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Article ; Online: The H1 linker histones: multifunctional proteins beyond the nucleosomal core particle.

Hergeth, Sonja P / Schneider, Robert

2015 Volume 16, Issue 11, Page(s) 1439–1453

Abstract: The linker histone H1 family members are a key component of chromatin and bind to the nucleosomal core particle around the DNA entry and exit sites. H1 can stabilize both nucleosome structure and higher-order chromatin architecture. In general, H1 ... ...

Abstract	The linker histone H1 family members are a key component of chromatin and bind to the nucleosomal core particle around the DNA entry and exit sites. H1 can stabilize both nucleosome structure and higher-order chromatin architecture. In general, H1 molecules consist of a central globular domain with more flexible tail regions at both their N- and C-terminal ends. The existence of multiple H1 subtypes and a large variety of posttranslational modifications brings about a considerable degree of complexity and makes studying this protein family challenging. Here, we review recent progress in understanding the function of linker histones and their subtypes beyond their role as merely structural chromatin components. We summarize current findings on the role of H1 in heterochromatin formation, transcriptional regulation and embryogenesis with a focus on H1 subtypes and their specific modifications.
MeSH term(s)	Animals ; Chromatin/metabolism ; Chromatin Assembly and Disassembly ; DNA Repair ; Embryonic Development ; Epigenesis, Genetic ; Gene Expression Regulation ; Heterochromatin/metabolism ; Histone Code ; Histones/chemistry ; Histones/classification ; Histones/genetics ; Histones/physiology ; Nucleosomes/chemistry ; Nucleosomes/physiology ; Protein Binding ; Protein Processing, Post-Translational ; Protein Structure, Tertiary
Chemical Substances	Chromatin ; Heterochromatin ; Histones ; Nucleosomes
Language	English
Publishing date	2015-10-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.15252/embr.201540749
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Article ; Online: Aurora B expression and histone variant H1.4S27 phosphorylation are no longer coordinated during metaphase in aneuploid colorectal carcinomas.

Sijare, Fahima / Geißler, Anna-Lena / Fichter, Christiane D / Hergeth, Sonja P / Bogatyreva, Lioudmila / Hauschke, Dieter / Schneider, Robert / Werner, Martin / Lassmann, Silke

Virchows Archiv : an international journal of pathology

2015 Volume 466, Issue 5, Page(s) 503–515

Abstract: ... significantly different between cell lines for Aurora B (p = 0.019) but not for H1.4S27p (p = 0.879). For Aurora ... no longer coordinated during metaphase in aneuploid HT29 cells (p = 0.039). In CRCs, immunoreactivity ... labeling of H1.4S27p was significantly higher in diploid than in aneuploid CRCs (p = 0.011). Aurora B was ...

Abstract	Experimental model systems identified phosphorylation of linker histone variant H1.4 at Ser 27 (H1.4S27p) as a novel mitotic mark set by Aurora B kinase. Here, we examined expression of Aurora B and H1.4S27p in colorectal carcinoma (CRC) cell lines (HCT116, DLD1, Caco-2, HT29) and tissue specimens (n = 36), in relation to microsatellite instability (MSI) status and ploidy. In vitro, Aurora B (pro-/meta-/anaphase) and H1.4S27p (pro-/metaphase) were localized in mitotic figures. The proportion of labeled mitoses was significantly different between cell lines for Aurora B (p = 0.019) but not for H1.4S27p (p = 0.879). For Aurora B, these differences were not associated with an altered Aurora B gene copy number (FISH) or messenger RNA (mRNA) expression level (qRT-PCR). Moreover, Aurora B expression and H1.4S27 phosphorylation were no longer coordinated during metaphase in aneuploid HT29 cells (p = 0.039). In CRCs, immunoreactivity for Aurora B or H1.4S27p did not correlate with T- or N-stage, grade, or MSI status. However, metaphase labeling of H1.4S27p was significantly higher in diploid than in aneuploid CRCs (p = 0.011). Aurora B was significantly correlated with H1.4S27p-positive metaphases in MSI (p = 0.010) or diploid (p = 0.003) CRCs. Finally, combined classification of MSI status and ploidy revealed a significant positive correlation of Aurora B with H1.4S27p in metaphases of diploid/MSI (p = 0.010) and diploid/microsatellite-stable (MSS; p = 0.031) but not of aneuploid/MSS (p = 0.458) CRCs. The present study underlines the functional link of Aurora B expression and H1.4S27p during specific phases of mitosis in diploid and/or MSI-positive CRCs in vitro and in situ. Importantly, the study shows that the coordination between Aurora B expression and phosphorylation of H1.4 at Ser 27 is lost in cycling aneuploid CRC cells.
MeSH term(s)	Adenocarcinoma/enzymology ; Adenocarcinoma/genetics ; Aneuploidy ; Aurora Kinase B/biosynthesis ; Colorectal Neoplasms/enzymology ; Colorectal Neoplasms/genetics ; Fluorescent Antibody Technique ; Histones/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Metaphase ; Microsatellite Instability ; Phosphorylation
Chemical Substances	Histones ; AURKB protein, human (EC 2.7.11.1) ; Aurora Kinase B (EC 2.7.11.1)
Language	English
Publishing date	2015-05
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1184867-4
ISSN	1432-2307 ; 0945-6317
ISSN (online)	1432-2307
ISSN	0945-6317
DOI	10.1007/s00428-015-1727-6
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Article ; Online: Isoform-specific phosphorylation of human linker histone H1.4 in mitosis by the kinase Aurora B.

