E2F Activation of S Phase Promoters via Association with HCF-1 and the MLL Family of Histone H3K4 Methyltransferases

Tyagi, Shweta; Chabes, Andrei; Wysocka, Joanna; Herr, Winship

doi:10.1016/j.molcel.2007.05.030

Cited by 225 publications

(341 citation statements)

References 54 publications

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“…MOZ is also associated with other transcription factors such as RUNX2, C/EBPa, C/EBPb, c-Jun, NF-kB, Nrf2/MafK and p53 (Pelletier et al, 2002;Ohta et al, 2005Ohta et al, , 2007Katsumoto et al, 2006;Chan et al, 2007;Rokudai et al, 2009). In addition, it was reported that MLL is a protein partner of p53 and HCF-1 in a cell cycle-dependent manner (Tyagi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

et al. 2010

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MOZ and MLL, encoding a histone acetyltransferase (HAT) and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. In MOZ (MOnocytic leukemia Zinc-finger protein)/CBP-or mixed lineage leukemia (MLL)-rearranged leukemias, abnormal levels of HOX transcription factors have been found to be critical for leukemogenesis. We show that MOZ and MLL cooperate to regulate these key genes in human cord blood CD34 þ cells. These chromatinmodifying enzymes interact, colocalize and functionally cooperate, and both are recruited to multiple HOX promoters. We also found that WDR5, an adaptor protein essential for lysine 4 trimethylation of histone H3 (H3K4me3) by MLL, colocalizes and interacts with MOZ. We detected the binding of the HAT MOZ to H3K4me3, thus linking histone methylation to acetylation. In CD34 þ cells, depletion of MLL causes release of MOZ from HOX promoters, which is correlated to defective histone activation marks, leading to repression of HOX gene expression and alteration of commitment of CD34 þ cells into myeloid progenitors. Thus, our results unveil the role of the interaction between MOZ and MLL in CD34 þ cells in which both proteins have a critical role in hematopoietic cell-fate decision, suggesting a new molecular mechanism by which MOZ or MLL deregulation leads to leukemogenesis.

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Section: Discussionmentioning

confidence: 99%

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

et al. 2010

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“…H3K4 methylation is primarily localized in the promoter and regulatory regions of genes. Some transcription factors, such as Menin, LEDGF, HCF1/2, E2F, NFE2, p53, and c-Myb, have been shown to interact with MLL family members, which could lead to methylation of H3K4 in a locus-or DNA sequence-specific manner [16,17,[25][26][27][28][29]. A recent study by our group identified a physical and functional interaction between RUNX1 and MLL, and showed that both are required for maintenance of the H3K4me3 mark at two critical regulatory regions of the RUNX1 target gene PU.1 locus [30].…”

Section: Mll and Its Role In Normal Hematopoiesismentioning

confidence: 99%

Disordered epigenetic regulation in MLL-related leukemia

et al. 2012

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Leukemias bearing rearrangements of chromosome 11q23 are of particular interest due to their unique clinical and biological characteristics. 11q23 abnormalities occur in up to 70 % of infant leukemias, and about 10 % of adult acute myelogenous leukemias (AML). Two major rearrangements of the MLL gene are found in MLL-related leukemia. The most common of these is balanced translocations in which the N-terminal portion of MLL is fused to the C-terminus of the translocation partner. To date, nearly 100 different chromosome bands have been described in rearrangements involving MLL, and more than 70 known fusion partners of MLL have been cloned and characterized at the molecular level. Another major aberration of the MLL gene creates a repeat within the N-terminal MLL resulting in an internal partial tandem duplication (PTD). As a consequence, an extra amino-terminus is added in-frame to full-length MLL, resulting in leukemogenic MLL-PTD. MLL-PTD occurs predominantly in myeloid dysplasia syndromes, secondary AML (s-AML), and de novo AML. The presence of an MLL rearrangement generally confers a poor prognosis. MLL fusions and MLL-PTD are transcriptional regulators that take control of targets normally controlled by MLL, with the clustered HOX homeobox genes as prominent examples. Several epigenetic regulators that modify DNA or histones have been implicated in MLL fusion driven leukemogenesis, including DNA methylation, histone acetylation, and histone methylation. Recently, the histone methyltransferase DOT1L, the bromodomain and extra-terminal (BET) family member BRD4, and the MLL-interacting protein Menin have emerged as important mediators of MLL fusion-mediated leukemic transformation. The clinical development of targeted inhibitors of these epigenetic regulators has heralded promise for the treatment of MLL fusion leukemia. Although the biological function and molecular mechanism for MLL-PTD remains largely unknown, based on the primary protein structure of MLL-PTD and the knowledge gained so far from MLL fusions, newly developed inhibitors of epigenetic regulators could potentially also prove effective in the treatment of MLL-PTD related leukemias.

