ALL-1 Is a Histone Methyltransferase that Assembles a Supercomplex of Proteins Involved in Transcriptional Regulation

Abstract

ALL-1 is a member of the human trithorax/Polycomb gene family and is also involved in acute leukemia. ALL-1 is present within a stable, very large multiprotein supercomplex composed of > or =29 proteins. The majority of the latter are components of the human transcription complexes TFIID (including TBP), SWI/SNF, NuRD, hSNF2H, and Sin3A. Other components are involved in RNA processing or in histone methylation. The complex remodels, acetylates, deacetylates, and methylates nucleosomes and/or free histones. The complex's H3-K4 methylation activity is conferred by the ALL-1 SET domain. Chromatin immunoprecipitations show that ALL-1 and other complex components examined are bound at the promoter of an active ALL-1-dependent Hox a9 gene. In parallel, H3-K4 is methylated, and histones H3 and H4 are acetylated at this promoter.

MLL: How complex does it get?

“…It is believed that Mll controls Hox gene expression by binding to Hox regulatory elements and association with other transcriptional regulators. Indeed, MLL binding to the promoters of HOXA9 and Hoxc8 was described recently [Milne et al, 2002;Nakamura et al, 2002]. Overexpression of some Hox genes, including Hoxa9, has been linked to leukemia in mouse models.…”

“…Interestingly, just like the MLL protein, the Set1 complex was shown to methylate lysine 4 on histone H3 [Nagy et al, 2002]. This purified MLL complex is able to perform chromatin remodeling, histone methylation, acetylation, and deacetylation suggesting that all the associated proteins retain their enzymatic activities [Nakamura et al, 2002]. All the complex components bind to the promoter of HOXA9 only when MLL is present, showing the MLL-dependence of the whole supercomplex being targeted to the target gene region.…”

“…Methylation of the lysine residues on histone tails is part of the proposed histone code in which different histone modifications direct the recruitment of transcriptional regulators, ultimately exerting an influence on gene expression [Jenuwein and Allis, 2001]. While the initial studies failed to confirm such enzymatic function in the MLL SET domain, more recently two groups have shown that mouse and human MLL SET domains are indeed able to methylate lysine residues on histone tails [Milne et al, 2002;Nakamura et al, 2002]. The specificity of the MLL SET domain is for lysine 4 (K4) on histone H3.…”

“…Recently two different MLL containing protein complexes were purified [Nakamura et al, 2002;Yokoyama et al, 2004]. The first study identified a very large complex comprised of more than 29 proteins associated with MLL [Nakamura et al, 2002].…”

ALL-1/MLL1, a homologue of Drosophila TRITHORAX, modifies chromatin and is directly involved in infant acute leukaemia

“…The ChIP methodology was recently applied to ALL-1 (Nakamura et al, 2002;Milne et al, 2002) and the protein was found bound at the promoters of HOX A9 and HOX C8 in cultured cells expressing these genes (homologues of Drosophila TREs and PREs have not been identified yet in mammals). Elimination of ALL-1, by applying interference RNA methodology, blocked transcription of HOX A9.…”