Hergeth, Sonja P / Dundr, Miroslav / Tropberger, Philipp / Zee, Barry M / Garcia, Benjamin A / Daujat, Sylvain / Schneider, Robert

Journal of cell science

2011 Volume 124, Issue Pt 10, Page(s) 1623–1628

Abstract: ... previously that phosphorylation of S27 in human histone H1.4 (H1.4S27-P), prevents binding of heterochromatin ... dimethylated K26. Here, we present the first functional characterization of H1.4S27-P in vivo and in vitro ...

Abstract	The linker histone H1 plays an essential role in maintaining and establishing higher-order chromatin structure. As with core histones, histone H1 is also extensively covalently modified. We showed previously that phosphorylation of S27 in human histone H1.4 (H1.4S27-P), prevents binding of heterochromatin protein 1 (HP1) family members (officially known as chromobox protein homologs) to the neighboring dimethylated K26. Here, we present the first functional characterization of H1.4S27-P in vivo and in vitro. We show that H1.4S27 phosphorylation is cell-cycle-regulated and its levels peak on metaphase chromosomes. We identify further Aurora B as the kinase phosphorylating H1.4S27. We demonstrate that histone H1.4 is the only somatic linker histone variant targeted by Aurora B and that Aurora B exclusively phosphorylates S27. Adjacent K26 dimethylation can regulate Aurora B activity towards S27, uncovering a crosstalk between these modifications. Finally, our fluorescence recovery after photobleaching (FRAP) analysis on histone H1.4 mutants suggests a role of S27 phosphorylation in the regulation of histone H1.4 mobility and chromatin binding in mitosis.
MeSH term(s)	Animals ; Aurora Kinase B ; Aurora Kinases ; Chromosomal Proteins, Non-Histone/chemistry ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; HeLa Cells ; Heterochromatin/metabolism ; Histones/chemistry ; Histones/genetics ; Histones/metabolism ; Humans ; Methylation ; Mice ; Mitosis/physiology ; NIH 3T3 Cells ; Phosphorylation ; Protein Isoforms ; Protein-Serine-Threonine Kinases/metabolism ; Substrate Specificity
Chemical Substances	Chromosomal Proteins, Non-Histone ; Heterochromatin ; Histones ; Protein Isoforms ; heterochromatin-specific nonhistone chromosomal protein HP-1 (107283-02-3) ; AURKB protein, human (EC 2.7.11.1) ; Aurkb protein, mouse (EC 2.7.11.1) ; Aurora Kinase B (EC 2.7.11.1) ; Aurora Kinases (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2011-05-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.084947
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Article: Characterization and functional analysis of osteoblast-derived fibulins in the human hematopoietic stem cell niche.

Hergeth, Sonja P / Aicher, Wilhelm K / Essl, Mike / Schreiber, Thomas D / Sasaki, Takako / Klein, Gerd

Experimental hematology

2008 Volume 36, Issue 8, Page(s) 1022–1034

Abstract: Objective: In the bone marrow stem cell niche, osteoblasts lining the endosteum are of major importance in supporting hematopoietic stem cell maintenance. Our objective was to analyze expression of the fibulins, highly conserved calcium-binding ... ...

