Abstract
The clear connection between ribosome biogenesis dysfunction and specific hematopoiesis-related disorders prompted us to examine the role of critical lineage-specific transcription factors in the transcriptional regulation of ribosomal protein (RP) genes during terminal erythroid differentiation. By applying EMSA and ChIP methodologies in mouse erythroleukemia cells we show that GATA1 and PU.1 bind in vitro and in vivo the proximal promoter region of the RPS19 gene which is frequently mutated in Diamond-Blackfan Anemia. Moreover, ChIPseq data analysis also demonstrates that several RP genes are enriched as potential GATA1 and PU.1 gene targets in mouse and human erythroid cells, with GATA1 binding showing an association with higher ribosomal protein gene expression levels during terminal erythroid differentiation in human and mouse. Our results suggest that RP gene expression and hence balanced ribosome biosynthesis may be specifically and selectively regulated by lineage specific transcription factors during hematopoiesis, a finding which may be clinically relevant to ribosomopathies.
Highlights
Ribosome biogenesis is a highly coordinated process leading to the stoichiometric assembly of all ribosomal components
We initially investigated the mouse RPS19 proximal promoter region experimentally verified from murine erythroleukemic (MEL) genomic DNA for the presence of consensus binding motifs using standard transcription factors (TFs) binding prediction tools
We identified potential PU.1 binding sites at positions -653bp and -709bp upstream of the RPS19 gene translation initiation codon and a potential GATA1 binding site located at position -694bp in close proximity to the PU.1 binding site at -709bp (Fig 1A)
Summary
Ribosome biogenesis is a highly coordinated process leading to the stoichiometric assembly of all ribosomal components. 4 rRNAs and 80 different ribosomal proteins (RPs) are produced, processed and assembled into functional ribosomes [1, 2]. RP biosynthesis is regulated at multiple levels by transcriptional, translational and post translational mechanisms so that RP balance is achieved [3, 4]. In higher eukaryotes little is known about the transcriptional regulation of RP genes which are scattered in different chromosomes and possess distinct promoters sharing certain structural features but no common motifs [5, 6]. Despite ubiquitous RP gene expression and functions across all tissues, RP gene haploinsufficiency leading to perturbation of balanced ribosome assembly results in clinical syndromes.
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