RNA-sequencing of DYRK1A-deficient (CKO) pre-B and pre-T cells

Pre-B and pre-T lymphocytes must orchestrate a transition from a highly proliferative state to a quiescent one during development. Cyclin D3 is essential for these cells’ proliferation, but little is known about its post-translational regulation at this stage. Here, we show that the dual specificity tyrosine-regulated kinase 1A (DYRK1A) restrains Cyclin D3 protein levels by phosphorylating T283 to induce its degradation. Loss of DYRK1A activity, via genetic inactivation or pharmacologic inhibition, caused accumulation of Cyclin D3 protein, incomplete repression of E2F-mediated gene transcription, and failure to properly couple cell cycle exit with differentiation. Expression of a non-phosphorylatable Cyclin D3 T283A mutant recapitulated these defects, while inhibition of Cyclin D:CDK4/6 mitigated the effects of DYRK1A inhibition. These data uncover a previously unknown role for DYRK1A in lymphopoiesis, and demonstrate how Cyclin D3 protein stability is negatively regulated during exit from the proliferative phases of B and T cell development. Overall design: 5 cell populations were analyzed (small pre-B cells, large pre-B cells, quiescent CD4+CD8+ thymocytes, cycling CD4+CD+ thymocytes, and mature granulocytes) from 2 Control mice (pooled) and 2 DYRK1A-deficient mice (pooled) for a total of 10 samples.

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Thompson BJ, Bhansali R, Diebold L, Cook DE, Stolzenburg L, Casagrande AS, Besson T, Leblond B, Désiré L, Malinge S, Crispino JD