Regulation of HOXA2 gene expression by the ATP‐dependent chromatin remodeling enzyme CHD8

Yates, Joel A.; Menon, Tushar; Thompson, B. A.; Bochar, Daniel A.

doi:10.1016/j.febslet.2010.01.022

Cited by 42 publications

(41 citation statements)

References 22 publications

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“…However, CHD3 can also be a coactivator for the c-myb transcription factor (53). Similarily, CHD8 is a repressor of HOXA2 transcription and of beta-catenin target genes and acts as a corepressor for p53 during early mouse embryogenesis (44,72,80), but CHD8 is also an activator of the cyclin E2 gene (50). CHD7 is part of a corepressor complex bound by peroxisome proliferator-activated receptor ␥ (PPAR-␥) (67) but acts also as a transcriptional activator of Sox9, Twist, and Slug transcription to induce the neural crest transcriptional circuitry (2).…”

Section: Discussionmentioning

confidence: 99%

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Interaction of the Papillomavirus E8∧E2C Protein with the Cellular CHD6 Protein Contributes to Transcriptional Repression

Fertey

Ammermann

Winkler³

et al. 2010

J Virol

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Expression of the E6 and E7 oncogenes of high-risk human papillomaviruses (HPV) is controlled by cellular transcription factors and by viral E2 and E8 ∧ E2C proteins, which are both derived from the HPV E2 gene. Both proteins bind to and repress the HPV E6/E7 promoter. Promoter inhibition has been suggested to be due to binding site competition with cellular transcription factors and to interactions of different cellular transcription modulators with the different amino termini of E2 and E8 ∧ E2C. We have now identified the cellular chromodomain helicase DNA binding domain 6 protein (CHD6) as a novel interactor with HPV31 E8 ∧ E2C by using yeast two-hybrid screening. Pull-down and coimmunoprecipitation assays indicate that CHD6 interacts with the HPV31 E8 ∧ E2C protein via the E2C domain. This interaction is conserved, as it occurs also with the E8 ∧ E2C proteins expressed by HPV16 and -18 and with the HPV31 E2 protein. Both RNA knockdown experiments and mutational analyses of the E2C domain suggest that binding of CHD6 to E8 ∧ E2C contributes to the transcriptional repression of the HPV E6/E7 oncogene promoter. We provide evidence that CHD6 is also involved in transcriptional repression but not activation by E2. Taken together our results indicate that the E2C domain not only mediates specific DNA binding but also has an additional role in transcriptional repression by recruitment of the CHD6 protein. This suggests that repression of the E6/E7 promoter by E2 and E8 ∧ E2C involves multiple interactions with host cell proteins through different protein domains.Persistent infections with "high-risk" human papillomaviruses (HPV) are a major risk factor for cervical cancer development (5, 10, 86). Carcinogenic HPV encode the E6 and E7 oncoproteins, which are required for the immortalization of normal human keratinocytes and the continous growth of cervical cancer cell lines, such as HeLa (40, 41). Expression of E6 and E7 transcripts is controlled by both cellular and viral transcription factors (70). Papillomavirus proteins derived from the E2 gene are involved in control of viral transcription, of DNA replication, and of segregation of viral genomes (29,37,38). The E2 open reading frame gives rise to multiple gene products by alternative RNA splicing. In addition to the full-length E2 protein, cells infected with bovine papillomavirus type 1 (BPV1), cottontail rabbit papillomavirus (CRPV), and HPV types 1, 11, 16, 31, and 33 express an E8 ∧ E2C transcript in which the small E8 domain is fused to the C-terminal domain of E2 (E2C) (9,18,28,46,52,58,63). Inactivation of E2 in the HPV16 genome increases E6/E7 transcription (59). Mutation of E8 ∧ E2C in the HPV31 or HPV16 genome increases genome copy number and E6/E7 transcripts, strongly suggesting that transcriptional repression by E8 ∧ E2C plays an important role in viral replication (31,63,85).The C-terminal domain (E2C) which is shared by E2 and E8 ∧ E2C is responsible for sequence-specific recognition of ACCN 6 GGT DNA sites (E2 binding site [E2BS]) and homoand he...

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Section: Discussionmentioning

confidence: 99%

“…CHD8 has been reported to recruit a WDR5/Ash2l/RBBP5 complex to inhibit HOXA2 and beta-catenin targets (72,80), whereas p53-dependent transcription is inhibited by a trimeric p53/CHD8/histone 1 complex (44). PPAR-␥-dependent transcription is inhibited by a CHD7/SETDB1/NLK complex (67).…”

Section: Discussionmentioning

confidence: 99%

Interaction of the Papillomavirus E8∧E2C Protein with the Cellular CHD6 Protein Contributes to Transcriptional Repression

Fertey

Ammermann

Winkler³

et al. 2010

J Virol

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“…The apparent molecular mass of this complex determined by gel filtration is comparable with the theoretical molecular mass for the WDR5, RbBP5, and Ash2L complex (156 kDa) with 1:1:1 stoichiometry and is consistent with our sedimentation velocity analytical ultracentrifugation characterization of WRA(D). WRA(D) has also been identified in other complexes that appear to lack SET1 family enzymes, such as the CHD8 and NIF1 complexes (63)(64)(65). Whether WRAD brings a histone methyltransferase activity to these complexes remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

A Novel Non-SET Domain Multi-subunit Methyltransferase Required for Sequential Nucleosomal Histone H3 Methylation by the Mixed Lineage Leukemia Protein-1 (MLL1) Core Complex

