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Journal Article Research Support, N.I.H., Extramural Ppublish 9 citations

PubMed: 37738561 DOI: 10.1182/blood.2022019495

HEXIM1 is an essential transcription regulator during human erythropoiesis.

Blood 142(25):2198-2215

Authors: Xiurui Lv, Kristin Murphy, Zachary Murphy, Michael Getman, Nabil Rahman, Yukio Nakamura, Lionel Blanc, Patrick G Gallagher, James Palis, Narla Mohandas, Laurie A Steiner

Affiliations

  • Center for Child Health Research, University of Rochester, Rochester, NY.
  • Rikagaku Kenkyūjyo (RIKEN) BioResource Research Center, Tsukuba Campus, Ibaraki, Japan.
  • Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY.
  • Department of Pediatrics, Yale University School of Medicine, New Haven, CT.
  • Red Cell Physiology Laboratory, Lindsey F. Kimball Research Institute, New York Blood Center, New York, NY.
  • Center for RNA Biology, University of Rochester, Rochester, NY.

Abstract

Regulation of RNA polymerase II (RNAPII) activity is an essential process that governs gene expression; however, its contribution to the fundamental process of erythropoiesis remains unclear. hexamethylene bis-acetamide inducible 1 (HEXIM1) regulates RNAPII activity by controlling the location and activity of positive transcription factor β. We identified a key role for HEXIM1 in controlling erythroid gene expression and function, with overexpression of HEXIM1 promoting erythroid proliferation and fetal globin expression. HEXIM1 regulated erythroid proliferation by enforcing RNAPII pausing at cell cycle check point genes and increasing RNAPII occupancy at genes that promote cycle progression. Genome-wide profiling of HEXIM1 revealed that it was increased at both repressed and activated genes. Surprisingly, there were also genome-wide changes in the distribution of GATA-binding factor 1 (GATA1) and RNAPII. The most dramatic changes occurred at the β-globin loci, where there was loss of RNAPII and GATA1 at β-globin and gain of these factors at γ-globin. This resulted in increased expression of fetal globin, and BGLT3, a long noncoding RNA in the β-globin locus that regulates fetal globin expression. GATA1 was a key determinant of the ability of HEXIM1 to repress or activate gene expression. Genes that gained both HEXIM1 and GATA1 had increased RNAPII and increased gene expression, whereas genes that gained HEXIM1 but lost GATA1 had an increase in RNAPII pausing and decreased expression. Together, our findings reveal a central role for universal transcription machinery in regulating key aspects of erythropoiesis, including cell cycle progression and fetal gene expression, which could be exploited for therapeutic benefit.

MeSH

Cell Cycle, Hematology, Erythropoiesis, Cells, Globins, Genes, Gene Expression, Rna Polymerase Ii

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