Genomic occupancy of the transcriptional co-activators p300 and CBP

Holmqvist, Per-Henrik; Mannervik, Mattias

doi:10.4161/trns.22601

Cited by 82 publications

(75 citation statements)

References 55 publications

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“…S1 A and B). This result is consistent with our previous observation from ChIP-chip data that PC and CBP co-occupy many genomic sites (36) with active or repressed marks (37).…”

Section: Significancesupporting

confidence: 83%

Polycomb inhibits histone acetylation by CBP by binding directly to its catalytic domain

Tie

Banerjee

et al. 2016

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

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Drosophila Polycomb (PC), a subunit of Polycomb repressive complex 1 (PRC1), is well known for its role in maintaining repression of the homeotic genes and many others and for its binding to trimethylated histone H3 on Lys 27 (H3K27me3) via its chromodomain. Here, we identify a novel activity of PC: inhibition of the histone acetylation activity of CREB-binding protein (CBP). We show that PC and its mammalian CBX orthologs interact directly with the histone acetyltransferase (HAT) domain of CBP, binding to the previously identified autoregulatory loop, whose autoacetylation greatly enhances HAT activity. We identify a conserved PC motif adjacent to the chromodomain required for CBP binding and show that PC binding inhibits acetylation of histone H3. CBP autoacetylation impairs PC binding in vitro, and PC is preferentially associated with unacetylated CBP in vivo. PC knockdown elevates the acetylated H3K27 (H3K27ac) level globally and at promoter regions of some genes that are bound by both PC and CBP. Conversely, PC overexpression decreases the H3K27ac level in vivo and also suppresses CBP-dependent Polycomb phenotypes caused by overexpression of Trithorax, an antagonist of Polycomb silencing. We find that PC is physically associated with the initiating form of RNA polymerase II (Pol II) and that many promoters co-occupied by PC and CBP are associated with paused Pol II, suggesting that PC may play a role in Pol II pausing. These results suggest that PC/PRC1 inhibition of CBP HAT activity plays a role in regulating transcription of both repressed and active PC-regulated genes.Polycomb | CBP | acetylation | histone H3K27 | Drosophila

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“…S1 A and B). This result is consistent with our previous observation from ChIP-chip data that PC and CBP co-occupy many genomic sites (36) with active or repressed marks (37).…”

Section: Significancesupporting

confidence: 83%

Polycomb inhibits histone acetylation by CBP by binding directly to its catalytic domain

Tie

Banerjee

et al. 2016

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

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“…Indeed, MED25 exhibited a role in altering H3K27 status at the HNF4␣ binding region. The H3K27ac marker, initiated by the conserved CREBBP/p300, prevents H3K27 trimethylation of PRC target genes in Drosophila, but although PRC2-related H3K27me3 in chromatin does not prevent CREBBP binding it can block CREBBP HAT activity (52,53). We show that H3K27 is increasingly methylated upon CAR and HNF4␣ overexpression with silencing of MED25, suggesting that at certain HNF4␣-responsive promoters, an H3K27me3-rich heterochromatin-like conformation occurs and HAT activity is lost, presumably in concurrence with the loss of CREBBP binding, as seen with ChIP and in vitro recruitment.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Modification of Histone 3 Lysine 27

Englert

Luo

Goldstein

et al. 2015

Journal of Biological Chemistry

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Background: Mediator subunit MED25 associates with hepatocyte nuclear factor 4␣ to initiate activation of select genes. Results: CYP2C9 activation by MED25 involves preinitiation complex formation, H3K27 acetylation, and chromatin conformation changes, and the absence of MED25 results in H3K27 trimethylation and Polycomb group recruitment. Conclusion: MED25 is a key regulator of epigenetic mechanisms. Significance: MED25 regulates human drug metabolism gene CYP2C9 by epigenetic modification.

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“…CBP-and p300-mediated histone acetylation at gene promoter/enhancer RESEARCH ARTICLE regions collaborates with SWI/SNF complexes to facilitate remodeling of chromatin into a relaxed state (26)(27)(28), allowing access by RNA polymerase II ( 29 ). We showed that approximately 10% to 15% of non-small cell and small cell lung cancers harbor loss-of-function aberrations in the CBP gene ( 30,31 ).…”

Section: Introductionmentioning

confidence: 99%

Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

Ogiwara¹,

Sasaki²,

Mitachi³

et al. 2016

Cancer Discovery

140

109

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Loss-of-function mutations in the CBP/CREBBP gene, which encodes a histone acetyltransferase (HAT), are present in a variety of human tumors, including lung, bladder, gastric, and hematopoietic cancers. Consequently, development of a molecular targeting method capable of specifi cally killing CBP-defi cient cancer cells would greatly improve cancer therapy. Functional screening of synthetic-lethal genes in CBP -defi cient cancers identifi ed the CBP paralog p300/EP300 . Ablation of p300 in CBP -knockout and CBP -defi cient cancer cells induced G 1 -S cell-cycle arrest, followed by apoptosis. Genome-wide gene expression analysis revealed that MYC is a major factor responsible for the synthetic lethality. Indeed, p300 ablation in CBP -defi cient cells caused downregulation of MYC expression via reduction of histone acetylation in its promoter, and this lethality was rescued by exogenous MYC expression. The p300-HAT inhibitor C646 specifi cally suppressed the growth of CBP -defi cient lung and hematopoietic cancer cells in vitro and in vivo ; thus p300 is a promising therapeutic target for treatment of CBP -defi cient cancers. SIGNIFICANCE:Targeting synthetic-lethal partners of genes mutated in cancer holds great promise for treating patients without activating driver gene alterations. Here, we propose a "synthetic lethalbased therapeutic strategy" for CBP -defi cient cancers by inhibition of the p300 HAT activity. Patients with CBP -defi cient cancers could benefi t from therapy using p300-HAT inhibitors. Cancer Discov; 6(4); 430-45.

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Genomic occupancy of the transcriptional co-activators p300 and CBP

Cited by 82 publications

References 55 publications

Polycomb inhibits histone acetylation by CBP by binding directly to its catalytic domain

Polycomb inhibits histone acetylation by CBP by binding directly to its catalytic domain

Epigenetic Modification of Histone 3 Lysine 27

Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

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