Identification of distal cis-regulatory elements at mouse mitoferrin loci using zebrafish transgenesis. - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Molecular and Cellular Biology Année : 2011

Identification of distal cis-regulatory elements at mouse mitoferrin loci using zebrafish transgenesis.

Julio D Amigo
  • Fonction : Auteur
Ming Yu
  • Fonction : Auteur
Babette Gwynn
  • Fonction : Auteur
Jeffrey D Cooney
  • Fonction : Auteur
Amy J Lambert
  • Fonction : Auteur
Neil C Chi
  • Fonction : Auteur
Mitchell J Weiss
  • Fonction : Auteur
Luanne L Peters
  • Fonction : Auteur
Alan B Cantor
  • Fonction : Auteur
Barry H Paw
  • Fonction : Auteur

Résumé

Mitoferrin 1 (Mfrn1; Slc25a37) and mitoferrin 2 (Mfrn2; Slc25a28) function as essential mitochondrial iron importers for heme and Fe/S cluster biogenesis. A genetic deficiency of Mfrn1 results in a profound hypochromic anemia in vertebrate species. To map the cis-regulatory modules (CRMs) that control expression of the Mfrn genes, we utilized genome-wide chromatin immunoprecipitation (ChIP) datasets for the major erythroid transcription factor GATA-1. We identified the CRMs that faithfully drive the expression of Mfrn1 during blood and heart development and Mfrn2 ubiquitously. Through in vivo analyses of the Mfrn-CRMs in zebrafish and mouse, we demonstrate their functional and evolutionary conservation. Using knockdowns with morpholinos and cell sorting analysis in transgenic zebrafish embryos, we show that GATA-1 directly regulates the expression of Mfrn1. Mutagenesis of individual GATA-1 binding cis elements (GBE) demonstrated that at least two of the three GBE within this CRM are functionally required for GATA-mediated transcription of Mfrn1. Furthermore, ChIP assays demonstrate switching from GATA-2 to GATA-1 at these elements during erythroid maturation. Our results provide new insights into the genetic regulation of mitochondrial function and iron homeostasis and, more generally, illustrate the utility of genome-wide ChIP analysis combined with zebrafish transgenesis for identifying long-range transcriptional enhancers that regulate tissue development.

Dates et versions

hal-01120680 , version 1 (26-02-2015)

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Citer

Julio D Amigo, Ming Yu, Marie-Berengere Troadec, Babette Gwynn, Jeffrey D Cooney, et al.. Identification of distal cis-regulatory elements at mouse mitoferrin loci using zebrafish transgenesis.. Molecular and Cellular Biology, 2011, 31 (7), pp.1344-56. ⟨10.1128/MCB.01010-10⟩. ⟨hal-01120680⟩
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