Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

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.

High-Resolution Profiling of Innate Immune Responses by Porcine Dendritic Cell Subsets in vitro and in vivo

“…The present study also identified a monocytic cell subset in porcine lymph nodes and tonsils characterized by high levels of CD14 expression, which clustered with monocytes and monocyte-derived macrophages in PCA, and expressed the monocyte/macrophage-specific lineage markers CD64 ( 53 ), CD68 ( 54 ) and SLC11A1 ( 55 ). The expression of ZFP36L1 , which is selectively upregulated during monocyte/macrophage differentiation ( 56 ), and the macrophage-specific transcription factors TFEC ( 57 ) and MAFB ( 58 ), together with CHIT1 , a gene involved in monocyte-to-macrophage differentiation ( 59 ), would indicate that this CD14 high population corresponds to monocyte-derived macrophages.…”

Polymorphisms and Associations of the NRAMP-1 and iNOS Genes on Newcastle Disease and Salmonella enteritidis Resistances in SenSi-1 Agrinak Chickens

“…NRAMP-1 triggers a non-immune response that works on the host cells and expressed on phagocytic cells (Cellier, 2017). NRAMP-1 functions to modulate cytocidal proteins that are toxic to the cells, such as bacterial cells and transmembrane conserving.…”

Egr2 upregulation induced mitochondrial iron overload implicating in sevoflurane-induced cognitive deficits in developing mice

“…Meanwhile, Egr2 gene may correlated with the HO-1 expression, which could convert heme to iron, and participated in memory, cognition and synaptic plasticity [56]. Furthermore, Egr2 may implicate in stimulating iron acquisition in pro-in ammatory conditions [57]. Consequently, we speculated that Egr2 may play a crucial role in cognitive function correlated to mitochondrial iron metabolism.…”