Alternative titles; symbols
HGNC Approved Gene Symbol: TRIM28
Cytogenetic location: 19q13.43 Genomic coordinates (GRCh38) : 19:58,544,064-58,550,715 (from NCBI)
TRIM28 is a scaffold protein involved in gene silencing, cell growth and differentiation, pluripotency, neoplastic transformation, apoptosis, DNA repair, and maintenance of genomic integrity. Sumoylated TRIM28 can assemble epigenetic machinery for gene silencing, while phosphorylated TRIM28 is involved in DNA repair (review by Iyengar and Farnham, 2011).
The KRAB (Kruppel-associated box) domain is a transcriptional repression domain encoded by many transcription factors, including many zinc finger transcription factors (e.g., ZNF45; 194554). Friedman et al. (1996) used affinity chromatography to identify cellular factors that could bind KRAB domains. They purified a 100-kD protein with binding activity and obtained a polypeptide sequence. A PCR product encoding this sequence was used as a probe to clone the gene from a human testis cDNA library. This gene, TRIM28, which the authors termed KAP1, encodes an 835-amino acid polypeptide containing a RING finger, B boxes, and a PHD finger.
Using the yeast 2-hybrid system to search for proteins that could interact with the KRAB domain of ZNF10 (194538), Moosmann et al. (1996) isolated a cDNA encoding TRIM28, which they called TIF1-beta, from a human peripheral blood lymphocyte cDNA library. The TIF1-beta protein is 31% identical to that of mouse nuclear factor Tif1 (TRIM24; 603406). Northern blot analysis revealed a transcript of approximately 3.3 kb in all tissues tested.
Using a yeast 2-hybrid screen to find molecules that could interact with the KRAB-A domain, Kim et al. (1996) isolated and cloned Krip1, the mouse homolog of KAP1.
In the TIF1 proteins, Venturini et al. (1999) identified a 25-amino acid stretch rich in tryptophan and phenylalanine located downstream of the coiled-coil motif. This 25-amino acid stretch is highly conserved between TIF1A, TIF1B, and TIF1G (605769), and the authors termed this the TIF1 signature sequence, or TSS.
By immunofluorescence analysis, Messerschmidt et al. (2012) found that Trim28 was highly expressed in mouse oocytes and early embryos.
By fluorescence in situ hybridization, Moosmann et al. (1996) mapped the TIF1-beta gene to 19q13.4.
Friedman et al. (1996) identified KAP1 as a KRAB-binding corepressor. When KAP1 was expressed in COS cells, it bound a wildtype KRAB domain, but not mutant KRAB domains that had no repression ability. Furthermore, KAP1 formed a complex with a KRAB-domain transcription factor and increased the efficiency of KRAB-mediated repression.
Moosmann et al. (1996) demonstrated that TIF1-beta repressed transcription only when bound to DNA.
Using luciferase analysis, Venturini et al. (1999) determined that TIF1B, like TIF1A and TIF1G, repressed transcription by binding through the TSS to promoter regions.
Moloney murine leukemia virus (MMLV) replication is restricted in embryonic carcinoma and embryonic stem cells. Using EMSA of MMLV-infected mouse embryonic cell lines, Wolf and Goff (2007) purified the repressor-binding site complex and identified Trim28 as an integral component of the complex. RNA interference-mediated knockdown of Trim28 in mouse embryonic carcinoma and embryonic stem cells relieved the restriction on MMLV replication, and Trim28 was bound to the primer-binding site when restriction took place. Wolf and Goff (2007) concluded that TRIM family members are involved in retroviral restriction.
Tian et al. (2009) found that APAK (ZNF420; 617216) interacted with p53 (TP53; 191170) and KAP1 via its zinc fingers and KRAB domain, respectively, in unstressed human cells. KAP1 recruited ATM (607585) and HDAC1 (601241) to attenuate acetylation of p53, thereby repressing p53 activity and expression of proapoptotic genes. APAK, KAP1, and ATM did not regulate p53 targets that induce cell cycle arrest. In response to DNA damage, ATM phosphorylated APAK on ser68, causing dissociation of APAK and HDAC1 from p53, allowing expression of proapoptotic p53 target genes and apoptosis.
Matsui et al. (2010) showed that the H3K9 methyltransferase ESET (604396) and KAP1 are required for H3K9 trimethylation (H3K9me3) and silencing of endogenous and introduced retroviruses specifically in mouse embryonic stem (ES) cells. Furthermore, whereas ESET enzymatic activity is crucial for binding heterochromatin protein-1 (HP1; 604478) and efficient proviral silencing, the H4K20 methyltransferases Suv420h1 (610881) and Suv420h2 (613198) are dispensable for silencing. Notably, in mouse ES cells null for 3 DNA methyltransferases (Dnmt1, 126375; Dnmt3a, 602769; Dnmt3b, 602900), ESET and KAP1 binding and ESET-mediated H3K9me3 were maintained and ERVs (endogenous retroviruses) were minimally derepressed. Matsui et al. (2010) proposed that a DNA methylation-independent pathway involving KAP1 and ESET/ESET-mediated H3K9me3 is required for proviral silencing during the period early in embryogenesis when DNA methylation is dynamically reprogrammed.
