2.1.1.366	drug target	downregulating SETDB1 is an attractive therapeutic option in AKT-driven cancer and for enhancing the immunotherapeutic response	777166	
2.1.1.366	malfunction	aberrant SETDB1 activity is linked to disease onset, including nervous, cardiovascular and gastrointestinal system disorders, as well as numerous inherited genetic syndromes. SETDB1 is most significantly involved in tumorigenesis by repressing tumor suppressor genes after establishing the H3K9me3 mark. SETDB1 activity results in higher aggressiveness and worse cancer prognosis and has therefore been regarded as an oncogene	778396	
2.1.1.366	malfunction	aberrant SETDB1 expression, and its oncogenic role is evident in many cancers. Amplified SETDB1 is associated with enhanced tumorigenesis and poor prognosis in a wide variety of cancers. This increased oncogenic effect is probably due to a SETDB1 methylation-associated suppressive effect on various tumor suppressors, AKT hyperactivation, and increased mutant p53 stability. SETDB1 overexpression shows a significant negative correlation with immunomodulatory outcomes through tumor immune evasion and IFN-I pathway repression	777166	
2.1.1.366	metabolism	CBX7 inhibition reduces H3K9 methylation levels. CBX7 inhibitors abolish the interaction between CBX7 and H3K9 methyltransferases and block both CBX7-and H3K9 methyltransferase-mediated gene repression	777284	
2.1.1.366	additional information	SETDB1 exists in three isoforms, with isoform 1 being considered as the canonical sequence, including all the necessary domains for full enzyme activity. Isoform 2 contains the same domains as isoform 1. Isoform 2 is produced by alternate splicing of an in-frame splice site which is present in the 3' coding region, resulting in C-terminal truncation in the post-SET domain, thus producing a shorter protein form. Isoform 3 lacks all the domains of the C-terminus that are required for enzyme activity	778396	
2.1.1.366	physiological function	ATFa-associated factor mAM stimulates ESET enzymatic activity by increasing the Vmax and decreasing the Km. mAM facilitates the ESET-dependent conversion of dimethyl H3-K9 to the trimethyl state both in vitro and in vivo. mAM enhances ESET-mediated transcriptional repression in a SAM-dependent manner, and this repression correlates with histone H3-K9 trimethylation at the promoter	757646	
2.1.1.366	physiological function	bivalend combinantion, dually marked histones H3K9me3/H3K14ac modification in the liver, is significantly decreased in old hepatocytes. A correlation between H3K9me3/H3K14ac bulk bivalent genomic regions and dually marked single nucleosomes is suggested. Histone H3K9 deacetylase Hdac3, as well as H3K9 methyltransferase Setdb1, found in complex Kap1, occupy both bulk and single nucleosome bivalent regions in both young and old livers, correlating to presence of H3K9me3. Expression of genes associated with bivalent regions in young liver, including those regulating cholesterol secretion and triglyceride synthesis, is upregulated in old liver once the bivalency is lost	758617	
2.1.1.366	physiological function	deletion of Setdb1 in Meckel's cartilage tissue leads to its enlargement. Chondrocytes from the Meckel's cartilage of Setdb1 conditional KO mice show increased size. At embryonic days 16.5 and 18.5, part of the perichondrium is disrupted and mineralization is observed in the Meckel's cartilage. Inhibition of Setdb1 causes increased proliferation in chondrocytes in the Meckel's cartilage as well as in siRNA-treated ATDC5 cells. Decreased expression of chondrogenic genes, such as Sox9, Mmp13, Collagen II, and Aggrecan, is observed as a result of Setdb1 inhibition in ATDC5 cells. SMAD-dependent BMP signaling is significantly increased by the loss of Setdb1 in both the Meckel's cartilage of Setdb1 conditional KO mice and siRNA-treated ATDC5 cells	758727	
2.1.1.366	physiological function	deletion of the catalytic domain of either histone methyltransferases EHMT2 or SETDB1 in growing oocytes leads to significant reduction of global H3K9me2 or H3K9me3 levels, respectively, in the maternal pronucleus. The asymmetry of global 5-methylcytosine (5mC) oxidation is significantly reduced in the zygotes that carry maternal mutation of either the Ehmt2 or Setdb1 genes. The levels of 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine increase, and 5mC levels decrease in the mutant maternal pronuclei. H3K9me3-rich rings around the nucleolar-like bodies retain 5mC in the maternal mutant zygotes. The maternal pronuclei expand in size in the mutant zygotes and contain a significantly increased number of nucleolar-like bodies compared with normal zygotes	760074	
