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Publications

Journal Article Preprint Epublish

PubMed: 40313744 DOI: 10.21203/rs.3.rs-6355281/v1

RNA Editors Sculpt the Transcriptome During Terminal Erythropoiesis.

Res Sq

Authors: Areum Han, Alena Yermalovich, Mohamad Ali T Najia, Daniel S Pearson, Yuko Fujiwara, Michael Bolgov, Caroline Kubaczka, Trista E North, Vanessa Lundin, Stuart Orkin, George Q Daley

Affiliations

  • Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
  • Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.
  • Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
  • Dana-Farber/Boston Children's Hospital Cancer and Blood Disorder Center, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.
  • Developmental and Regenerative Biology Program, Harvard Medical School, Boston, MA, USA.
  • Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Sweden.

Abstract

Selective RNA degradation during terminal erythropoiesis results in a globin-rich transcriptome in mature erythrocytes, but the specific RNA decay pathways remain unknown. We found that deficiency of the terminal uridylyl transferase enzyme Zcchc6 and the 3'-5' exoribonuclease Dis3l2 in mouse models led to fetal and perinatal reticulocytosis, an accumulation of RNA-rich precursors of terminal erythroid cells, suggesting their crucial roles in terminal red cell differentiation. Notably, knockout embryos exhibited persistent high-level expression of globin, the ortholog of human fetal globin. Perturbation of the Zcchc6-Dis3l2 pathway in mice engineered to express the human b-globin locus likewise increased -globin levels in fetal erythroid cells, suggesting that globin switching entails post-transcriptional mechanisms of mRNA destabilization in addition to transcriptional down-regulation. We cultured human hematopoietic stem and progenitor cells (HSPCs), performed CRISPR/Cas9-mediated knockout of ZCCHC6 and DIS3L2, and observed accumulation of RNA and elevated γ-globin levels in terminal erythroid cells. Our findings reveal a conserved role for the ZCCHC6/DIS3L2 RNA editors in terminal erythropoiesis and demonstrate a post-transcriptional mechanism for globin gene switching, advancing research into erythrocyte generation and globin stabilization to ameliorate hemoglobinopathies.

MeSH

Cells, Genes, Erythroid Cells, Erythrocytes, Transcriptome, Globins, Erythropoiesis, Rna