The human immunodeficiency virus (HIV)-1 enzyme integrase (IN) catalyzes integration of viral cDNA into the host genome and is positively regulated by acetylation. Using yeast 2-hybrid and coimmunoprecipitation analyses, Allouch et al. (2011) found that KAP1 bound acetylated IN. KAP1 induced IN deacetylation through the formation of a complex with HDAC1. Modulation of intracellular KAP1 levels in various cell types, including T cells, the primary HIV-1 target, revealed that KAP1 curtailed viral infectivity by selectively affecting HIV-1 integration. Allouch et al. (2011) concluded that acetylation of IN is a crucial step in the viral infectious cycle and that KAP1 is a cellular factor that restricts HIV-1 infection.
Barde et al. (2013) found that in mice, hematopoietic-restricted deletion of Kap1 results in severe hyperproliferative anemia. Kap1-deleted erythroblasts failed to induce mitophagy-associated genes and retained mitochondria. This was due to persistent expression of microRNAs targeting mitophagy transcripts, itself secondary to a lack of repression by stage-specific KRAB zinc finger proteins. The KRAB/KAP1-miRNA regulatory cascade is evolutionarily conserved, as it also controls mitophagy during human erythropoiesis. Barde et al. (2013) concluded that a multilayered transcription regulatory system is present, in which protein and RNA-based repressors are superimposed in combinatorial fashion to govern the timely triggering of an important differentiation event.
By yeast 2-hybrid and coimmunoprecipitation analyses, Huang et al. (2013) showed that the proline-rich N terminus of FOXP3 (300292) interacted with the C terminus of FIK, an isoform of ZFP90 (609451). Expression of FOXP3 and FIK in Jurkat T cells led to decreased expression of IL2 (147680) and IFNG (147570), and chromatin immunoprecipitation analysis showed that FOXP3, FIK, and KAP1, which binds to the A box within the KRAB domain of FIK, were present on the same site on the IL2 and IFNG promoters. FIK was highly expressed in Tregs, and disruption of the FOXP3-FIK-KAP1 complex in Tregs abrogated their suppressor activity. Huang et al. (2013) concluded that FIK has a critical role in regulating FOXP3 activity and Treg function.
Van Meter et al. (2014) reported that the longevity-regulating protein SIRT6 (606211) is a powerful repressor of L1 (see LRE1, 151626) activity. Specifically, SIRT6 binds to the 5-prime UTR of L1 loci, where it mono-ADP ribosylates the nuclear corepressor protein KAP1 and facilitates KAP1 interaction with the heterochromatin factor HP1, thereby contributing to the packaging of L1 elements into transcriptionally repressive heterochromatin. During the course of aging, and also in response to DNA damage, however, Van Meter et al. (2014) found that SIRT6 is depleted from L1 loci, allowing the activation of these previously silenced retroelements.
Elsasser et al. (2015) showed that the replacement histone variant H3.3 (601128) is enriched at class I and class II endogenous retroviral elements (ERVs), notably those of the early transposon/MusD family and intracisternal A-type particles. Deposition at a subset of these elements is dependent on the H3.3 chaperone complex containing ATRX (300032) and DAXX (603186). Elsasser et al. (2015) demonstrated that recruitment of DAXX, H3.3, and KAP1 to ERVs is codependent and occurs upstream of ESET (SETDB1; 604396), linking H3.3 to ERV-associated H3K9me3. Importantly, H3K9me3 is reduced at ERVs upon H3.3 deletion, resulting in derepression and dysregulation of adjacent, endogenous genes, along with increased retrotransposition of intracisternal A-type particles. Elsasser et al. (2015) concluded that their study identifies a unique heterochromatin state marked by the presence of both H3.3 and H3K9me3, and establishes an important role for H3.3 in control of ERV retrotransposition in embryonic stem cells.
Messerschmidt et al. (2012) deleted Trim28 from mouse oocytes that were then fertilized by wildtype males. Embryos derived from this mating lacked both Trim28 RNA and protein until transcription from the paternal allele ensued after zygotic gene activation at the early 2-cell stage. Despite normal development to the blastocyst stage, highly pleiotropic defects resulted in complete lack of live births. Observed defects included edemas, craniofacial malformations, hemorrhage, and complete and hemianophthalmia. Microarray analysis revealed that maternal Trim28 mutants showed misregulation of the H19 (103280)/Igf2 (147470) imprinted cluster. Examination of the methylation status of the H19/Igf2 cluster suggested that maternal Trim28 protects the H19 differentially methylated region (DMR) on the paternal chromosome from aberrant DNA demethylation. Other DMRs were variably demethylated in mutant embryos, which likely contributed to the highly variable phenotype. Messerschmidt et al. (2012) concluded that TRIM28 is required to maintain genomic imprints.
