title: Neonatal monocytes exhibit a unique histone modification landscape.
abstract: Neonates have dampened expression of pro-inflammatory cytokines and difficulty clearing pathogens. This makes them uniquely susceptible to infections, but the factors regulating neonatal-specific immune responses are poorly understood. Epigenetics, including histone modifications, can activate or silence gene transcription by modulating chromatin structure and stability without affecting the DNA sequence itself and are potentially modifiable. Histone modifications are known to regulate immune cell differentiation and function in adults but have not been well studied in neonates.
  
  
  
  To elucidate the role of histone modifications in neonatal immune function, we performed chromatin immunoprecipitation on mononuclear cells from 45 healthy neonates (gestational ages 23-40 weeks). As gestation approached term, there was increased activating H3K4me3 on the pro-inflammatoryIL1B,IL6,IL12B, andTNFcytokine promoters (p< 0.01) with no change in repressive H3K27me3, suggesting that these promoters in preterm neonates are less open and accessible to transcription factors than in term neonates. Chromatin immunoprecipitation with massively parallel DNA sequencing (ChIP-seq) was then performed to establish the H3K4me3, H3K9me3, H3K27me3, H3K4me1, H3K27ac, and H3K36me3 landscapes in neonatal and adult CD14+ monocytes. As development progressed from neonate to adult, monocytes lost the poised enhancer mark H3K4me1 and gained the activating mark H3K4me3, without a change in additional histone modifications. This decreased H3K4me3 abundance at immunologically important neonatal monocyte gene promoters, includingCCR2,CD300C,ILF2,IL1B, andTNFwas associated with reduced gene expression.
  
  
  
  These results provide evidence that neonatal immune cells exist in an epigenetic state that is distinctly different from adults and that this state contributes to neonatal-specific immune responses that leaves them particularly vulnerable to infections.
authors.affiliation: Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of Michigan Medical Center, 1540 E. Medical Center Drive, C.S. Mott Children's Hospital Room 8-621, Ann Arbor, MI 48109 USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Bermick
authors.affiliation: Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of Michigan Medical Center, 1540 E. Medical Center Drive, C.S. Mott Children's Hospital Room 8-621, Ann Arbor, MI 48109 USA.
authors.forename: Nathalie J
authors.initials: NJ
authors.lastname: Lambrecht
authors.affiliation: Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109 USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: denDekker
authors.affiliation: Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109 USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.affiliation: Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109 USA.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
authors.affiliation: Department of Medicine, Division of Pulmonary & Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048 USA.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.affiliation: Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109 USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Schaller
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature / Q000276:immunology; D009000:Monocytes / Q000166:cytology* / Q000276:immunology; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D016207:Cytokines; D006657:Histones
keywords: ChIP-sequencing (ChIP-seq); Development; Epigenetics; Histone modification; Innate immunity