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.
Highlights
NRAMP1 gene encodes a phagocytosis-related function that is expressed in mature myelo-monocytic cells
Analysis of high throughput datasets depicting DNAse footprinting (DNase 1 hypersentitive sites, DHSs), chromatin immuno-precipitations coupled to deep sequencing (ChIP-seq) and targeting specific histone modifications or RNA polymerase II (RNA Pol II), CCCTC-binding factor (CTCF) and various transcription factors (TFs) interacting with NRAMP1 locus, in both acute myeloid leukemia (AML) cell lines and primary monocytes, allowed us to delineate a ~40 kb regulatory domain insulated by CTCF sites [11]
NRAMP1 differs from many inflammatory loci locked in repressed chromatin configuration in mature phagocytes until primary stimulation and training; and given the importance of signal transducer and activator of transcription 1 (STAT1) activation for the induction of trained immunity [194], NRAMP1 epigenetic status may owe in part to constitutive binding of STAT1 at several sites of the locus [99], as well as constitutive association with the master regulators PU.1 and CCAAT enhancer binding protein beta (C/EBPb) [13,25,72]
Summary
NRAMP1 gene encodes a phagocytosis-related function that is expressed in mature myelo-monocytic cells. Analysis of high throughput datasets (mostly from ENCODE consortium [9,10]) depicting DNAse footprinting (DNase 1 hypersentitive sites, DHSs), chromatin immuno-precipitations coupled to deep sequencing (ChIP-seq) and targeting specific histone modifications or RNA polymerase II (RNA Pol II), CCCTC-binding factor (CTCF) and various transcription factors (TFs) interacting with NRAMP1 locus, in both acute myeloid leukemia (AML) cell lines and primary monocytes, allowed us to delineate a ~40 kb regulatory domain insulated by CTCF sites [11]. Because active enhancers (including S-Es) overlap with RNA Pol II bound regions and display (bidirectional) elongation of eRNAs, evaluating the transcriptional status of potential regulatory elements previously delineated at NRAMP1 locus should inform on regulation of gene expression. Howdeivffeerr,etnhtieatciaonndaride acotemrmegonultaotNorryamepl1emanednNtsRiAdMenPt1ifioertdhoalnodgs,thaseiwrepllaatsteinrnvoolvf emmoebnitloizfamtiaosnteraTpFpseared diversguecnhtabsePtuw.1eeanndmCa/mebmpsa. lHiaonwsepveecr,ieths.e candidate regulatory elements identified and their pattern of mobilization appeared divergent between mammalian species
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