Allouch, A., Di Primio, C., Alpi, E., Lusic, M., Arosio, D., Giacca, M., Cereseto, A. The TRIM family protein KAP1 inhibits HIV-1 integration. Cell Host Microbe 9: 484-495, 2011. [PubMed: 21669397] [Full Text: https://doi.org/10.1016/j.chom.2011.05.004]
Barde, I., Rauwel, B., Marin-Florez, R. M., Corsinotti, A., Laurenti, E., Verp, S., Offner, S., Marquis, J., Kapopoulou, A., Vanicek, J., Trono, D. A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy. Science 340: 350-353, 2013. [PubMed: 23493425] [Full Text: https://doi.org/10.1126/science.1232398]
Elsasser, S. J., Noh, K.-M., Diaz, N., Allis, C. D., Banaszynski, L. A. Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells. Nature 522: 240-244, 2015. [PubMed: 25938714] [Full Text: https://doi.org/10.1038/nature14345]
Friedman, J. R., Fredericks, W. J., Jensen, D. E., Speicher, D. W., Huang, X.-P., Neilson, E. G., Rauscher, F. J., III. KAP-1, a novel corepressor for the highly conserved KRAB repression domain. Genes Dev. 10: 2067-2078, 1996. [PubMed: 8769649] [Full Text: https://doi.org/10.1101/gad.10.16.2067]
Huang, C., Martin, S., Pfleger, C., Du, J., Buckner, J. H., Bluestone, J. A., Riley, J. L., Ziegler, S. F. Cutting edge: a novel, human-specific interacting protein couples FOXP3 to a chromatin-remodeling complex that contains KAP1/TRIM28. J. Immun. 190: 4470-4473, 2013. [PubMed: 23543754] [Full Text: https://doi.org/10.4049/jimmunol.1203561]
Iyengar, S., Farnham, P. J. KAP1 protein: an enigmatic master regulator of the genome. J. Biol. Chem. 286: 26267-26276, 2011. [PubMed: 21652716] [Full Text: https://doi.org/10.1074/jbc.R111.252569]
Kim, S.-S., Chen, Y.-M., O'Leary, E., Witzgall, R., Vidal, M., Bonventre, J. V. A novel member of the RING finger family, KRIP-1, associates with the KRAB-A transcriptional repressor domain of zinc finger proteins. Proc. Nat. Acad. Sci. 93: 15299-15304, 1996. [PubMed: 8986806] [Full Text: https://doi.org/10.1073/pnas.93.26.15299]
Matsui, T., Leung, D., Miyashita, H., Maksakova, I. A., Miyachi, H., Kimura, H., Tachibana, M., Lorincz, M. C., Shinkai, Y. Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature 464: 927-931, 2010. Note: Erratum: Nature 513: 128 only, 2014. [PubMed: 20164836] [Full Text: https://doi.org/10.1038/nature08858]
Messerschmidt, D. M., de Vries, W., Ito, M., Solter, D., Ferguson-Smith, A., Knowles, B. B. Trim28 is required for epigenetic stability during mouse oocyte to embryo transition. Science 335: 1499-1502, 2012. [PubMed: 22442485] [Full Text: https://doi.org/10.1126/science.1216154]
Moosmann, P., Georgiev, O., Le Douarin, B., Bourquin, J.-P., Schaffner, W. Transcriptional repression by RING finger protein TIF1-beta that interacts with the KRAB repressor domain of KOX1. Nucleic Acids Res. 24: 4859-4867, 1996. [PubMed: 9016654] [Full Text: https://doi.org/10.1093/nar/24.24.4859]
Tian, C., Xing, G., Xie, P., Lu, K., Nie, J., Wang, J., Li, L., Gao, M., Zhang, L., He, F. KRAB-type zinc-finger protein Apak specifically regulates p53-dependent apoptosis. Nature Cell Biol. 11: 580-591, 2009. [PubMed: 19377469] [Full Text: https://doi.org/10.1038/ncb1864]
Van Meter, M., Kashyap, M., Rezazadeh, S., Geneva, A. J., Morello, T. D., Seluanov, A., Gorbunova, V. SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nature Commun. 5: 5011, 2014. Note: Electronic Article. [PubMed: 25247314] [Full Text: https://doi.org/10.1038/ncomms6011]
Venturini, L., You, J., Stadler, M., Galien, R., Lallemand, V., Koken, M. H. M., Mattei, M. G., Ganser, A., Chambon, P., Losson, R., de The, H. TIF1-gamma, a novel member of the transcriptional intermediary factor 1 family. Oncogene 18: 1209-1217, 1999. [PubMed: 10022127] [Full Text: https://doi.org/10.1038/sj.onc.1202655]
Wolf, D., Goff, S. P. TRIM28 mediates primer binding site-targeted silencing of murine leukemia virus in embryonic cells. Cell 131: 46-57, 2007. [PubMed: 17923087] [Full Text: https://doi.org/10.1016/j.cell.2007.07.026]