# Regulation of rRNA transcription in mammalian tissues

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2020 · $405,025

## Abstract

Abstract / Project Summary
Ribosomal RNA (rRNA) comprises 90% of cellular RNA, and ribosome biogenesis is one of the most
energy-consuming processes in the cell. The core rRNA transcriptional machinery is evolutionarily ancient and
highly conserved from unicellular eukaryotes to mammals, but the bodies of higher organisms have different
ribosome production rates in different cell types, responsive to unique tissue-specific demands. Mutations in
ribosome biogenesis proteins cause cell-type-specific “ribosomopathies” in humans, manifested by
developmental abnormalities, specific organ dysfunctions, or cancers. However, there is little understanding of
the transcriptional and epigenetic factors that differentially regulate ribosome biogenesis across normal cells
types in intact organisms. Specifically, no one has characterized the protein composition of nucleoli, or the
components of rRNA transcription complexes, in any primary mammalian tissue. This represents a key
knowledge gap in our understanding of eukaryotic biology.
Using quantitative proteomics and transcription factor (TF) mapping studies in a mouse model system, we
have identified nucleolar localization and abundant, specific binding to ribosomal DNA (rDNA) of several
cell-type-specific TFs (Pu.1, Irf8, Etv6) that are known to be critical for normal development and survival, but
whose roles in ribosome biogenesis have never been reported. We propose in this application a combination of
unbiased as well as focused approaches to identify and dissect the roles of cell-type-specific rRNA regulators
in tissue homeostasis. We will pursue this goal through the following projects:
PROJECT 1: DISCOVERY: We will use nucleolar and rDNA-chromatin proteomics in defined primary mouse
cell types to identify proteins with cell-type-specific nucleolar localization and rDNA binding. The goal of this
project is to identify novel regulators of differential rRNA transcription in intact tissues.
PROJECT 2: MECHANISM: We will use ​in vitro and ​in vivo degron and chromatin tethering approaches to
dissect the direct roles of rDNA-binding cell-type-specific TFs (Pu.1, Irf8, Etv6, others) in the regulation of
rDNA chromatin, rRNA transcription, and tissue homeostasis. The goal of this project is to understand how
TF-rDNA binding regulates normal tissue biology.
The long-term goal of this work is to gain a detailed understanding of how the ancient process of ribosome
biogenesis has evolved to meet diverse tissue needs in complex organisms, and how disruption of this
regulation can derange tissue homeostasis and cause disease.

## Key facts

- **NIH application ID:** 10028009
- **Project number:** 1R35GM138035-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Vikram R. Paralkar
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,025
- **Award type:** 1
- **Project period:** 2020-08-21 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10028009

## Citation

> US National Institutes of Health, RePORTER application 10028009, Regulation of rRNA transcription in mammalian tissues (1R35GM138035-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10028009. Licensed CC0.

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