Developmental Control of NRAMP1 SLC11A1 Expression in Professional PhagocytesReportar como inadecuado


Developmental Control of NRAMP1 SLC11A1 Expression in Professional Phagocytes


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Inrs-Institut Armand-Frappier, 531, Bd des prairies, Laval, QC H7V 1B7, Canada





Academic Editor: Chris O’Callaghan

Abstract NRAMP1 SLC11A1 is a professional phagocyte membrane importer of divalent metals that contributes to iron recycling at homeostasis and to nutritional immunity against infection. Analyses of data generated by several consortia and additional studies were integrated to hypothesize mechanisms restricting NRAMP1 expression to mature phagocytes. Results from various epigenetic and transcriptomic approaches were collected for mesodermal and hematopoietic cell types and compiled for combined analysis with results of genetic studies associating single nucleotide polymorphisms SNPs with variations in NRAMP1 expression eQTLs. Analyses establish that NRAMP1 is part of an autonomous topologically associated domain delimited by ubiquitous CCCTC-binding factor CTCF sites. NRAMP1 locus contains five regulatory regions: a predicted super-enhancer S-E key to phagocyte-specific expression; the proximal promoter; two intronic areas, including 3′ inhibitory elements that restrict expression during development; and a block of upstream sites possibly extending the S-E domain. Also the downstream region adjacent to the 3′ CTCF locus boundary may regulate expression during hematopoiesis. Mobilization of the locus 14 predicted transcriptional regulatory elements occurs in three steps, beginning with hematopoiesis; at the onset of myelopoiesis and through myelo-monocytic differentiation. Basal expression level in mature phagocytes is further influenced by genetic variation, tissue environment, and in response to infections that induce various epigenetic memories depending on microorganism nature. Constitutively associated transcription factors TFs include CCAAT enhancer binding protein beta C-EBPb, purine rich DNA binding protein PU.1, early growth response 2 EGR2 and signal transducer and activator of transcription 1 STAT1 while hypoxia-inducible factors HIFs and interferon regulatory factor 1 IRF1 may stimulate iron acquisition in pro-inflammatory conditions. Mouse orthologous locus is generally conserved; chromatin patterns typify a de novo myelo-monocytic gene whose expression is tightly controlled by TFs Pu.1, C-ebps and Irf8; Irf3 and nuclear factor NF-kappa-B p 65 subunit RelA regulate expression in inflammatory conditions. Functional differences in the determinants identified at these orthologous loci imply that species-specific mechanisms control gene expression. View Full-Text

Keywords: natural resistance-associated macrophage protein NRAMP; solute carrier family 11 SLC11; hematopoiesis; professional phagocytes; gene expression; transcription factor; epigenetics; single nucleotide polymorphism; expression quantitative trait locus eQTL natural resistance-associated macrophage protein NRAMP; solute carrier family 11 SLC11; hematopoiesis; professional phagocytes; gene expression; transcription factor; epigenetics; single nucleotide polymorphism; expression quantitative trait locus eQTL





Autor: Mathieu F. M. Cellier

Fuente: http://mdpi.com/



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