Mechanism governing heme synthesis reveals a GATA factor/heme circuit that controls differentiation

Nobuyuki Tanimura, Eli Miller, Kazuhiko Igarashi, David Yang, Judith N. Burstyn, Colin N. Dewey, Emery H. Bresnick

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)


Metal ion-containing macromolecules have fundamental roles in essentially all biological processes throughout the evolutionary tree. For example, iron-containing heme is a cofactor in enzyme catalysis and electron transfer and an essential hemoglobin constituent. To meet the intense demand for hemoglobin assembly in red blood cells, the cell type-specific factor GATA-1 activates transcription of Alas2, encoding the rate-limiting enzyme in heme biosynthesis, 5-aminolevulinic acid synthase-2 (ALAS-2). Using genetic editing to unravel mechanisms governing heme biosynthesis, we discovered a GATA factor- and heme-dependent circuit that establishes the erythroid cell transcriptome. CRISPR/Cas9-mediated ablation of two Alas2 intronic cis elements strongly reduces GATA-1-induced Alas2 transcription, heme biosynthesis, and surprisingly, GATA-1 regulation of other vital constituents of the erythroid cell transcriptome. Bypassing ALAS-2 function in Alas2 cis element-mutant cells by providing its catalytic product 5-aminolevulinic acid rescues heme biosynthesis and the GATA-1-dependent genetic network. Heme amplifies GATA-1 function by downregulating the heme-sensing transcriptional repressor Bach1 and via a Bach1-insensitive mechanism. Through this dual mechanism, heme and a master regulator collaborate to orchestrate a cell type-specific transcriptional program that promotes cellular differentiation.

Original languageEnglish
Pages (from-to)249-265
Number of pages17
JournalEMBO Reports
Issue number2
Publication statusPublished - 2016 Feb 1


  • Bach1
  • GATA factor
  • heme
  • network
  • transcriptome


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