Transcription factor regulation of ribosomal RNA in hematopoiesis

Abstract

Purpose of review: Ribosomal RNAs (rRNAs) are transcribed within nucleoli from rDNA repeats by RNA Polymerase I (Pol I). There is variation in rRNA transcription rates across the hematopoietic tree, and leukemic blast cells have prominent nucleoli, indicating abundant ribosome biogenesis. The mechanisms underlying these variations are poorly understood. The purpose of this review is to summarize findings of rDNA binding and Pol I regulation by hematopoietic transcription factors.

Recent findings: Our group recently used custom genome assemblies optimized for human and mouse rDNA mapping to map nearly 2200 ChIP-Seq datasets for nearly 250 factors to rDNA, allowing us to identify conserved occupancy patterns for multiple transcription factors. We confirmed known rDNA occupancy of MYC and RUNX factors, and identified new binding sites for CEBP factors, IRF factors, and SPI1 at canonical motif sequences. We also showed that CEBPA degradation rapidly leads to reduced Pol I occupancy and nascent rRNA in mouse myeloid cells.

Summary: We propose that a number of hematopoietic transcription factors bind rDNA and potentially regulate rRNA transcription. Our model has implications for normal and malignant hematopoiesis. This review summarizes the literature, and outlines experimental considerations to bear in mind while dissecting transcription factor roles on rDNA.

FIGURE 1.

Basics of rRNA transcription. rDNA repeats are present in hundreds of near-identical copies per cell in tandem arrays. A subset of repeats is activated and transcribed in any given cell. Note: Pol I and SL-1 occupancy is seen both at the Spacer promoter and the 47S promoter, but their functions at the former are unknown. Adapted from [3■].

FIGURE 2.

Occupancy patterns of selected hematopoietic transcription factors on mouse rDNA. Patterns of ChIP-Seq occupancy on mouse rDNA, shown as averaged consensus track signals for multiple factors per pattern. Select transcription factors of relevance to normal and malignant hematopoiesis are listed in bold for each binding pattern. Adapted from [2■■].

FIGURE 3.

Model of Pol I regulation by CEBPA. We propose that in myeloid progenitors and in AML, CEBPA promotes the loading of Pol I-RRN3 complex on rDNA and/or the elongation of Pol I along the transcribed region. We speculate that this mechanism may be shared by other rDNA-binding TFs.

FIGURE 4.

Considerations for TF-rDNA studies. We list several experimental considerations to be borne in mind while investigating whether a TF of interest directly regulates the transcription of rDNA into rRNA.