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EID3 is a novel EID family member and an inhibitor of CBP-dependent co-activation.

ABSTRACT: EID1 (E1A-like inhibitor of differentiation 1) functions as an inhibitor of nuclear receptor-dependent gene transcription by directly binding to co-regulators. Alternative targets include the co-repressor small heterodimer partner (SHP, NR0B2) and the co-activators CBP/p300, indicating that EID1 utilizes different inhibitory strategies. Recently, EID2 was characterized as an inhibitor of muscle differentiation and as an antagonist of both CBP/p300 and HDACs. Here, we describe a third family member designated EID3 that is highly expressed in testis and shows homology to a region of EID1 implicated in binding to CBP/p300. We demonstrate that EID3 acts as a potent inhibitor of nuclear receptor transcriptional activity by a mechanism that is independent of direct interactions with nuclear receptors, including SHP. Furthermore, EID3 directly binds to and blocks the SRC-1 interacting domain of CBP, which has been implicated to act as the interaction surface for nuclear receptor co-activators. Consistent with this idea, EID3 prevents recruitment of CBP to a natural nuclear receptor-regulated promoter. Our study suggests that EID-family members EID3 and EID1 act as inhibitors of CBP/p300-dependent transcription in a tissue-specific manner.

SUBMITTER: Bavner A

PROVIDER: S-EPMC1159117 | biostudies-literature | 2005

REPOSITORIES: biostudies-literature

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EID3 is a novel EID family member and an inhibitor of CBP-dependent co-activation.

Båvner Ann A Matthews Jason J Sanyal Sabyasachi S Gustafsson Jan-Ake JA Treuter Eckardt E

Nucleic acids research 20050624 11

EID1 (E1A-like inhibitor of differentiation 1) functions as an inhibitor of nuclear receptor-dependent gene transcription by directly binding to co-regulators. Alternative targets include the co-repressor small heterodimer partner (SHP, NR0B2) and the co-activators CBP/p300, indicating that EID1 utilizes different inhibitory strategies. Recently, EID2 was characterized as an inhibitor of muscle differentiation and as an antagonist of both CBP/p300 and HDACs. Here, we describe a third family memb ...[more]

PMID: 15987788

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Project description:BackgroundSperm cells must regulate the timing and location of activation to maximize the likelihood of fertilization. Sperm from most species, including the nematode Caenorhabditis elegans, activate upon encountering an external signal. Activation for C. elegans sperm occurs as spermatids undergo spermiogenesis, a profound cellular reorganization that produces a pseudopod. Spermiogenesis is initiated by an activation signal that is transduced through a series of gene products. It is now clear that an inhibitory pathway also operates in spermatids, preventing their premature progression to spermatozoa and resulting in fine-scale control over the timing of activation. Here, we describe the involvement of a newly assigned member of the inhibitory pathway: spe-4, a homolog of the human presenilin gene PS1. The spe-4(hc196) allele investigated here was isolated as a suppressor of sterility of mutations in the spermiogenesis signal transduction gene spe-27.ResultsThrough mapping, complementation tests, DNA sequencing, and transformation rescue, we determined that allele hc196 is a mutation in the spe-4 gene. Our data show that spe-4(hc196) is a bypass suppressor that eliminates the need for the spermiogenesis signal transduction. On its own, spe-4(hc196) has a recessive, temperature sensitive spermatogenesis-defective phenotype, with mutants exhibiting (i) defective spermatocytes, (ii) defective spermatids, (iii) premature spermatid activation, and (iv) spermatozoa defective in fertilization, in addition to a small number of functional sperm which appear normal microscopically.ConclusionA fraction of the sperm from spe-4(hc196) mutant males progress directly to functional spermatozoa without the need for an activation signal, suggesting that spe-4 plays a role in preventing spermatid activation. Another fraction of spermatozoa from spe-4(hc196) mutants are defective in fertilization. Therefore, prematurely activated spermatozoa may have several defects: we show that they may be defective in fertilization, and earlier work showed that they obstruct sperm transfer from males at mating. hc196 is a hypomorphic allele of spe-4, and its newly-discovered role inhibiting spermiogenesis may involve known proteolytic and/or calcium regulatory aspects of presenilin function, or it may involve yet-to-be discovered functions.

Project description:High morbidity and mortality are associated with acute liver injury (ALI) for which no effective targeted drugs or pharmacotherapies are available. Discovery of potential therapeutic targets as well as inhibitors that can alleviate ALI is imperative. As excessive inflammatory cytokines released by macrophages are a critical cause of liver injury, we aimed to find novel compounds that could inhibit macrophage expression of inflammatory cytokines and alleviate liver injury. Methods: A high throughput assay was established to screen a small molecule inhibitor library of epigenetic targets. A highly selective catalytic p300/CBP inhibitor A-485 was identified as a potent hit in vitro and administrated to the lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced mice in vivo. For in vitro analysis, RAW264.7 cells and primary BMDM cells exposed to LPS were co-incubated with A-485. A model of acute liver injury induced by LPS and GalN was used for evaluation of in vivo treatment efficacy. Results: A-485 inhibited LPS-induced inflammatory cytokine expression in a concentration-dependent manner in vitro. Significantly, A-485 administration alleviated histopathological abnormalities, lowered plasma aminotransferases, and improved the survival rate in the LPS/GalN-stimulated mice. Integrative ChIP-Seq and transcriptome analysis in the ALI animal model and macrophages revealed that A-485 preferentially blocked transcriptional activation of a broad set of pathologic genes enriched in inflammation-related signaling networks. Significant inhibition of H3K27ac/H3K18ac at promoter regions of these pivotal inflammatory genes was observed, in line with their suppressed transcription after A-485 treatment. Reduced expression of these pathological pro-inflammatory genes resulted in a decrease in inflammatory pathway activation, M1 polarization as well as reduced leukocyte infiltration in ALI mouse model, which accounted for the protective effects of A-485 on liver injury. Conclusion: Using a novel strategy targeting macrophage inflammatory activation and cytokine expression, we established a high-throughput screening assay to discover potential candidates for ALI treatment. We demonstrated that A-485, which targeted pathological inflammatory signaling networks at the level of chromatin, was pharmacologically effective in vivo and in vitro. Our study thus provided a novel target as well as a potential drug candidate for the treatment of liver injury and possibly for other acute inflammatory diseases.

Dataset Information

EID3 is a novel EID family member and an inhibitor of CBP-dependent co-activation.

Publications

EID3 is a novel EID family member and an inhibitor of CBP-dependent co-activation.

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