manuscript. XHZ and XY participated in the revision and literature search. All authors contributed to the editing process and read and approved the final manuscript.

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Luo, H., Wu, X., Zhu, XH. et al. The functions of SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) in biological process and disease. Epigenetics & Chromatin 16, 47 (2023). https://doi.org/10.1186/s13072-023-00519-1

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