The structure, binding and function of a Notch transcription complex involving RBPJ and the epigenetic reader protein L3MBTL3

Hall, Daniel; Giaimo, Benedetto Daniele; Hemmer, Wiebke; Friedrich, Tobias; Ferrante, Francesca; Bartkuhn, Marek; Yuan, Zhenyu; Oswald, Franz; Borggrefe, Tilman; Rual, Jean François; Kovall, Rhett A.

doi:10.1093/nar/gkac1137

Cited by 3 publications

(2 citation statements)

References 64 publications

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“…Several studies have focused on the identification and characterization of components of both the corepressor and coactivator complexes, thereby elucidating on the regulation of the chromatin environment at Notch target genes ( 3–13 ). The exact mechanism of repression is well-documented and includes additional cofactors such as the SHARP/NCoR complex recruiting HDACs ( 8 , 9 , 12 ) and histone demethylases ( 6 , 10 , 14 ). Several studies have also analyzed the genome-wide distribution of RBPJ in various models ( 15–25 ).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive genomic features indicative for Notch responsiveness

Giaimo,

Friedrich,

Ferrante

et al. 2024

Nucleic Acids Research

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Transcription factor RBPJ is the central component in Notch signal transduction and directly forms a coactivator complex together with the Notch intracellular domain (NICD). While RBPJ protein levels remain constant in most tissues, dynamic expression of Notch target genes varies depending on the given cell-type and the Notch activity state. To elucidate dynamic RBPJ binding genome-wide, we investigated RBPJ occupancy by ChIP-Seq. Surprisingly, only a small set of the total RBPJ sites show a dynamic binding behavior in response to Notch signaling. Compared to static RBPJ sites, dynamic sites differ in regard to their chromatin state, binding strength and enhancer positioning. Dynamic RBPJ sites are predominantly located distal to transcriptional start sites (TSSs), while most static sites are found in promoter-proximal regions. Importantly, gene responsiveness is preferentially associated with dynamic RBPJ binding sites and this static and dynamic binding behavior is repeatedly observed across different cell types and species. Based on the above findings we used a machine-learning algorithm to predict Notch responsiveness with high confidence in different cellular contexts. Our results strongly support the notion that the combination of binding strength and enhancer positioning are indicative of Notch responsiveness.

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Section: Introductionmentioning

confidence: 99%

Comprehensive genomic features indicative for Notch responsiveness

Giaimo,

Friedrich,

Ferrante

et al. 2024

Nucleic Acids Research

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“…Several studies have focused on the identification and characterization of components of both the corepressor and coactivator complexes, thereby elucidating on the regulation of the chromatin environment at Notch target genes (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). The exact repressing mechanism is welldocumented and includes additional cofactors such as the SHARP/NCoR complex recruiting HDACs (8,9,12) and histone demethylases (6,10,14). Several studies have also analyzed the genome-wide distribution of RBPJ in various different models (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Genomic Features indicative for Notch Responsiveness

Giaimo,

Friedrich,

Ferrante

et al. 2023

Preprint

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Transcriptional specificity is often determined by transcription factor levels and/or chromatin context. In the Notch signal transduction pathway, transcription factor RBPJ is the central component and directly forms a coactivator complex together with the Notch intracellular domain (NICD). While the RBPJ protein levels remain constant in most tissues, dynamic expression of Notch target genes varies depending on the given cell-type and the Notch activity state. To elucidate dynamic RBPJ binding genome-wide, we investigated RBPJ occupancy by ChIP-Seq making use of Notch-dependent T cells. Surprisingly, only a small set of the total RBPJ sites show a dynamic binding behavior in response to Notch signaling. Compared to static RBPJ sites, dynamic sites differ in regard to their chromatin state, binding strength and enhancer positioning. Dynamic RBPJ sites are predominantly located distal to transcriptional start sites (TSS), while most static sites are found in promoter-proximal regions. Importantly, gene responsiveness is preferentially associated with dynamic RBPJ binding sites and this static and dynamic binding behavior is repeatedly observed in different cell types and species. Based on the above findings we used a machine-learning algorithm to predict Notch responsiveness with high confidence in different cellular contexts. This approach is potentially applicable to other transcription factors regulating signal-induced gene sets. Our results strongly support the notion that the combination of binding strength and enhancer positioning are indicative of Notch responsiveness.

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Cardiometabolic traits mediating the effect of education on the risk of DKD and CKD: a Mendelian randomization study

Wang,

Chen,

Wang

et al. 2024

Front. Nutr.

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BackgroundBoth diabetic kidney disease (DKD) and chronic kidney disease (CKD) are more prevalent among individuals with lower levels of education in observational studies. To quantify the mediation effect of recognized cardiometabolic traits, we obtain causal estimates between education and DKD as well as CKD.Materials and methodsWe assessed the causal effect of education on DKD and CKD, separately estimated the causal effect of 26 cardiometabolic traits on DKD and CKD, and finally calculated the mediating effects and mediating proportions of each using two-step, two-sample multivariable Mendelian randomization (MVMR). Furthermore, the genetic association between exposure, mediators, and outcomes was investigated using linkage disequilibrium score (LDSC) regression analysis. Expression quantitative trait loci (eQTL) were retrieved from the Genotype-Tissue Expression Project (GTEx) v8 to serve as genetic instrumental variables. Transcriptome-wide association studies (TWAS), Bayesian colocalization analysis, and Summary-data-based Mendelian Randomization (SMR) analysis were performed to explore underlying susceptibility genes between education, mediators, and kidney diseases.ResultsHigher education with a genetically predicted 1-SD (4.2 years) was linked to a 48.64% decreased risk of DKD and a 29.08% decreased risk of CKD. After extensive evaluation of 26 cardiometabolic traits, 7 and 6 causal mediators were identified as mediating the effects of education on DKD and CKD, respectively. The largest mediating factor between education and DKD was BMI, which was followed by WHR, T2D, fasting insulin, SBP, fasting glucose, and DBP. In contrast, candidate mediators in the education-to-CKD pathway included BMI, followed by cigarettes smoked per day, WHR, SBP, T2D, and DBP. MR analysis revealed that TP53INP1 was found to be a shared susceptibility gene for cardiometabolic traits and DKD, while L3MBTL3 was found to be a shared susceptibility gene for cardiometabolic traits and CKD.ConclusionOur findings provide solid evidence that education has a causally protective effect on the development of DKD and CKD. We additionally reveal significant directions for intervention on cardiometabolic traits that mitigate the negative effects of educational inequities on the onset of DKD and CKD. Our work demonstrates a shared genetic basis between education, cardiometabolic traits, and kidney diseases. Future research aiming at lowering kidney risk may benefit from these findings.

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The structure, binding and function of a Notch transcription complex involving RBPJ and the epigenetic reader protein L3MBTL3

Cited by 3 publications

References 64 publications

Comprehensive genomic features indicative for Notch responsiveness

Comprehensive genomic features indicative for Notch responsiveness

Comprehensive Genomic Features indicative for Notch Responsiveness

Cardiometabolic traits mediating the effect of education on the risk of DKD and CKD: a Mendelian randomization study

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