Genomics

Dataset Information

158

DNA breaks and chromatin structural changes enhance the transcription of Autoimmune Regulator target genes [FAIRE-Seq]


ABSTRACT: The Autoimmune Regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T-cells by promoting the ectopic expression of tissue-specific genes in thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA-seq, we found that the inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by topoisomerase 1 (TOP1) inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional upregulation to co-occur with the chromatin structural changes within the genomic cluster of carcino-embryonic antigen-like cellular adhesion molecule (CEACAM) genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes. Overall design: FAIRE-seq of 8 AIRE-Tet cell line samples belonging to 4 experimental conditions, each in duplicate

INSTRUMENT(S): Illumina HiSeq 2000 (Homo sapiens)

SUBMITTER: Pärt Peterson  

PROVIDER: GSE89892 | GEO | 2017-03-13

SECONDARY ACCESSION(S): PRJNA353659

REPOSITORIES: GEO

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DNA breaks and chromatin structural changes enhance the transcription of autoimmune regulator target genes.

Guha Mithu M   Saare Mario M   Maslovskaja Julia J   Kisand Kai K   Liiv Ingrid I   Haljasorg Uku U   Tasa Tõnis T   Metspalu Andres A   Milani Lili L   Peterson Pärt P  

The Journal of biological chemistry 20170227 16


The autoimmune regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T cells by promoting the ectopic expression of tissue-specific genes in the thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromat  ...[more]

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