Tissue-Specific Control of Ribosomal RNA Synthesis Revealed by Transcription Factor Profiling

Antony, C.; George, S. S.; Blum, J.; Somers, P.; Thorsheim, C. L.; Wu-Corts, D. J.; Ai, Y.; Gao, L.; Lv, K.; Tremblay, M. G.; Moss, T.; Tan, K.; Wilusz, J. E.; Ganley, A. R. D.; Pimkin, M.; Paralkar, V. R.

doi:10.1101/2022.01.21.476118

bioRxiv · 10.1101/2022.01.21.476118

Tissue-Specific Control of Ribosomal RNA Synthesis Revealed by Transcription Factor Profiling

Antony, C.·George, S. S.·Blum, J.·Somers, P.·Thorsheim, C. L.·Wu-Corts, D. J.·Ai, Y.·Gao, L.·Lv, K.·Tremblay, M. G.·Moss, T.·Tan, K.·Wilusz, J. E.·Ganley, A. R. D.·Pimkin, M.·Paralkar, V. R.

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Abstract

Ribosomal RNAs (rRNAs) are the most abundant cellular RNAs, and their synthesis from rDNA repeats by RNA Polymerase I accounts for the bulk of all transcription. Despite substantial variation in rRNA transcription rates across cell types, little is known about cell-type-specific factors that bind rDNA and regulate rRNA transcription to meet tissue-specific needs. Using hematopoiesis as a model system, we mapped about 2200 ChIP-Seq datasets for 250 transcription factors (TFs) and chromatin proteins to human and mouse rDNA, and identified robust binding of multiple TF families to canonical TF motifs on rDNA. Using a 47S-FISH-Flow assay developed for nascent rRNA quantification, we demonstrated that targeted degradation of CEBPA (C/EBP alpha), a critical hematopoietic TF with conserved rDNA binding, caused rapid reduction in rRNA transcription due to reduced Pol I occupancy. Our work identifies numerous potential rRNA regulators, and provides a template for dissection of TF roles in rRNA transcription. HIGHLIGHTSO_LIMultiple cell-type-specific transcription factors (TFs) bind canonical motifs on rDNA. C_LIO_LIThe hematopoietic TF CEBPA binds to active rDNA alleles at a conserved site. C_LIO_LICEBPA promotes Polymerase I occupancy and rRNA transcription in myeloid progenitors. C_LIO_LIWe present 47S-FISH-Flow, a sensitive assay to quantify nascent rRNA. C_LI

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Antony, C., George, S. S., Blum, J., Somers, P., Thorsheim, C. L., Wu-Corts, D. J., Ai, Y., Gao, L., Lv, K., Tremblay, M. G., Moss, T., Tan, K., Wilusz, J. E., Ganley, A. R. D., Pimkin, M., Paralkar, V. R.. 2022-01-22. Tissue-Specific Control of Ribosomal RNA Synthesis Revealed by Transcription Factor Profiling. https://doi.org/10.1101/2022.01.21.476118

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