title: DNA methylation profiling reveals differences in the 3 human monocyte subsets and identifies uremia to induce DNA methylation changes during differentiation.
abstract: Human monocytes are a heterogeneous cell population consisting of 3 subsets: classical CD14++CD16-, intermediate CD14++CD16+ and nonclassical CD14+CD16++ monocytes. Via poorly characterized mechanisms, intermediate monocyte counts rise in chronic inflammatory diseases, among which chronic kidney disease is of particular epidemiologic importance. DNA methylation is a central epigenetic feature that controls hematopoiesis. By applying next-generation Methyl-Sequencing we now tested how far the 3 monocyte subsets differ in their DNA methylome and whether uremia induces DNA methylation changes in differentiating monocytes. We found that each monocyte subset displays a unique phenotype with regards to DNA methylation. Genes with differentially methylated promoter regions in intermediate monocytes were linked to distinct immunological processes, which is in line with results from recent gene expression analyses. In vitro, uremia induced dysregulation of DNA methylation in differentiating monocytes, which affected several transcription regulators important for monocyte differentiation (e.g., FLT3, HDAC1, MNT) and led to enhanced generation of intermediate monocytes. As potential mediator, the uremic toxin and methylation inhibitor S-adenosylhomocysteine induced shifts in monocyte subsets in vitro, and associated with monocyte subset counts in vivo. Our data support the concept of monocyte trichotomy and the distinct role of intermediate monocytes in human immunity. The shift in monocyte subsets that occurs in chronic kidney disease, a proinflammatory condition of substantial epidemiological impact, may be induced by accumulation of uremic toxins that mediate epigenetic dysregulation.
authors.affiliation: a Department of Internal Medicine IV , Saarland University Medical Center , Homburg , Germany.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Zawada
authors.affiliation: a Department of Internal Medicine IV , Saarland University Medical Center , Homburg , Germany.
authors.forename: Jenny S
authors.initials: JS
authors.lastname: Schneider
authors.affiliation: a Department of Internal Medicine IV , Saarland University Medical Center , Homburg , Germany.
authors.forename: Anne I
authors.initials: AI
authors.lastname: Michel
authors.affiliation: a Department of Internal Medicine IV , Saarland University Medical Center , Homburg , Germany.|b University Heart Center Luebeck, Medical Clinic II (Cardiology/Angiology/Intensive Care Medicine), University Hospital Schleswig-Holstein , Luebeck , Germany.
authors.forename: Kyrill S
authors.initials: KS
authors.lastname: Rogacev
authors.affiliation: c Department of Clinical Hemostaseology and Transfusion Medicine , Saarland University Medical Center , Homburg , Germany.|d Clinical Chemistry and Laboratory Medicine/Central Laboratory, Saarland University Medical Center , Homburg , Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Hummel
authors.affiliation: e GenXPro GmbH , Frankfurt/Main , Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Krezdorn
authors.affiliation: e GenXPro GmbH , Frankfurt/Main , Germany.|f Department of Neurological Surgery , University of California, San Francisco , San Francisco , CA , USA.
authors.forename: Soeren
authors.initials: S
authors.lastname: Müller
authors.affiliation: e GenXPro GmbH , Frankfurt/Main , Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Rotter
authors.affiliation: e GenXPro GmbH , Frankfurt/Main , Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Winter
authors.affiliation: d Clinical Chemistry and Laboratory Medicine/Central Laboratory, Saarland University Medical Center , Homburg , Germany.
authors.forename: Rima
authors.initials: R
authors.lastname: Obeid
authors.affiliation: d Clinical Chemistry and Laboratory Medicine/Central Laboratory, Saarland University Medical Center , Homburg , Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Geisel
authors.affiliation: a Department of Internal Medicine IV , Saarland University Medical Center , Homburg , Germany.
authors.forename: Danilo
authors.initials: D
authors.lastname: Fliser
authors.affiliation: a Department of Internal Medicine IV , Saarland University Medical Center , Homburg , Germany.
authors.forename: Gunnar H
authors.initials: GH
authors.lastname: Heine
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D058851:GPI-Linked Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D064368:Healthy Volunteers; D059014:High-Throughput Nucleotide Sequencing; D056284:Histone Deacetylase 1 / Q000235:genetics*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D009000:Monocytes / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics*; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D014511:Uremia / Q000235:genetics* / Q000473:pathology; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D018950:Lipopolysaccharide Receptors; C106465:MNT protein, human; D017452:Receptors, IgG; D012097:Repressor Proteins; D012435:S-Adenosylhomocysteine; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: CD14; CD16; DNA methylation; S-adenosylhomocysteine; chronic kidney disease; monocyte subsets