Alternative titles; symbols
HGNC Approved Gene Symbol: KMT5A
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38) : 12:123,384,132-123,409,353 (from NCBI)
SETD8 is a lysine methyltransferase (EC 2.1.1.43) that predominantly monomethylates lysine-20 (K20) of histone H4 (see 602822). Through its methyltransferase activity, SETD8 influences transcriptional regulation, heterochromatin formation, genomic stability, cell cycle progression, and development (Yang et al., 2012).
By purifying histone H4 lysine methyltransferase activity from HeLa cell nuclear lysates, followed by peptide sequencing, database analysis, and PCR of a HeLa cell cDNA library, Nishioka et al. (2002) cloned SETD8, which they designated PR/SET7. The deduced 322-amino acid protein has a C-terminal SET domain but lacks pre- and post-SET domains found in other histone methyltransferases. Database analysis revealed orthologs of SETD8 in worms, flies, and vertebrates, but not in lower eukaryotes.
Yang et al. (2012) showed that full-length SET8 contains 352 amino acids; the SET domain encompasses amino acids 216 through 343.
Hartz (2013) mapped the SETD8 gene to chromosome 12q24.31 based on an alignment of the SETD8 sequence (GenBank AF287261) with the genomic sequence (GRCh37).
Nishioka et al. (2002) showed that a mutation in Drosophila Pr/set7 was lethal: second instar larval death coincided with the loss of H4-lys20 methylation, indicating a fundamental role for Pr/set7 in development. Transcriptionally competent regions lacked H4-lys20 methylation, but the modification coincided with condensed chromosomal regions on polytene chromosomes, including chromocenter and euchromatic arms. The Drosophila male X chromosome, which is hyperacetylated at H4-lys16, had significantly decreased levels of lys20 methylation compared with that of females. In vitro, methylation of lys20 and acetylation of lys16 on the H4 tail were competitive. Taken together, these results supported the hypothesis that methylation of H4-lys20 maintains silent chromatin, in part, by precluding neighboring acetylation on the H4 tail.
Shi et al. (2007) showed that SET8 monomethylated p53 (TP53; 191170) in human cell lines. This monomethylation suppressed p53-mediated transcriptional activation of highly responsive target genes, such as p21 (CDKN1A; 116899) and PUMA (BBC3; 605854), but it had little influence on weak p53 targets. Depletion of SET8 augmented the proapoptotic and checkpoint activation functions of p53, and SET8 expression was downregulated upon DNA damage.
Song et al. (2009) found evidence that expression of SET8 is regulated by the microRNA MIR502 (300893; see MOLECULAR GENETICS).
Kudithipudi et al. (2012) synthesized peptides based on the SET8 recognition site surrounding monomethylated H4K20. They found that the isolated SET domain of SET8 had a relatively long recognition sequence covering 7 amino acids. SET8 methylated a number of the synthesized peptides, suggesting that it could potentially methylate several nonhistone proteins in addition to p53.
By immunoprecipitation analysis of MCF-7 human breast cancer cells, Yang et al. (2012) found that SET8 interacts with TWIST (TWIST1; 601622), a basic helix-loop-helix transcriptional factor that regulates epithelial-mesenchymal transition (EMT). Domain analysis revealed that the N-terminal half of SET8 was required for the interaction. TWIST and SET8 cooperated to promote EMT and metastasis in breast cancer cells following implantation in mice. In knockdown and overexpression studies, TWIST recruited SET8 to the promoter regions of E-cadherin (CDH1; 192090) and N-cadherin (CDH2; 114020), and histone H4K20 monomethylation by SET8 resulted in downregulation of E-cadherin and upregulation of N-cadherin.
Song et al. (2009) identified a SNP (rs16917496C-T) in the SET8 miR502 (300893)-binding site that influenced SET8 expression. Breast cancer tissues with the CC genotype, which represents the perfect complementary seed sequence for miR502, had lower expression of SET8 mRNA than those with the TT genotype.
Hartz, P. A. Personal Communication. Baltimore, Md. 3/22/2013.
Kudithipudi, S., Dhayalan, A., Kebede, A. F., Jeltsch, A. The SET8 H4K20 protein lysine methyltransferase has a long recognition sequence covering seven amino acid residues. Biochimie 94: 2212-2218, 2012. [PubMed: 22583696] [Full Text: https://doi.org/10.1016/j.biochi.2012.04.024]
Nishioka, K., Rice, J. C., Sarma, K., Erdjument-Bromage, H., Werner, J., Wang, Y., Chuikov, S., Valenzuela, P., Tempst, P., Steward, R., Lis, J. T., Allis, C. D., Reinberg, D. PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Molec. Cell 9: 1201-1213, 2002. [PubMed: 12086618] [Full Text: https://doi.org/10.1016/s1097-2765(02)00548-8]
Shi, X., Kachirskaia, I., Yamaguchi, H., West, L. E., Wen, H., Wang, E. W., Dutta, S., Appella, E., Gozani, O. Modulation of p53 function by SET8-mediated methylation at lysine 382. Molec. Cell 27: 636-646, 2007. [PubMed: 17707234] [Full Text: https://doi.org/10.1016/j.molcel.2007.07.012]
Song, F., Zheng, H., Liu, B., Wei, S., Dai, H., Zhang, L., Calin, G. A., Hao, X., Wei, Q., Zhang, W., Chen, K. An miR-502-binding site single-nucleotide polymorphism in the 3-prime-untranslated region of the SET8 gene is associated with early age of breast cancer onset. Clin. Cancer Res. 15: 6292-6300, 2009. [PubMed: 19789321] [Full Text: https://doi.org/10.1158/1078-0432.CCR-09-0826]
Yang, F., Sun, L., Li, Q., Han, X., Lei, L., Zhang, H., Shang, Y. SET8 promotes epithelial-mesenchymal transition and confers TWIST dual transcriptional activities. EMBO J. 31: 110-123, 2012. [PubMed: 21983900] [Full Text: https://doi.org/10.1038/emboj.2011.364]