DNA Breaks and Chromatin Structural Changes Enhance the Transcription of Autoimmune Regulator Target Genes

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2017 Mar 1

PMID 28242760

Citations 20

Authors

Mithu Guha

Mario Saare

Julia Maslovskaja

Kai Kisand

Ingrid Liiv

Uku Haljasorg

Tonis Tasa

Andres Metspalu

Lili Milani

Part Peterson

Affiliations

Soon will be listed here.

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 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 chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA sequencing, we found that 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 the 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 up-regulation to co-occur with the chromatin structural changes within the genomic cluster of carcinoembryonic antigen-like cellular adhesion molecule 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.

Citing Articles

The Autoimmune Regulator (AIRE) Gene, The Master Activator of Self-Antigen Expression in the Thymus.

Giraud M, Peterson P Adv Exp Med Biol. 2025; 1471:199-221.

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Weighted Gene Co-expression Network Analysis and Machine Learning Validation for Identifying Major Genes Related to Sjogren's Syndrome.

Luo Q, Wu K, Li H, Wang H, Wang C, Xia D Biochem Genet. 2024; .

PMID: 38678487 DOI: 10.1007/s10528-024-10750-4.

Thymic Mimetic Cells: Ontogeny as Immunology.

Michelson D, Mathis D Annu Rev Cell Dev Biol. 2024; 40(1):283-300.

PMID: 38608315 PMC: 11446667. DOI: 10.1146/annurev-cellbio-112122-023316.

AIRE relies on Z-DNA to flag gene targets for thymic T cell tolerization.

Fang Y, Bansal K, Mostafavi S, Benoist C, Mathis D Nature. 2024; 628(8007):400-407.

PMID: 38480882 PMC: 11091860. DOI: 10.1038/s41586-024-07169-7.

Novel Insights into the Autoimmunity from the Genetic Approach of the Human Disease.

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