Long non-coding RNA-dependent mechanism to regulate heme biosynthesis and erythrocyte development

Nat Commun. 2018 Oct 22;9(1):4386. doi: 10.1038/s41467-018-06883-x.

Abstract

In addition to serving as a prosthetic group for enzymes and a hemoglobin structural component, heme is a crucial homeostatic regulator of erythroid cell development and function. While lncRNAs modulate diverse physiological and pathological cellular processes, their involvement in heme-dependent mechanisms is largely unexplored. In this study, we elucidated a lncRNA (UCA1)-mediated mechanism that regulates heme metabolism in human erythroid cells. We discovered that UCA1 expression is dynamically regulated during human erythroid maturation, with a maximal expression in proerythroblasts. UCA1 depletion predominantly impairs heme biosynthesis and arrests erythroid differentiation at the proerythroblast stage. Mechanistic analysis revealed that UCA1 physically interacts with the RNA-binding protein PTBP1, and UCA1 functions as an RNA scaffold to recruit PTBP1 to ALAS2 mRNA, which stabilizes ALAS2 mRNA. These results define a lncRNA-mediated posttranscriptional mechanism that provides a new dimension into how the fundamental heme biosynthetic process is regulated as a determinant of erythrocyte development.

Publication types

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

MeSH terms

  • 5-Aminolevulinate Synthetase / genetics
  • 5-Aminolevulinate Synthetase / metabolism
  • Antigens, CD34 / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Erythroid Cells / metabolism
  • Erythropoiesis / genetics
  • Erythropoiesis / physiology
  • Heme / metabolism*
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism
  • Humans
  • Polypyrimidine Tract-Binding Protein / genetics
  • Polypyrimidine Tract-Binding Protein / metabolism
  • Protein Binding
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Messenger / metabolism
  • Stem Cells / metabolism

Substances

  • Antigens, CD34
  • Heterogeneous-Nuclear Ribonucleoproteins
  • PTBP1 protein, human
  • RNA, Long Noncoding
  • RNA, Messenger
  • UCA1 RNA, human
  • Polypyrimidine Tract-Binding Protein
  • Heme
  • 5-Aminolevulinate Synthetase
  • ALAS2 protein, human