2.1.1.366	physiological function	embryonic stem cells exhibit high expression of the ubiquitin-conjugating enzyme UBE2K. Loss of UBE2K upregulates the trimethyltransferase SETDB1, resulting in H3K9 trimethylation and repression of neurogenic genes during differentiation	759079	
2.1.1.366	physiological function	ESET interacts with transcription factor EST	757872	
2.1.1.366	physiological function	H3K9 methylation reader M-phase phosphoprotein 8 (MPP8) interacts physically and functionally with SETDB1 in embryonic stem cells. MPP8 and SETDB1 coregulate a significant number of common genomic targets, especially the DNA satellite repeats	759299	
2.1.1.366	physiological function	histone H3K9 methyltransferases G9a/KMT1C, GLP/KMT1D, SETDB1/KMT1E, and Suv39h1/KMT1A, coexist in the same megacomplex. In Suv39h or G9a null cells, the remaining histone H3K9 methyltransferases are destabilized at the protein level, indicating. The four enzymes are recruited to major satellite repeats, a known Suv39h1 genomic target, but also to multiple G9a target genes. The four H3K9 histone H3K9 methyltransferases display a functional cooperation in the regulation of known G9a target genes	759762	
2.1.1.366	physiological function	histone methyltransferase SETDB1 safeguards mouse fetal hematopoiesis by suppressing activation of cryptic enhancers maintaining the proper balance and differentiation of mouse fetal liver hematopoietic stem and progenitor cells	779191	
2.1.1.366	physiological function	microRNA, miR-152-3p is involved in the regulation of SETDB1 protein levels and plays a positive regulatory role for SETDB1 expression. Inhibition of miR-152-3p results in a robust reduction in SETDB1 protein levels, though SETDB1 mRNA levels are unaffected. This is accompanied by a blockade of the biochemical pathway proceeding from H3K9me2 to H3K9me3. H3K9me2 accumulates in cells treated with an anti-miR that targets miR-152-3p. The action of a miR-152-3p mimic increases flux of the reaction leading to H3K9me3	759155	
2.1.1.366	physiological function	SETDB1 has a central role in normal physiology and nervous system development, having been implicated in the regulation of cell cycle progression, inactivation of the X chromosome, immune cells function, expression of retroelements and formation of promyelocytic leukemia nuclear bodies. SETDB1 has been frequently deregulated in carcinogenesis, being implicated in the pathogenesis of gliomas, melanomas, as well as in lung, breast, gastrointestinal and ovarian tumors, where it mainly exerts an oncogenic role	778396	
2.1.1.366	physiological function	Setdb1 has a constant role in endogenous retrovirus silencing. Distinctive sets of endogenous retroviruses are reactivated in different types of Setdb1-deficient somatic cells, including the VL30-class of endogenous retroviruses in mouse embryonic fibroblasts. A viral defense response is induced in immortalized Setdb1 knock-out embryonic fibroblasts	759835	
2.1.1.366	physiological function	Setdb1 in macrophages potently suppresses Toll-like receptor TLR4-mediated expression of proinflammatory cytokines including interleukin-6 through its methyltransferase activity. Setdb1-deficiency decreases the basal H3K9 methylation levels and augments TLR4-mediated NF-kappaB recruitment on the proximal promoter region of interleukin-6, thereby accelerating interleukin-6 promoter activity. Macrophage-specific Setdb1-knockout mice exhibit higher serum interleukin-6 concentrations in response to lipopolysaccharide challenge and are more susceptible to endotoxin shock than wild-type mice	755432	
2.1.1.366	physiological function	SETDB1 is a major enzyme for H3K9 histone methylation in heterochromatin	759155	
2.1.1.366	physiological function	SETDB1 is an epigenetic regulator of primordial germ cell fate determination. SETDB1-deficient embryos exhibit drastic reduction of nascent primordial germ cells. Dppa2, Otx2 and Utf1 are derepressed whereas mesoderm development-related genes, including BMP4 signaling-related genes, are downregulated by SETDB1 knockdown during primordial germ cell-like cell induction. Binding of SETDB1 is observed at the flanking regions of Dppa2, Otx2 and Utf1 in cell aggregates containing primordial germ cell-like cell induction, and trimethylation of lysine 9 of histone H3 is reduced by SETDB1 knockdown at those regions	759113	
