title: A role for KMT1c in monocyte to dendritic cell differentiation: Epigenetic regulation of monocyte differentiation.
abstract: Monocytes play a key role in immune system function. Chromatin remodeling is crucial for various differentiation and gene regulation processes and is rather well studied in T cells. However, for monocytes not much is known regarding how the epigenetic machinery influences the differentiation into various effector cell types. In the work presented here, we explore the epigenetic underpinnings of monocyte differentiation. By transcriptional profiling we show that transcription of lysine methyltransferases (KMTs) and in particular KMT1c is markedly up regulated after differentiation of monocytes into immature dendritic cells (iDCs). Specifically inhibiting KMT1c function, using the small-molecule inhibitor BIX-01294, changes the transcription levels of the DC marker DC-SIGN, but does not affect surface protein expression. Blocking global KMT activity, using DZNep, does influence monocyte differentiation into iDCs, indicated by a loss of DC-SIGN surface expression. When BIX-01294 and DZNep treatment was combined DC-SIGN expression was almost lost completely. This work shows that the activities of KMTs are required for successful differentiation of monocyte-derived dendritic cells. Furthermore it shows the importance of KMT inhibitors in the field of epigenetic immune therapy, which is still much focused around HDAC inhibitors.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rutger J
authors.initials: RJ
authors.lastname: Wierda
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Goedhart
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marja C J A
authors.initials: MC
authors.lastname: van Eggermond
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Alice F
authors.initials: AF
authors.lastname: Muggen
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Xanne M
authors.initials: XM
authors.lastname: Miggelbrink
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Sacha B
authors.initials: SB
authors.lastname: Geutskens
authors.affiliation: Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: van Zwet
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Geert W
authors.initials: GW
authors.lastname: Haasnoot
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: pjvdelsen@lumc.nl.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van den Elsen
mesh_terms: D000107:Acetylation; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002843:Chromatin / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D006649:Histocompatibility Antigens / Q000235:genetics* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D061251:Primary Cell Culture; D011799:Quinazolines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000241:Adenosine; D001381:Azepines; D015815:Cell Adhesion Molecules; D002843:Chromatin; D006649:Histocompatibility Antigens; D011495:Histone-Lysine N-Methyltransferase; D037181:Lectins, C-Type; D011799:Quinazolines; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C518299:BIX 01294; C048460:3-deazaneplanocin; C445405:EHMT2 protein, human
keywords: Dendritic cells; Epigenetics; Macrophages; Monocyte differentiation; Monocytes