Survivin-dependent Regulation of Bivalent Chromatin and Its Relevance for Adaptive Immunity

Venkataragavan Chandrasekaran¹, Nina Oparina², Karin Andersson², Malin Erlandsson², Maria-Jose Garcia-Bonete³, Maja Jensen⁴, Gergely Katona⁵ and Maria Bokarewa⁶, ¹Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, ²Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Goteborg, Sweden, ³Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden, ⁴Department of Chemistry and Molecular Biology, Gothenburg, Sweden, ⁵Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden, ⁶Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden

Meeting: ACR Convergence 2022

Keywords: Epigenetics, Gene Expression, genomics, rheumatoid arthritis, T Cell

Session Information

Date: Sunday, November 13, 2022

Title: RA – Etiology and Pathogenesis Poster

Session Type: Poster Session B

Session Time: 9:00AM-10:30AM

Background/Purpose: Bivalent chromatin (BvCR) is characterized by simultaneous binding of active and repressive modifications to the histone H3 proteins. Influencing expression of the genes, BvCR determine cell fate and lineage commitment of primary T cells. Survivin is important for T cell development in the thymus and in effector Th1 cell function, contributing to aggravation of autoimmune inflammation. Survivin physically binds to DNA, and mechanistic data point to its potential chromatin regulatory role. This study establishes the colocalization of survivin with BvCRs and deduces functional effect of their collaboration on adaptive immunity.

Methods: Chromatin from 14 primary CD4+ T cell cultures was immunoprecipitated with a survivin antibody, with H3K27ac, H3K27me3, H3K4me3 antibodies, and coupled with DNA sequencing (ChIPseq, Hiseq2000, Illumina). BvCR were identified as exact overlaps of the three histone H3 peaks. BvCR co-localized with survivin were found using the ‘ChIPPeakAnno’ Bioconductor package. BvCR within the gene regulatory elements (RE) were identified through the GeneHancer database. K27me3 and K27ac tag count differences indicated inactive and active BvCR. Survivin-dependent changeability of the H3 modifications in BvCR and differentially expressed genes (DEG) were identified by treatment of CD4+ cells with a survivin inhibitor YM155.

Results: Co-localization of survivin with individual H3 modifications was significantly less frequent compared to its overlap with BvCR (7.1% vs 29.8%, p=8.9e-13). Survivin containing (Surv-) BvCR were more prevalent (66%) compared to survivin-free BvCR (66% vs 34%, respectively). Notably, survivin peaks were 5.5-fold higher in BvCR compared to those co-localized with no, or any single H3 (p< 2.2e-16). Further comparison of Surv-BvCR (n=4085), and survivin-free BvCR (n=2131) demonstrated that survivin was mostly associated with inactive BvCR (OR1.29, p=6.6e-6), while no such specificity was found for the survivin-free BvCR.

Inhibition of survivin significantly affected all histone H3 modifications, where K27me3 tags were affected the most. Surv-BvCR in the inactive state were less frequently located in RE compared to those in active Surv-BvCR (p=7.2e-8) and in inactive survivin-free BvCR (p=1.9e-13). Survivin inhibition revealed that 25% of DEG were connected to the RE containing Surv-BvCR, which also were more frequently changeable. Pathway enrichment analysis of DEG showed enrichment of adaptive immune processes, DNA metabolism and nitrogen catabolism.

Conclusion: This study provides experimental evidence for binding specificity of survivin in BvCR of CD4+ T cells, which regulates CD4+ T cell renewal and has functional importance in resistance to autoimmunity.

Disclosures: V. Chandrasekaran, None; N. Oparina, None; K. Andersson, None; M. Erlandsson, None; M. Garcia-Bonete, None; M. Jensen, None; G. Katona, None; M. Bokarewa, None.

To cite this abstract in AMA style:

Chandrasekaran V, Oparina N, Andersson K, Erlandsson M, Garcia-Bonete M, Jensen M, Katona G, Bokarewa M. Survivin-dependent Regulation of Bivalent Chromatin and Its Relevance for Adaptive Immunity [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/survivin-dependent-regulation-of-bivalent-chromatin-and-its-relevance-for-adaptive-immunity/. Accessed .

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