CHASERR-CHD2 dynamics in T cell quiescence and its modulation by cyclosporine

Frontiers in Immunology. 2025. Vol. 16. Article 1652359.

Budkina A., Zubritskiy A., Marakulina D., Loguinova M., Sergeev N., Medvedeva Y.

Background: CHASERR, a conserved long non-coding RNA located upstream of CHD2, transcriptionally represses CHD2 in cis. Both genes are highly expressed in lymphocytes, suggesting roles in immune regulation, though their functions remain undefined.

Results: We identified elevated expression of CHASERR and CHD2 in naïve and regulatory T cells through analysis of single-cell and bulk RNA-seq datasets. Both their promoters are bound by FOXP3, the key regulator of Treg cells, and FOXP1, the key regulator of naïve T cell quiescence. Expression dynamics during early T cell activation revealed that a decline in CHASERR precedes a transient increase in CHD2. Correlation analysis linked CHASERR/CHD2 expression to quiescence-associated genes, suggesting a role in maintaining T cell homeostasis. We predicted and experimentally validated that cyclosporine A, a calcineurin inhibitor and potent immunosuppressant, mitigates the transcriptional changes induced by CHASERR loss, notably reducing elevated CHD2 expression in vitro after CHASERR knockdown.

Conclusions: Our results position the CHASERR-CHD2 axis as a potential regulator of T cell homeostasis and activation. Furthermore, we propose cyclosporine A as a potential therapeutic strategy for conditions involving CHASERR deficiency.

Keywords: single-cell, lncRNA, Transcription, T cell activation, T cell quiescence