Structure of the MLL CXXC domain–DNA complex and its functional role in MLL-AF9 leukemia

Cierpicki, Tomasz; Risner, Laurie E.; Grembecka, Jolanta; Lukasik, Stephen M.; Popovic, Relja; Omonkowska, M.; Shultis, David; Zeleznik‐Le, Nancy J.; Bushweller, John H.

doi:10.1038/nsmb.1714

Cited by 158 publications

(215 citation statements)

References 42 publications

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“…Consistent with this observation, MLL fusion proteins preferentially associate with the promoterproximal regions [56] rather than the gene body region, which is known to be enriched with H3K36me3 [61]. The CXXC domain of MLL binds to non-methylated CpGs [62][63][64]. A genome-wide DNA methylation analysis showed an enrichment of non-methylated CpGs in the promoters of MLL target genes and a depletion of methylated CpGs at the loci [56].…”

Section: Mechanisms Of Target Recognition By Mll Fusion Proteinssupporting

confidence: 56%

Molecular mechanisms of MLL-associated leukemia

Yokoyama

2015

Int J Hematol

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genes [1][2][3]. To date, more than 70 MLL fusion genes have been reported [4]. Leukemia associated with MLL gene alterations (hereafter referred to as MLL-associated leukemia) accounts for ~5-10 % of total acute leukemia cases and is a major cause of infant acute lymphoblastic leukemia [5]. Clinical outcomes of MLL-associated leukemia are often unfavorable; therefore, the development of better therapeutic strategies is needed.Significant progress in understanding MLL-associated leukemia has been achieved in the past two decades. The coding sequence of the MLL gene was established in the early 1990s [1,2]. The first mouse model of MLL-associated leukemia using retroviral gene transduction or knockin strategies was generated in the late 1990s [6,7], and several other sophisticated disease models using murine cells [8][9][10][11][12] and human cells [13,14] that mimic the human disease have been developed. Recent technological advances in genetics, such as DNA microarray and short hairpin RNA library screening have enabled identification of a number of novel pathways that play critical roles in the development of MLL-associated leukemia, and these are reviewed in detail elsewhere [15]. In this review, I focus on the mechanistic aspects of MLL fusion-dependent leukemic transformation. MLL activates transcription of cellular memory genesMLL is structurally similar to the Drosophila trithorax protein, as both have an evolutionarily conserved SET domain (Fig. 1a) [1, 2]. Knockout of Mll results in a loss of the expression of several posterior homeobox (Hox) genes [16,17], similar to the consequences of the genetic ablation of trithorax in Drosophila [18,19]. Hox genes are Abstract Gene rearrangements of the mixed lineage leukemia (MLL) gene cause aggressive leukemia. The fusion of MLL and its partner genes generates various MLL fusion genes, and their gene products trigger aberrant self-renewal of hematopoietic progenitors leading to leukemia. Since the identification of the MLL gene two decades ago, a substantial amount of information has been obtained regarding the mechanisms by which MLL mutations cause leukemia. Wild-type MLL maintains the expression of Homeobox (HOX) genes during development. MLL activates the expression of posterior HOX-A genes in the hematopoietic lineage to stimulate the expansion of immature progenitors. MLL fusion proteins constitutively activate the HOX genes, causing aberrant self-renewal. The modes of transcriptional activation vary depending on the fusion partners and can be categorized into at least four groups. Here I review the recent progress in research related to the molecular mechanisms of MLL fusion-dependent leukemogenesis.

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Section: Mechanisms Of Target Recognition By Mll Fusion Proteinssupporting

confidence: 56%

Molecular mechanisms of MLL-associated leukemia

Yokoyama

2015

Int J Hematol

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“…Most histone modification enzymes have not been observed to bind DNA, except for REF6 and MLL1, which contain a zinc finger domain and CXXC domain, respectively (Cierpicki et al, 2010;Cui et al, 2016). The fundamental question of how these histone modification proteins target specific genes to carry out their functions remains to be explored.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Histone H2A at Serine 95: A Plant-Specific Mark Involved in Flowering Time Regulation and H2A.Z Deposition

Wang

Zhang

et al. 2017

Plant Cell

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Phosphorylation of histone H3 affects transcription, chromatin condensation, and chromosome segregation. However, the role of phosphorylation of histone H2A remains unclear. Here, we found that Arabidopsis thaliana MUT9P-LIKE-KINASE (MLK4) phosphorylates histone H2A on serine 95, a plant-specific modification in the histone core domain. Mutations in MLK4 caused late flowering under long-day conditions but no notable phenotype under short days. MLK4 interacts with CIRCADIAN CLOCK ASSOCIATED1 (CCA1), which allows MLK4 to bind to the GIGANTEA (GI) promoter. CCA1 interacts with YAF9a, a co-subunit of the Swi2/Snf2-related ATPase (SWR1) and NuA4 complexes, which are responsible for incorporating the histone variant H2A.Z into chromatin and histone H4 acetylase activity, respectively. Importantly, loss of MLK4 function led to delayed flowering by decreasing phosphorylation of H2A serine 95, along with attenuated accumulation of H2A.Z and the acetylation of H4 at GI, thus reducing GI expression. Together, our results provide insight into how phosphorylation of H2A serine 95 promotes flowering time and suggest that phosphorylation of H2A serine 95 modulated by MLK4 is required for the regulation of flowering time and is involved in deposition of the histone variant H2A.Z and H4 acetylation in Arabidopsis.

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“…Although reversible, histone lysine methylation is regulated by systems evolved towards its stable maintenance, propagation and transmission. Both transcription activating Trx complexes and transcription repressing Polycomb complexes may be recruited by a combination of factors including GC-rich elements, [1][2][3][4] histone binding proteins, [5][6][7] transcription factors and non-coding RNA (ncRNA). 8 Here, we shall discuss the recent progress regarding the composition, recruitment and regulation of the activity of the PRC2 complex and the implications for its physiological functions.…”

Section: Introductionmentioning

confidence: 99%

Composition, recruitment and regulation of the PRC2 complex

Nayak

Xu²,

Min³

2011

Nucleus

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T he PRC2 histone methyltransferase complex is an important regulator of gene expression programs in metazoans. Gene expression regulation by the PRC2 complex is critical for development and cell differentiation. Several recent studies have begun to shed light on the molecular basis for the physiological function of the PRC2 complex. Here, we discuss some of these results and how they provide new insights into the composition, recruitment and regulation of the PRC2 complex.

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Structure of the MLL CXXC domain–DNA complex and its functional role in MLL-AF9 leukemia

Cited by 158 publications

References 42 publications

Molecular mechanisms of MLL-associated leukemia

Molecular mechanisms of MLL-associated leukemia

Phosphorylation of Histone H2A at Serine 95: A Plant-Specific Mark Involved in Flowering Time Regulation and H2A.Z Deposition

Composition, recruitment and regulation of the PRC2 complex

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