Patel

Vought

Dharmarajan

et al. 2011

Journal of Biological Chemistry

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Gene expression within the context of eukaryotic chromatin is regulated by enzymes that catalyze histone lysine methylation. Histone lysine methyltransferases that have been identified to date possess the evolutionarily conserved SET or Dot1-like domains. We previously reported the identification of a new multi-subunit histone H3 lysine 4 methyltransferase lacking homology to the SET or Dot1 family of histone lysine methyltransferases. This enzymatic activity requires a complex that includes WRAD (WDR5, RbBP5, Ash2L, and DPY-30), a complex that is part of the MLL1 (mixed lineage leukemia protein-1) core complex but that also exists independently of MLL1 in the cell. Here, we report that the minimal complex required for WRAD enzymatic activity includes WDR5, RbBP5, and Ash2L and that DPY-30, although not required for enzymatic activity, increases the histone substrate specificity of the WRAD complex. We also show that WRAD requires zinc for catalytic activity, displays Michaelis-Menten kinetics, and is inhibited by S-adenosylhomocysteine. In addition, we demonstrate that WRAD preferentially methylates lysine 4 of histone H3 within the context of the H3/H4 tetramer but does not methylate nucleosomal histone H3 on its own. In contrast, we find that MLL1 and WRAD are required for nucleosomal histone H3 methylation, and we provide evidence suggesting that each plays distinct structural and catalytic roles in the recognition and methylation of a nucleosome substrate. Our results indicate that WRAD is a new H3K4 methyltransferase with functions that include regulating the substrate and product specificities of the MLL1 core complex.Eukaryotic gene expression programs are established and maintained in part by enzymes that methylate the epsilon amino group of histone lysine residues. Histone lysine methylation regulates gene expression by recruiting proteins that stabilize or remodel distinct chromatin states (1-3). Lysine residues can be mono-, di-, or trimethylated with distinct functional consequences, increasing the combinatorial signaling potential of lysine methylation (4, 5). Although it has become increasingly clear that regulation of the degree of lysine methylation plays a functionally significant role in eukaryotic gene regulation, the molecular mechanisms involved are only beginning to be understood.Recent data suggest several models for the regulation of the degree of methylation by histone lysine methyltransferases. One model suggests that multiple methylation is achieved by distinct histone lysine methyltransferases that have evolved to catalyze the addition of one, two, or three methyl groups to a single lysine side chain. In this model, the addition of each methyl group is sequentially catalyzed by a distinct enzyme and is supported by the existence of several SET domain enzymes that differ in their abilities to use mono-or dimethyllysine as a substrate for further methylation (6), a phenomenon known as "product specificity" (7). In contrast, an alternative model suggests that multiple lysine methylation...

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“…The COOH-terminal region of full-length CHD8 (CHD8 L ) interacts with the insulator-binding protein CTCF, with this interaction being important for insulator activity (14). CHD8 has also been implicated as a positive or negative transcriptional regulator of various genes (19,32,33,45,46). We previously showed that Chd8 Ϫ/Ϫ mice die early during embryogenesis, manifesting widespread apoptosis (28), whereas additional deletion of the tumor suppressor gene p53 ameliorated this developmental arrest (29).…”

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confidence: 99%

Histone H1 Recruitment by CHD8 Is Essential for Suppression of the Wnt–β-Catenin Signaling Pathway

Nishiyama

Skoultchi

Nakayama

2012

Molecular and Cellular Biology

123

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Members of the chromodomain helicase DNA-binding (CHD) family of proteins are thought to regulate gene expression. Among mammalian CHD proteins, CHD8 was originally isolated as a negative regulator of the Wnt-␤-catenin signaling pathway that binds directly to ␤-catenin and suppresses its transactivation activity. The mechanism by which CHD8 inhibits ␤-catenin-dependent transcription has been unclear, however. Here we show that CHD8 promotes the association of ␤-catenin and histone H1, with formation of the trimeric complex on chromatin being required for inhibition of ␤-catenin-dependent transactivation. A CHD8 mutant that lacks the histone H1 binding domain did not show such inhibitory activity, indicating that histone H1 recruitment is essential for the inhibitory effect of CHD8. Furthermore, either depletion of histone H1 or expression of a dominant negative mutant of this protein resulted in enhancement of the response to Wnt signaling. These observations reveal a new mode of regulation of the Wnt signaling pathway by CHD8, which counteracts ␤-catenin function through recruitment of histone H1 to Wnt target genes. Given that CHD8 is expressed predominantly during embryogenesis, it may thus contribute to setting a threshold for responsiveness to Wnt signaling that operates in a development-dependent manner.

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Regulation of HOXA2 gene expression by the ATP‐dependent chromatin remodeling enzyme CHD8

Cited by 42 publications

References 22 publications

Interaction of the Papillomavirus E8∧E2C Protein with the Cellular CHD6 Protein Contributes to Transcriptional Repression

Interaction of the Papillomavirus E8∧E2C Protein with the Cellular CHD6 Protein Contributes to Transcriptional Repression

A Novel Non-SET Domain Multi-subunit Methyltransferase Required for Sequential Nucleosomal Histone H3 Methylation by the Mixed Lineage Leukemia Protein-1 (MLL1) Core Complex

Histone H1 Recruitment by CHD8 Is Essential for Suppression of the Wnt–β-Catenin Signaling Pathway

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