SUV39H1 interacts with AML1 and abrogates AML1 transactivity. AML1 is methylated in vivo

Abstract

Acute myeloid leukemia 1 (AML1) belongs to a family of DNA-binding proteins highly conserved through evolution. AML1 regulates the expression of several hematopoietic genes and is essential for murine fetal liver hematopoiesis. We report here that the histone methyltransferase SUV39H1, a mammalian ortholog of the Drosophila melanogaster SU(VAR) 3-9, forms complex with AML1. SUV39H1 methylates lysine 9 of the histone protein H3 leading to the formation of the high-affinity binding site on chromatin for proteins of the heterochromatin protein 1 family (HP1). The interaction of AML1 with SUV39H1 requires the N-terminus of AML1 where the Runt domain is located. Binding of AML1 to SUV39H1 abrogates the transactivating and DNA-binding properties of AML1 and dissociates the net-like nuclear structure of AML1. It has been reported that AML1 is capable of interaction with histone acetyl transferases (CBP, p300, and MOZ) and with component of the histone deacetylase complex (Sin3), and that the interaction with these coregulators affects the strength of AML1 in promoter regulation. Our data suggest that other enzymes are also involved in gene regulation by AML1 activity by modulating the affinity of AML1 for DNA.

RUNX1 associates with histone deacetylases and SUV39H1 to repress transcription

“…Alternatively, RUNX1 may have promoter/enhancer-specific functions dependent on the context of the RUNX1-binding sites. In addition, our data raise the possibility that RUNX1 forms two distinct complexes with SUV39H1, one that contacts DNA to silence gene expression in addition to the complex that cannot bind to DNA (Chakraborty et al, 2003).…”

“…Independently, this same interaction was identified, but it was found that when SUV39H1 was overexpressed, it contacted the Runt domain and inhibited the ability of RUNX1 to bind to DNA in vitro, thus creating an apparently inactive complex (Chakraborty et al, 2003). Given that the Runt domains of the RUNX family members are nearly identical, the association between SUV39H1 and RUNX1 and RUNX3, but not RUNX2, suggested that a domain(s) outside the Runt domain must contribute to or mediate the association with SUV39H1.…”

“…However, TEL contributes repression domains to this fusion protein, which limits our ability to determine whether SUV39H1 recruitment contributes to repression (Reed-Inderbitzin and Hiebert, unpublished data). RUNX1 residues 1-204 are also retained in the t(8;21) fusion protein, which again predicts that this fusion protein can recruit SUV39H1, although this association may negatively affect DNA binding (Chakraborty et al, 2003). Although the inv(16) contains no homology to RUNX1, it acts as a corepressor for RUNX1 (Lutterbach et al, 1999;Durst et al, 2003).…”

“…In addition, deletion of residues 469-480 (RD3) did not affect the association with SUV39H1. However, a deletion of RD2, residues 290-432, appeared to significantly reduce the association between RUNX1 and SUV39H1 (Figure 2b), although it retained some ability to copurify, likely due to the association between SUV39H1 and the RUNX1 DNA-binding domain (Chakraborty et al, 2003). Thus, RUNX1 may contact SUV39H1 through multiple domains, one of which lies within a previously identified repression domain (residues 290-432) (Lutterbach et al, 2000).…”

Plant homeodomain finger protein 2 promotes bone formation by demethylating and activating Runx2 for osteoblast differentiation

“…For example, G9a has been found to methylate p53, WIZ, CDYL1, ACINUS, and Reptin [19,20,26,27]. Similarly, Chakraborty et al [28] have reported that SUV39H1 interacts with the N-terminus of Runx1 (alternatively called AML1), and suggested that SUV39H1 inhibits the transcriptional activity of Runx1 by blocking its DNA-binding ability. However, it is still controversial whether SUV39H1 directly methylates Runx1 as the methylation level of Runx1 was not significantly augmented by SUV39H1 overexpression [28].…”