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

Abstract : 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.
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01120680
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Submitted on : Thursday, February 26, 2015 - 1:10:14 PM
Last modification on : Friday, March 27, 2020 - 2:53:34 AM

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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, American Society for Microbiology, 2011, 31 (7), pp.1344-56. ⟨10.1128/MCB.01010-10⟩. ⟨hal-01120680⟩

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