The London Research Institute hosts a number of conferences throughout the year and has extensive seminar schedules as part of its education programme.
Highlighted Paper: Recruitment of TIF1γ to Chromatin via Its PHD Finger-Bromodomain Activates Its Ubiquitin Ligase and Transcriptional Repressor Activities
Submitted by goodwi02 on Thu, 08/09/2011 - 09:43
The Developmental Signalling Lab headed by Caroline Hill published this paper in Mol Cell.
Agricola E, Randall RA, Gaarenstroom T, Dupont S, Hill CS. Recruitment of TIF1γ to Chromatin via Its PHD Finger-Bromodomain Activates Its Ubiquitin Ligase and Transcriptional Repressor Activities. Mol Cell. 2011;43(1):85-96
This study started with our discovery of TIF1γ (also called TRIM33) in a high throughput siRNA screen designed to find regulators of TGF-β-induced transcriptional responses. Knocking down TIF1γ strongly increased TGF-β-induced transcription, indicating that TIF1γ normally acts to repress TGF-β-induced transcription.
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TIF1γ contains a TRIM domain at its N-terminus comprising a RING domain, two B-boxes and a coiled-coil, and in its C-terminus it contains a linked PHD finger-bromodomain. We found that both of these domains were essential for its repressive activity on TGF-β transcriptional responses, and for ubiquitination of its known substrate, Smad4. Using chromatin immunoprecipitations, we showed that TIF1γ was recruited to chromatin upon TGF-β induction. We went on to show that this recruitment depends on the PHD finger-bromodomain and demonstrated that this domain constitutes a novel multivalent histone-binding module that specifically binds histone H3 tails unmethylated at K4 and R2 and acetylated at two key consecutive lysines. Moreover, we showed that the E3 ubiquitin ligase activity of TIF1γ is induced by binding to nucleosomes, as a result of release from autoinhibition of the TRIM domain by the PHD finger-bromodomain.
Our results suggest a model of TIF1γ activity in which recruitment of TIF1γ to chromatin at TGF-β-responsive enhancers is driven by recognition of a specific histone code on the H3 tail. This results in activation of TIF1γ, and subsequently ubiquitination of Smad4 in DNA-bound activated Smad complexes, which leads to dissociation of these complexes from DNA. We propose that TIF1γ represses TGF-β-induced transcription by restricting the residence time of individual activated Smad complexes on the promoters of target genes (see figure).
