Analysis of the Human Endogenous Coregulator Complexome

Malovannaya, Anna; Lanz, Rainer B.; Jung, Sung Yun; Bulynko, Yaroslava; Le, Nguyen T.; Chan, Doug W.; Chen, Ding; Shi, Yi; Yucer, Nur; Krenciute, Giedre; Kim, Beom-Jun; Li, Chunshu; Chen, Rui; Li, Wei; Wang, Yi; O’Malley, Bert W.; Qin, Jun

doi:10.1016/j.cell.2011.05.006

Cited by 393 publications

(428 citation statements)

References 68 publications

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“…Consistent with the classical definition of a transcriptional coactivator as an amplifier and stabilizer of coregulator complexes (2,9,10,14,15), loss of SRC-2 strikingly reduced the recruitment of metabolically responsive proteins to both Gck and G6pc promoters (Fig. 3C).…”

Section: Src-2 Recruits Distinct Coregulator Complexes To Regulate Gcsupporting

confidence: 58%

“…supports this notion (9). The dynamic interaction of multiple protein networks is collectively referred to as the "interactome," and it is acutely responsive to cellular signaling cues (10).…”

mentioning

confidence: 72%

“…Recently published work from our laboratory showing that coregulators form hormonally responsive transcriptional complexes suggests that platform coactivators such as SRC-2 may differentially influence transcriptional complexes in response to metabolic cues (9,10). The mapping of protein complexes that provide the foundation for the coregulator "complexome" further Significance Maintenance of glucose concentrations within a homeostatic range is essential for preserving the function of glucose-sensitive tissues.…”

mentioning

confidence: 99%

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SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis

Fleet

Zhang

Lin

et al. 2015

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

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Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate-limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation.

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Section: Src-2 Recruits Distinct Coregulator Complexes To Regulate Gcsupporting

confidence: 58%

mentioning

confidence: 72%

mentioning

confidence: 99%

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SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis

Fleet

Zhang

Lin

et al. 2015

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

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“…We find that multiple genetic targets of BRD4-NUT or ZNF532-NUT, including ZNF532 and ZMYND8, encode components of BRD4 regulatory complexes. Interestingly, it was previously reported that ZMYND8/ZNF532/ZNF592/ZNF687 interact with each other as a central hub in a large transcriptional network (26,30). ZMYND8 has several important chromatin-binding domains (bromodomain, PWWP, PHD finger, MYND), and can function as a combinatorial reader of histone modifications such as H3K4me1 and H3K14ac (31).…”

Section: Discussionmentioning

confidence: 99%

Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

Alekseyenko

Walsh

Zee

et al. 2017

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

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To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT midline carcinoma (NMC), we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared with wild-type BRD4. Using cross-linking, affinity purification, and mass spectrometry, we identified the EP300 acetyltransferase as uniquely associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also discovered ZNF532 associated with BRD4-NUT in NMC patient cells but not detectable in 293T cells. EP300 and ZNF532 are both implicated in feed-forward regulatory loops leading to propagation of the oncogenic chromatin complex in BRD4-NUT patient cells. Adding key functional significance to our biochemical findings, we independently discovered a ZNF532-NUT translocation fusion in a newly diagnosed NMC patient. ChIP sequencing of the major players NUT, ZNF532, BRD4, EP300, and H3K27ac revealed the formation of ZNF532-NUT-associated hyperacetylated megadomains, distinctly localized but otherwise analogous to those found in BRD4-NUT patient cells. Our results support a model in which NMC is dependent on ectopic NUT-mediated interactions between EP300 and components of BRD4 regulatory complexes, leading to a cascade of misregulation.BioTAP-XL | hyperacetylation | ZNF532-NUT | topological domains | BRD4

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“…Notably, nuclear hormone receptors have been shown to associate with upward of 10,000 "coregulatory" proteins (73), yet the complete ER␤ interactome has not been described. The data herein contribute to our understanding of the ER␤ interactome in the brain and also quantify ER␤-protein interactions as a function of age.…”

Section: Discussionmentioning

confidence: 99%

Age-dependent Effects of 17β-estradiol on the Dynamics of Estrogen Receptor β (ERβ) Protein–Protein Interactions in the Ventral Hippocampus

Mott

Pinceti

Rao

et al. 2014

Molecular & Cellular Proteomics

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Recent clinical evidence suggests that the neuroprotective and beneficial effects of hormone therapy may be limited by factors related to age and reproductive status. The patient's age and length of time without circulating ovarian hormones are likely to be key factors in the specific neurological outcomes of hormone therapy. However, the mechanisms underlying age-related changes in hormone efficacy have not been determined. We hypothesized that there are intrinsic changes in estrogen receptor ␤ (ER␤) function that determine its ability to mediate the actions of 17␤-estradiol (E2) in brain regions such as the ventral hippocampus. In this study, we identified and quantified a subset of ER␤ protein interactions in the ventral hippocampus that were significantly altered by E2 replacement in young and aged animals, using two-dimensional differential gel electrophoresis coupled with liquid chromatography-electrospray ionization-tandem mass spectrometry. This study demonstrates quantitative changes in ER␤ protein-protein interactions with E2 replacement that are dependent upon age in the ventral hippocampus and how these changes could alter processes such as transcriptional regulation. Thus, our data provide evidence that changes in ER␤ protein interactions are a potential mechanism for age-related changes in E2 responsiveness in the brain after menopause. Molecular & Cellular Proteomics 13: 10.1074/mcp.M113.031559, 760-779, 2014.The neuroprotective and beneficial effects of estrogens in the brain have been reported for decades, yet recent evidence from clinical trials suggests that the benefits of estrogens in postmenopausal women might not outweigh the risks (1-3). Specifically, the risk of cardiovascular disease and invasive breast cancer was significantly increased in postmenopausal women given hormone therapy as part of the largest clinical trial performed to date (Women's Health Initiative). These results sharply contradicted substantial evidence from numerous studies in animal models, prompting a reevaluation of the data from the Women's Health Initiative studies. Later it was determined that factors contributing to the observed detrimental effects of hormone therapy in the Women's Health Initiative study included advanced age, the types of synthetic estrogens and progestins used in the study, and, perhaps most important, the number of years postmenopause prior to the initiation of hormone therapy (4). However, more than 10 years after the conclusion of these studies there is little to no mechanistic explanation for how aging contributes to a change in estrogen signaling.One possibility is that there are age-related changes in the way the brain responds to estrogens. We hypothesized that there are intrinsic changes in the function of estrogen receptors in the brain with advanced age, and estrogen receptor ␤ (ER␤) 1 in particular has been shown to be a critical regulator of many neurobiological functions. An important component of ER␤ signaling is requisite associations with intracellular coregulatory proteins. ...

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Analysis of the Human Endogenous Coregulator Complexome

Cited by 393 publications

References 68 publications

SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis

SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis

Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

Age-dependent Effects of 17β-estradiol on the Dynamics of Estrogen Receptor β (ERβ) Protein–Protein Interactions in the Ventral Hippocampus

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