Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30784792_1.fastq.gz | Fastqsanger.gz | |||
| SRR30784792_2.fastq.gz | Fastqsanger.gz |
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Project description:Gene expression is controlled by transcription factors (TFs) that consist of DNA-binding domains (DBDs) and activation domains (ADs). The DBDs have been well- characterized, but little is known about the mechanisms by which ADs effect gene activation. Here we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues. For the estrogen receptor (ER), a ligand-dependent activator, we show that estrogen enhances phase separation with Mediator, again linking phase separation with gene activation. These results suggest that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensates with Mediator is involved in gene activation.
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Project description:CD4+ T cells play a crucial role in adaptive immune responses and have been implicated in the pathogenesis of autoimmune diseases (ADs). Despite numerous studies, the molecular mechanisms underlying T cell dysregulation in ADs remain incompletely understood. Here, we used transcriptomic and epigenomic data from CD4+ T cells of healthy donors and patients with systemic lupus erythematosus (SLE), psoriasis, juvenile idiopathic arthritis (JIA), and Graves' disease to investigate the role of enhancers in AD pathogenesis. By generating enhancer-based gene regulatory networks (eGRNs), we identified disease-specific dysregulated pathways and potential downstream target genes of enhancers harbouring AD-associated single-nucleotide polymorphisms, which we also validated using CRISPRi in primary CD4+ T cells. Our results suggest that alterations in the regulatory landscapes of CD4+ T cells, including enhancers, contribute to the development of ADs and provide a basis for developing new therapeutic approaches.
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Project description:Gene expression is controlled by transcription factors (TFs) that consist of DNA-binding domains (DBDs) and activation domains (ADs). The DBDs have been well- characterized, but little is known about the mechanisms by which ADs effect gene activation. Here we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues. For the estrogen receptor (ER), a ligand-dependent activator, we show that estrogen enhances phase separation with Mediator, again linking phase separation with gene activation. These results suggest that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensates with Mediator is involved in gene activation.
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Project description:Activation domains (ADs) within transcription factors (TFs) induce gene expression by recruiting coactivators to specific regulatory regions. Within the prevailing model, TF-coactivator recruitment is independent of DNA binding, which is consistent with direct AD-coactivator interactions seen outside cells. However, this independence was not yet tested within the genomic context. Here, we targeted two Med15-interacting ADs to hundreds of budding yeast promoters through fusions with multiple DNA binding domains (DBDs), gradually controlling their abundances using libraries of synthetic promoters. Genomic profiling revealed that AD identity influences DNA binding locations and that transcription induction and Med15 recruitment are restricted to a subset of DBD-bound promoters displaying flexible expression, multiple-TFs binding, and fuzzy nucleosome architecture. Further, when fused to a DBD, Med15 redirected binding towards promoters of fuzzy nucleosomes, overcoming DBD-based preferences. Our results demonstrate that ADs and their recruited coactivators posses an inherent preference for genomic localization and, therefore, define the subset of induced promoters.
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2013-06-27 | E-GEOD-48343 | biostudies-arrayexpress
Project description:Arabidopsis gene expression is regulated by more than 1,900 transcription factors (TFs), which have been identified genome-wide by the presence of well-conserved DNA binding domains. Activator TFs contain activation domains (ADs) that recruit coactivator complexes; however, for most Arabidopsis TFs, we lack knowledge about the presence, location, and transcriptional strength of their ADs. To address this gap, we experimentally identified Arabidopsis ADs on a proteome-wide scale, finding that over half of Arabidopsis TFs carry an AD. We annotated 1,553 ADs, the vast majority of which were previously unknown. We used the dataset generated to develop a neural network to accurately predict ADs and to identify sequence features necessary to recruit coactivator complexes. We uncovered six distinct sequence feature combinations that resulted in activation activity, providing a framework to interrogate activation domain sub-functionalization. Furthermore, we identified activation domains within the ancient AUXIN RESPONSE FACTOR (ARF) family of transcription factors, finding conservation of AD positioning in distinct clades. Our findings provide a deep resource for understanding transcriptional activation, a framework for examination of function within intrinsically disordered regions, and a predictive model of activation domains.
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