EVI1 recruits the histone methyltransferase SUV39H1 for transcription repression

Abstract

EVI1 is an oncoprotein inappropriately expressed in acute myeloid leukemia and myelodysplastic syndrome cells. In vitro studies indicate that diverse biological properties can be attributed to this protein. Its role in leukemogenesis is still unclear but it is thought that overall EVI1 can act mostly as a transcription repressor through its interaction with a subset of histone deacetylases. Studies with histone deacetylase inhibitors have however indicated that EVI1-mediated repression can be only partially rescued by deacetylase inhibitor drugs, suggesting that additional chromosomal modifications might occur to induce gene repression by EVI1. To investigate whether histone methylation contributes to the repressive potential of EVI1, we examined a potential association between EVI1, the histone methyltransferase (HMT) SUV39H1, and methyltransferase activity in vitro. We find that EVI1 directly interacts with SUV39H1 and that the proteins form an active complex with methyltransferase activity in vitro. Our data indicate that SUV39H1 enhances the transcription repressive potential of EVI1 in vivo. We suggest that EVI1 affects promoters' activity in two different pathways, by association with histone deacetylases and by recruiting chromatin-modifying enzymes to impose a heterochromatin-like structure establishing a lasting transcription repression.

EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization

“…21,22 In contrast to these reports, we found that SUV39H1-H324K acts in a dominant-negative manner to abrogate EVI-1-mediated repression of p3TP-Lux reporter activity, whereas wild-type SUV39H1 has little effect on the repression by EVI-1. This discrepancy is probably because of the different cell types and/or promoters used for the assays.…”

“…16 In addition, EVI-1 contains a highly acidic domain at the C-terminus, which is required for EVI-1-mediated P-Sp haematopoiesis. 26 In contrast to the earlier reports, which showed that EVI-1 interacts with SUV39H1 through ZF1, 21,22 all of these deletion mutants associate with both SUV39H1 and G9a almost as efficiently as full-length EVI-1 (Figure 2b and c).…”

“…Very recently, it was shown that EVI-1 physically interacts with H3K9 HMTs, 21,22 suggesting that EVI-1 regulates transcription by recruiting these HMTs. Here, we extended these analyses and found that the HMTs are important for colony-replating ability of Evi-1.…”

“…20 Very recently, two independent groups reported that EVI-1 physically interacts with the H3K9 HMTs, SUV39H1 and G9a. 21,22 However, functional roles of these HMTs in EVI-1-mediated leukemogenesis remain unclear.…”

EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia

“…2 Interestingly, myeloid malignancies associated with EVI1 overexpression often show dysplastic megakaryopoiesis. 1,6 Although the EVI1 function is not fully understood, recent studies suggest that this gene is involved in chromatin remodeling, through interactions with H3K9 methyltransferases 7,8 Five splice variants of EVI1 have been reported, that is EVI1-1A, -1B, -1C, -1D, and -3L, as well as the MDS1/EVI1 intergenic splice variant. 9,10 The MDS1 gene is located upstream of EVI1 and its function is currently unknown.…”