A dynamic intron retention program enriched in RNA processing genes regulates gene expression during terminal erythropoiesis

Nucleic Acids Res. 2016 Jan 29;44(2):838-51. doi: 10.1093/nar/gkv1168. Epub 2015 Nov 3.

Abstract

Differentiating erythroblasts execute a dynamic alternative splicing program shown here to include extensive and diverse intron retention (IR) events. Cluster analysis revealed hundreds of developmentally-dynamic introns that exhibit increased IR in mature erythroblasts, and are enriched in functions related to RNA processing such as SF3B1 spliceosomal factor. Distinct, developmentally-stable IR clusters are enriched in metal-ion binding functions and include mitoferrin genes SLC25A37 and SLC25A28 that are critical for iron homeostasis. Some IR transcripts are abundant, e.g. comprising ∼50% of highly-expressed SLC25A37 and SF3B1 transcripts in late erythroblasts, and thereby limiting functional mRNA levels. IR transcripts tested were predominantly nuclear-localized. Splice site strength correlated with IR among stable but not dynamic intron clusters, indicating distinct regulation of dynamically-increased IR in late erythroblasts. Retained introns were preferentially associated with alternative exons with premature termination codons (PTCs). High IR was observed in disease-causing genes including SF3B1 and the RNA binding protein FUS. Comparative studies demonstrated that the intron retention program in erythroblasts shares features with other tissues but ultimately is unique to erythropoiesis. We conclude that IR is a multi-dimensional set of processes that post-transcriptionally regulate diverse gene groups during normal erythropoiesis, misregulation of which could be responsible for human disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cation Transport Proteins / genetics
  • Cell Differentiation / genetics
  • Cell Nucleus / genetics
  • Cells, Cultured
  • Cluster Analysis
  • Codon, Nonsense
  • Erythroblasts / cytology
  • Erythroblasts / physiology*
  • Erythropoiesis / genetics*
  • Exons
  • Gene Expression Regulation*
  • Humans
  • Introns* / genetics
  • Microfilament Proteins / genetics
  • Mitochondrial Proteins / genetics
  • Nonsense Mediated mRNA Decay
  • Phosphoproteins / genetics
  • RNA Splice Sites
  • RNA Splicing Factors
  • Ribonucleoprotein, U2 Small Nuclear / genetics
  • Spectrin / genetics

Substances

  • Cation Transport Proteins
  • Codon, Nonsense
  • JRAB protein, human
  • MFRN1 protein, human
  • Microfilament Proteins
  • Mitochondrial Proteins
  • Phosphoproteins
  • RNA Splice Sites
  • RNA Splicing Factors
  • Ribonucleoprotein, U2 Small Nuclear
  • SF3B1 protein, human
  • SLC25A28 protein, human
  • Spectrin