2.1.1.366	physiological function	SETDB1 is the bridge linking the DNA damage response to meiotic silencing in male mice. At the onset of silencing, X chromosome H3K9 trimethylation enrichment is downstream of DNA damage response factors. Without SETDB1, the X chromosome accrues DNA damage response proteins but not H3K9me3, so sex chromosome remodeling and silencing fail, causing germ cell apoptosis. Setdb1 deletion causes midpachytene apoptosis. SETDB1 is required for epigenetic remodeling of the XY pair, for condensation of the XY pair and for XY silencing at pachynema	759112	
2.1.1.366	physiological function	SETDB1 methylation regulates H3K9me3 in the OTX2 promoter region and inhibits the expression of OTX2. SETDB1 expression is downregulated in osteoporotic femoral tissues and is involved in osteogenic differentiation. Upregulation of SETDB1 promotes osteogenic differentiation by inhibiting OTX2 and activating the BMP-Smad and Wnt/beta-catenin pathways in osteoporosis	777586	
2.1.1.366	physiological function	SETDB1 regulates the development of cortical Htr3a-positive interneurons and mood behaviors	776709	
2.1.1.366	physiological function	SETDB1 regulates the PTEN/AKT/FOXO1 pathway to inhibit spermatogonial stem cell apoptosis. SETDB1 interacts and coordinates with AKT to regulate FOXO1 activity and expression of the downstream target genes Bim and Puma. Among the SETDB1-bound genes, the H3K9me3 levels on the promoter regions of Bim and Pten decrease in the SETDB1-knock down group. The H3K9me3 status on promoters of Bax and Puma remains unchanged	758839	
2.1.1.366	physiological function	SETDB1 strengthens non-small cell lung cancer cell migratory and invasive abilities by promoting invadopodia formation and extracellular matrix degradation. At the molecular level, SETDB1 suppresses the expression of FOXA2, a crucial tumor and metastasis suppressor via coordinated epigenetic mechanisms. SETDB1 not only catalyzes histone H3K9 methylation on FOXA2 genomic locus, but also recruits DNMT3A to regulate DNA methylation on CpG island. Setdb1 is essential for malignant progression and metastasis of murine lung adenocarcinoma	778826	
2.1.1.366	physiological function	the cytoplasmic fraction of the histone lysine methyltransferase Setdb1 is essential for survival of embryonic stem cells. Setdb1 interacts with many RNA-binding proteins and translation regulators such as Trim71. Setdb1 is required for Trim71 complex integrity cSetdb1 regulates the abundance of specific mRNAs, of which Trim71 and hnRNPc targets	777831	
2.1.1.366	physiological function	the enzyme is involved in heterochromatin formation and silencing of repeat elements	778808	
2.1.1.366	physiological function	the enzyme is involved in various regulatory processes such as cell proliferation, progression, migration, survival, and apoptosis. The enzyme is an important epigenetic regulator catalyzing histone H3 lysine 9 (H3K9) methylation, specifically di-/tri-methylation. This regulation promotes gene silencing through heterochromatin formation. SETDB1 altered lymphocyte and cytokine expression, disrupts the IFN-I response, promotes TAM recruitment, induces ERV silencing, and facilitates tumor immune escape	777166	
2.1.1.366	physiological function	the SETDB1 repressor complex, which involves multiple KRAB zinc finger proteins, shields neuronal genomes from excess CTCF binding and is critically required for structural maintenance of cPcdh topologically associated domain. Neuronal ablation of Setdb1 leads to locus-specific disintegration of megabase-scale chromosomal conformations. The cPcdh topologically associated domain in neurons from mutant mice shows abnormal accumulation of the transcriptional regulator and three-dimensional genome organizer CTCF at cryptic binding sites, in conjunction with DNA cytosine hypomethylation, histone hyperacetylation and upregulated expression. Genes encoding stochastically expressed protocadherins are transcribed by increased numbers of cortical neurons. SETDB1-dependent loop formations bypass 0.2-1 Mb of linear genome and radiate from the cPcdh topologically associated domain fringes toward cis-regulatory sequences within the cPcdh locus	759838