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Bivalent chromatin accommodates survivin and BRG1/SWI complex to activate DNA damage response in CD4+ cells.
Chandrasekaran, Venkataragavan; Andersson, Karin M E; Erlandsson, Malin; Li, Shuxiang; Olsson, Torbjörn Nur; Garcia-Bonete, Maria-Jose; Malmhäll-Bah, Eric; Johansson, Pegah; Katona, Gergely; Bokarewa, Maria I.
Afiliación
  • Chandrasekaran V; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, Gothenburg, 40530, Sweden.
  • Andersson KME; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, Gothenburg, 40530, Sweden.
  • Erlandsson M; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, Gothenburg, 40530, Sweden.
  • Li S; Rheumatology Clinic, Sahlgrenska University Hospital, Gröna Stråket 16, Gothenburg, 41346, Sweden.
  • Olsson TN; Computational Biology and Biophysics Lab, Queen's University, Kingston, Canada.
  • Garcia-Bonete MJ; Department of Chemistry and Molecular Biology, Faculty of Science, University of Gothenburg, Gothenburg, Sweden.
  • Malmhäll-Bah E; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, SE, 405 30, Sweden.
  • Johansson P; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, Gothenburg, 40530, Sweden.
  • Katona G; Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
  • Bokarewa MI; Department of Chemistry and Molecular Biology, Faculty of Science, University of Gothenburg, Gothenburg, Sweden.
Cell Commun Signal ; 22(1): 440, 2024 Sep 11.
Article en En | MEDLINE | ID: mdl-39261837
ABSTRACT

BACKGROUND:

Bivalent regions of chromatin (BvCR) are characterized by trimethylated lysine 4 (H3K4me3) and lysine 27 on histone H3 (H3K27me3) deposition which aid gene expression control during cell differentiation. The role of BvCR in post-transcriptional DNA damage response remains unidentified. Oncoprotein survivin binds chromatin and mediates IFNγ effects in CD4+ cells. In this study, we explored the role of BvCR in DNA damage response of autoimmune CD4+ cells in rheumatoid arthritis (RA).

METHODS:

We performed deep sequencing of the chromatin bound to survivin, H3K4me3, H3K27me3, and H3K27ac, in human CD4+ cells and identified BvCR, which possessed all three histone H3 modifications. Protein partners of survivin on chromatin were predicted by integration of motif enrichment analysis, computational machine-learning, and structural modeling, and validated experimentally by mass spectrometry and peptide binding array. Survivin-dependent change in BvCR and transcription of genes controlled by the BvCR was studied in CD4+ cells treated with survivin inhibitor, which revealed survivin-dependent biological processes. Finally, the survivin-dependent processes were mapped to the transcriptome of CD4+ cells in blood and in synovial tissue of RA patients and the effect of modern immunomodulating drugs on these processes was explored.

RESULTS:

We identified that BvCR dominated by H3K4me3 (H3K4me3-BvCR) accommodated survivin within cis-regulatory elements of the genes controlling DNA damage. Inhibition of survivin or JAK-STAT signaling enhanced H3K4me3-BvCR dominance, which improved DNA damage recognition and arrested cell cycle progression in cultured CD4+ cells. Specifically, BvCR accommodating survivin aided sequence-specific anchoring of the BRG1/SWI chromatin-remodeling complex coordinating DNA damage response. Mapping survivin interactome to BRG1/SWI complex demonstrated interaction of survivin with the subunits anchoring the complex to chromatin. Co-expression of BRG1, survivin and IFNγ in CD4+ cells rendered complete deregulation of DNA damage response in RA. Such cells possessed strong ability of homing to RA joints. Immunomodulating drugs inhibited the anchoring subunits of BRG1/SWI complex, which affected arthritogenic profile of CD4+ cells.

CONCLUSIONS:

BvCR execute DNA damage control to maintain genome fidelity in IFN-activated CD4+ cells. Survivin anchors the BRG1/SWI complex to BvCR to repress DNA damage response. These results offer a platform for therapeutic interventions targeting survivin and BRG1/SWI complex in autoimmunity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Daño del ADN / Proteínas Nucleares / Cromatina / Linfocitos T CD4-Positivos / ADN Helicasas / Survivin Límite: Humans Idioma: En Revista: Cell Commun Signal Año: 2024 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Daño del ADN / Proteínas Nucleares / Cromatina / Linfocitos T CD4-Positivos / ADN Helicasas / Survivin Límite: Humans Idioma: En Revista: Cell Commun Signal Año: 2024 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Reino Unido