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Aire, guardian of immunological tolerance, binds to and activates super-enhancers

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE92654 | GEO | 2017/01/22

SECONDARY ACCESSION(S): PRJNA358241

REPOSITORIES: GEO

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Aire, guardian of immunological tolerance, binds to and activates super-enhancers [expression]

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Aire, guardian of immunological tolerance, binds to and activates super-enhancers

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The transcriptional regulator Aire binds to and activates super-enhancers.

Project description:Aire is a transcription factor that controls T cell tolerance by inducing the expression of a large repertoire of genes specifically in thymic stromal cells. It interacts with scores of protein partners of diverse functional classes. We found that Aire and some of its partners, notably those implicated in the DNA-damage response, preferentially localized to and activated long chromatin stretches that were overloaded with transcriptional regulators, known as super-enhancers. We also identified topoisomerase 1 as a cardinal Aire partner that colocalized on super-enhancers and was required for the interaction of Aire with all of its other associates. We propose a model that entails looping of super-enhancers to efficiently deliver Aire-containing complexes to local and distal transcriptional start sites.

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Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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NF-kB coordinates rapid, BRD4-dependent remodeling of proinflammatory super-enhancers

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Sirt1 is essential for Aire-mediated induction of central immunological tolerance

Project description:Autoimmune regulator (Aire) is a unique transcriptional regulator that induces promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for induction of immunological self-tolerance. Although several recent studies provided very important molecular insights into how Aire operates, a more comprehensive understanding of this process still remains elusive. Here we demonstrate that a lysine deacetylase Sirtuin-1 (Sirt1) is predominantly expressed in mature Aire+ mTECs, where it is required for expression of Aire-dependent TRA genes and a subsequent induction of immunological self-tolerance. Our study elucidates a previously unknown molecular mechanism for Aire-mediated transcriptional regulation and uncovers a unique functional role for Sirt1 in preventing organ-specific autoimmunity. ~100ng of total RNA isolated by Trizol extraction from MHC-II low and high mTECs (pool of 3 mice) was used to generate poly-A-selected transcriptome libraries using the non-directionnal TruSeq V3 RNA Sample Prep Kit (without additional pre-amplification) following the manufacturer's protocols. Enrichment of DNA fragment with adapter molecules on both ends was done using 15 cycles of PCR amplification using the Illumina PCR mix and primer cocktail. Paired-end (2 × 100 bp) sequencing was performed using the Illumina HiSeq2000 machine.

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Histone H3K4me1 strongly activates the DNase I hypersensitive sites in super-enhancers than those in typical enhancers.

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