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“…HCF-1 was initially identified as a human coactivator for immediate-early gene expression of herpes simplex virus (HSV) by forming a complex (VP16-induced complex, VIC) with the HSV protein VP16 and the cellular transcriptional regulator Oct-1 (1). HCF-1 regulates cell-cycle progression by mediating associations between DNA-binding transcription factors and chromatin modifying complexes (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

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confidence: 99%

HCF-1 self-association via an interdigitated Fn3 structure facilitates transcriptional regulatory complex formation

Park

Lammers

Herr

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Host-cell factor 1 (HCF-1) is an unusual transcriptional regulator that undergoes a process of proteolytic maturation to generate N-(HCF-1 N ) and C-(HCF-1 C ) terminal subunits noncovalently associated via self-association sequence elements. Here, we present the crystal structure of the self-association sequence 1 (SAS1) including the adjacent C-terminal HCF-1 nuclear localization signal (NLS). SAS1 elements from each of the HCF-1 N and HCF-1 C subunits form an interdigitated fibronectin type 3 (Fn3) tandem repeat structure. We show that the C-terminal NLS recruited by the interdigitated SAS1 structure is required for effective formation of a transcriptional regulatory complex: the herpes simplex virus VP16-induced complex. Thus, HCF-1 N -HCF-1 C association via an integrated Fn3 structure permits an NLS to facilitate formation of a transcriptional regulatory complex.crystallography | chromatin | nuclear localization sequence H ost cell factor-1 (HCF-1; also known as HCFC1) is a metazoan transcriptional regulator. HCF-1 was initially identified as a human coactivator for immediate-early gene expression of herpes simplex virus (HSV) by forming a complex (VP16-induced complex, VIC) with the HSV protein VP16 and the cellular transcriptional regulator Oct-1 (1). HCF-1 regulates cell-cycle progression by mediating associations between DNA-binding transcription factors and chromatin modifying complexes (2-12).Many HCF-1 proteins, including all known vertebrate HCF-1s, undergo a process of proteolytic maturation. Thus, human HCF-1 is synthesized as a 2035-aa precursor, which is cleaved and modified by O-GlcNAC transferase (13) to generate HCF-1 N and HCF-1 C subunits possessing different roles in, for example, cell-cycle regulation (14). After cleavage, the two resulting HCF-1 N and HCF-1 C subunits remain noncovalently associated via two "selfassociation sequences" called SAS1 and SAS2: SAS1 is the primary association element and its sequence is conserved in HCF-1, whereas SAS2 is secondary, less well conserved, and not considered in this study (15).SAS1 is composed of a short 43-aa HCF-1 N segment called SAS1N and a 197-aa HCF-1 C segment called SAS1C (Fig. 1A). Wilson et al. (15) suggested that SAS1C has two tandem fibronectin type 3 (Fn3) repeat structures forming a binding site for the 43-aa SAS1N to promote HCF-1 N -HCF-1 C association.To understand the mechanism of HCF-1 self-association, we have determined the crystal structure of SAS1 with the neighboring nuclear localization signal (called here SAS1-NLS). Contrary to expectation, SAS1N and SAS1C together-not SAS1C aloneform an integrated tandem Fn3 structure. Furthermore, we show that the self-association tethers the basic NLS to the HCF-1 N Kelch domain to facilitate VP16-induced complex formation. ResultsCrystal Structure of the HCF-1 SAS1 Self-Association Domain. The SAS1-NLS crystal structure (Fig. 1B) was determined to 2.7 Å resolution using the Se single-wavelength anomalous dispersion (SAD) method (Table S1 and Fig. S1). Fig. S2 details schematically...

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E2F Activation of S Phase Promoters via Association with HCF-1 and the MLL Family of Histone H3K4 Methyltransferases

Cited by 225 publications

References 54 publications

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

Disordered epigenetic regulation in MLL-related leukemia

HCF-1 self-association via an interdigitated Fn3 structure facilitates transcriptional regulatory complex formation

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