Chromatin Regulator | Alias |
| WHSC1 | WHS; NSD2; TRX5; MMSET; REIIBP |
External Links: | Wiki GeneCards NCBI UniProt |
Related histone modifications: | H4K20me2;H4K20me3;H3K4me3;H3K27me3;H3K36me3;H3K36me2 |
Introduction | |
| Full Name: Wolf-Hirschhorn syndrome candidate 1
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WHSC1 is a member of the nuclear receptor-binding SET domain (NSD) protein family. It possesses a proline-tryptophan-tryptophan-proline (PWWP) sequence as well as high-mobility group (HMG box) and plant homeodomain (PHD) domains, and its overexpression is linked to several cancers. WHSC1 plays an important role in proliferation, differentiation, development, cell cycle control, and tumor progression (1-14).
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Function and Interaction | |
| WHSC1 reportedly forms a complex with HDAC1 and HDAC2, mSin3a, and the histone demethylase LSD1, indicating its role as a component of this corepressor complex (2). WHSC1 interacts with some developmental transcription factors, including Sall1, Sall4, and Nanog in embryonic stem cells and Nkx2-5 in embryonic hearts, thus altering the expression of their target genes and preventing some related pathophysiologies (4). In multiple myeloma cells, overexpression of WHSC1 can result in a high level of H3K36 dimethylation and a reduced level of H3K27 methylation, regulating many genes involved in the p53 pathway, cell cycle regulation (CCND2, CCNG1, BRCA1, AURKA, and CHEK1), apoptosis (CASP1, CASP4, and FOXO3A), cell adhesion (ADAM9 and DSG2) and integrin signaling. deletion of WHSC1 in multiple myeloma cells affects chromatin accessibility and results in apoptosis and growth inhibition (5,13). WHSC1 is involved in the DNA damage response (DDR) pathway. It can control the methylation of the K20 residue of histone H4 through its SET domain and is in responsible for 53BP1 recruitment to sites of DNA damage (6,15). Furthermore, WHSC1 is involved in the WNT pathway, as it is associated with related proteins, and it is able to control the population of cancer cells from S phase to the G2/M phase during the cell cycle (14). WHSC1 interacts with the androgen receptor (AR) through its HMG domain and promotes AR-related transcriptional activation in the presence of a ligand, indicating its association with prostate carcinogenesis (8).
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Disease Association | |
| WHSC1 is associated with several types of diseases. WHSC1 haploinsufficiency is associated with Wolf Hirschhorn syndrome (WHS), which is characterized by growth retardation, mental retardation, and immunodeficiency. This gene is also generally overexpressed in t(4;14) multiple myelomas, and it could trigger oncogenic programming by interfering with the genomic distribution of dimethylation of H3 at lysine 36 (H3K36me2) (7,9-10). The transcription and protein levels of WHSC1 are upregulated in cancers of the bladder, colon and lung as well as neuroblastomas (11-12,14).
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ChIP-Seq data
ChIP-Seq data of related histone modifications
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References | |
1. Kim, J.Y., Kee, H.J., Choe, N.W., Kim, S.M., Eom, G.H., Baek, H.J., Kook, H., Kook, H. and Seo, S.B. (2008) Multiple myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity. Mol Cell Biol, 28, 2023-2034.
2. Marango, J., Shimoyama, M., Nishio, H., Meyer, J.A., Min, D.J., Sirulnik, A., Martinez-Martinez, Y., Chesi, M., Bergsagel, P.L., Zhou, M.M. et al. (2008) The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood, 111, 3145-3154.
3. Li, Y., Trojer, P., Xu, C.F., Cheung, P., Kuo, A., Drury, W.J., Qiao, Q., Neubert, T.A., Xu, R.M., Gozani, O. et al. (2009) The Target of the NSD Family of Histone Lysine Methyltransferases Depends on the Nature of the Substrate. J Biol Chem, 284, 34283-34295.
4. Nimura, K., Ura, K., Shiratori, H., Ikawa, M., Okabe, M., Schwartz, R.J. and Kaneda, Y. (2009) A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature, 460, 287-U157.
5. Martinez-Garcia, E., Popovic, R., Min, D.J., Sweet, S.M.M., Thomas, P.M., Zamdborg, L., Heffner, A., Will, C., Lamy, L., Staudt, L.M. et al. (2011) The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood, 117, 211-220.
6. Pei, H.D., Zhang, L., Luo, K.T., Qin, Y.X., Chesi, M., Fei, F., Bergsagel, P.L., Wang, L.W., You, Z.S. and Lou, Z.K. (2011) MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature, 470, 124-U144.
7. Kuo, A.J., Cheung, P., Chen, K.F., Zee, B.M., Kioi, M., Lauring, J., Xi, Y.X., Park, B.H., Shi, X.B., Garcia, B.A. et al. (2011) NSD2 Links Dimethylation of Histone H3 at Lysine 36 to Oncogenic Programming. Mol Cell, 44, 609-620.
8. Kang, H.B., Choi, Y., Lee, J.M., Choi, K.C., Kim, H.C., Yoo, J.Y., Lee, Y.H. and Yoon, H.G. (2009) The histone methyltransferase, NSD2, enhances androgen receptor-mediated transcription. Febs Lett, 583, 1880-1886.
9. Stec, I., Wright, T.J., van Ommen, C.J.B., de Boer, P.A.J., van Haeringen, A., Moorman, A.F.M., Altherr, M.R. and den Dunnen, J.T. (1998) WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to the Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma (vol 7, pg 1071, 1998). Hum Mol Genet, 7, 1527-1528.
10. Santra, M., Zhan, F.H., Tian, E.M., Barlogie, B. and Shaughnessy, J. (2003) A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood, 101, 2374-2376.
11. Hudlebusch, H.R., Santoni-Rugiu, E., Simon, R., Ralfkiaer, E., Rossing, H.H., Johansen, J.V., Jorgensen, M., Sauter, G. and Helin, K. (2011) The Histone Methyltransferase and Putative Oncoprotein MMSET Is Overexpressed in a Large Variety of Human Tumors. Clin Cancer Res, 17, 2919-2933.
12. Hudlebusch, H.R., Skotte, J., Santoni-Rugiu, E., Zimling, Z.G., Lees, M.J., Simon, R., Sauter, G., Rota, R., De Ioris, M.A., Quarto, M. et al. (2011) MMSET Is Highly Expressed and Associated with Aggressiveness in Neuroblastoma. Cancer Res, 71, 4226-4235.
13. Brito, J.L.R., Walker, B., Jenner, M., Dickens, N.J., Brown, N.J.M., Ross, F.M., Avramidou, A., Irving, J.A.E., Gonzalez, D., Davies, F.E. et al. (2009) MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells. Haematol-Hematol J, 94, 78-86.
14. Toyokawa, G., Cho, H.S., Masuda, K., Yamane, Y., Yoshimatsu, M., Hayami, S., Takawa, M., Iwai, Y., Daigo, Y., Tsuchiya, E. et al. (2011) Histone Lysine Methyltransferase Wolf-Hirschhorn Syndrome Candidate 1 Is Involved in Human Carcinogenesis through Regulation of the Wnt Pathway. Neoplasia, 13, 887-U826.
15. Hajdu, I., Ciccia, A., Lewis, S.M. and Elledge, S.J. (2011) Wolf-Hirschhorn syndrome candidate 1 is involved in the cellular response to DNA damage. P Natl Acad Sci USA, 108, 13130-13134.
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