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

Charles Antony, Subin S. George, Justin Blum, Patrick Somers, Chelsea L. Thorsheim, Dexter J. Wu-Corts, Yuxi Ai, Long Gao, Kaosheng Lv, Michel G. Tremblay, Tom Moss, Kai Tan, View ORCID ProfileJeremy E. Wilusz, View ORCID ProfileAusten R. D. Ganley, View ORCID ProfileMaxim Pimkin, View ORCID ProfileVikram R. Paralkar
doi: https://doi.org/10.1101/2022.01.21.476118
Charles Antony
1Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
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Subin S. George
2Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
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Justin Blum
3The College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
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Patrick Somers
1Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
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Chelsea L. Thorsheim
4Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
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Dexter J. Wu-Corts
3The College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
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Yuxi Ai
5Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
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Long Gao
6Beijing Advanced Innovation Center for Genomics (ICG) & Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing 100871, China
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Kaosheng Lv
7Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Michel G. Tremblay
8Laboratory of Growth and Development, St Patrick Research Group in Basic Oncology, Cancer Division of the Quebec University Hospital Research Centre (CRCHU de Québec-Université Laval), Québec, QC, G1R 3S3, Canada
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Tom Moss
8Laboratory of Growth and Development, St Patrick Research Group in Basic Oncology, Cancer Division of the Quebec University Hospital Research Centre (CRCHU de Québec-Université Laval), Québec, QC, G1R 3S3, Canada
9Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec, QC, G1V 0A6, Canada
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Kai Tan
10Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
11Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
16Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
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Jeremy E. Wilusz
12Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX 77030, USA
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Austen R. D. Ganley
13School of Biological Sciences, University of Auckland, Auckland 0623, New Zealand
14Digital Life Institute, University of Auckland, Auckland 0632, New Zealand
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Maxim Pimkin
15Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA 02215, USA
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Vikram R. Paralkar
1Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
16Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
17Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
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  • For correspondence: vikram.paralkar@pennmedicine.upenn.edu
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SUMMARY

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.

HIGHLIGHTS

  • Multiple cell-type-specific transcription factors (TFs) bind canonical motifs on rDNA.

  • The hematopoietic TF CEBPA binds to active rDNA alleles at a conserved site.

  • CEBPA promotes Polymerase I occupancy and rRNA transcription in myeloid progenitors.

  • We present ‘47S-FISH-Flow,’ a sensitive assay to quantify nascent rRNA.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 22, 2022.
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Tissue-Specific Control of Ribosomal RNA Synthesis Revealed by Transcription Factor Profiling
Charles Antony, Subin S. George, Justin Blum, Patrick Somers, Chelsea L. Thorsheim, Dexter J. Wu-Corts, Yuxi Ai, Long Gao, Kaosheng Lv, Michel G. Tremblay, Tom Moss, Kai Tan, Jeremy E. Wilusz, Austen R. D. Ganley, Maxim Pimkin, Vikram R. Paralkar
bioRxiv 2022.01.21.476118; doi: https://doi.org/10.1101/2022.01.21.476118
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Tissue-Specific Control of Ribosomal RNA Synthesis Revealed by Transcription Factor Profiling
Charles Antony, Subin S. George, Justin Blum, Patrick Somers, Chelsea L. Thorsheim, Dexter J. Wu-Corts, Yuxi Ai, Long Gao, Kaosheng Lv, Michel G. Tremblay, Tom Moss, Kai Tan, Jeremy E. Wilusz, Austen R. D. Ganley, Maxim Pimkin, Vikram R. Paralkar
bioRxiv 2022.01.21.476118; doi: https://doi.org/10.1101/2022.01.21.476118

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