Abstract	Objective: In the bone marrow stem cell niche, osteoblasts lining the endosteum are of major importance in supporting hematopoietic stem cell maintenance. Our objective was to analyze expression of the fibulins, highly conserved calcium-binding glycoproteins, which are components of the extracellular matrix of human osteoblasts, and to provide insights into their functional interactions with hematopoietic progenitor cells. Materials and methods: Expression of the fibulins by human osteoblasts was determined by reverse transcription polymerase chain reaction analysis and by immunofluorescence staining and immunoblotting using fibulin-specific antisera. Recombinant fibulins were used in cell proliferation and differentiation assays with human CD34(+) hematopoietic progenitor cells. Adhesive interactions of CD34(+) cells with fibulins were investigated using cell-adhesion assays. Results: Human osteoblasts strongly express and secrete fibulin-1 and -2. Whereas fibulin-1 is secreted in its intact form, fibulin-2 synthesized by human osteoblasts undergoes rapid proteolytic degradation. The matrix metalloproteinase-2, which is constitutively expressed by the osteoblasts, seems to be responsible for fibulin-2 degradation. Fibulin-1 showed an inhibitory effect on short-term CD34(+) hematopoietic progenitor cell proliferation. Both fibulin-1 and fibulin-2 were able to diminish erythroid and myeloid colony formation. The CD34(+) cell line KG1a strongly attached to fibulin-2, whereas magnetic-activated cell sorted CD34(+) hematopoietic progenitors did not adhere to either fibulin-1 or fibulin-2. On the other hand, fibulin-1 can strongly interfere with CD34(+) cell adhesion to fibronectin. Conclusion: Fibulins seem to be important components of the extracellular matrix of osteoblasts and are likely to negatively influence the proliferation rate of stem cells and the overall adhesive properties of the endosteal stem cell niche.
MeSH term(s)	Antigens, CD34/metabolism ; Blotting, Western ; Calcium-Binding Proteins/chemistry ; Calcium-Binding Proteins/genetics ; Calcium-Binding Proteins/metabolism ; Cell Adhesion/physiology ; Cell Differentiation/physiology ; Cell Proliferation ; Cells, Cultured ; Fibronectins/metabolism ; Gelatinases/chemistry ; Gene Expression ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/metabolism ; Humans ; Osteoblasts/cytology ; Osteoblasts/metabolism ; Reverse Transcriptase Polymerase Chain Reaction
Chemical Substances	Antigens, CD34 ; Calcium-Binding Proteins ; Fibronectins ; fibulin ; Gelatinases (EC 3.4.24.-)
Language	English
Publishing date	2008-08
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	185107-x
ISSN	1873-2399 ; 0301-472X ; 0531-5573
ISSN (online)	1873-2399
ISSN	0301-472X ; 0531-5573
DOI	10.1016/j.exphem.2008.03.013
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Article ; Online: Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression.

Lindau, Alexandra / Härdtner, Carmen / Hergeth, Sonja P / Blanz, Kelly Daryll / Dufner, Bianca / Hoppe, Natalie / Anto-Michel, Nathaly / Kornemann, Jan / Zou, Jiadai / Gerhardt, Louisa M S / Heidt, Timo / Willecke, Florian / Geis, Serjosha / Stachon, Peter / Wolf, Dennis / Libby, Peter / Swirski, Filip K / Robbins, Clinton S / McPheat, William /

Hawley, Shaun / Braddock, Martin / Gilsbach, Ralf / Hein, Lutz / von zur Mühlen, Constantin / Bode, Christoph / Zirlik, Andreas / Hilgendorf, Ingo

Basic research in cardiology

2016 Volume 111, Issue 2, Page(s) 20

Abstract: Macrophages in the arterial intima sustain chronic inflammation during atherogenesis. Under hypercholesterolemic conditions murine Ly6C(high) monocytes surge in the blood and spleen, infiltrate nascent atherosclerotic plaques, and differentiate into ... ...

Abstract	Macrophages in the arterial intima sustain chronic inflammation during atherogenesis. Under hypercholesterolemic conditions murine Ly6C(high) monocytes surge in the blood and spleen, infiltrate nascent atherosclerotic plaques, and differentiate into macrophages that proliferate locally as disease progresses. Spleen tyrosine kinase (SYK) may participate in downstream signaling of various receptors that mediate these processes. We tested the effect of the SYK inhibitor fostamatinib on hypercholesterolemia-associated myelopoiesis and plaque formation in Apoe(-/-) mice during early and established atherosclerosis. Mice consuming a high cholesterol diet supplemented with fostamatinib for 8 weeks developed less atherosclerosis. Histologic and flow cytometric analysis of aortic tissue showed that fostamatinib reduced the content of Ly6C(high) monocytes and macrophages. SYK inhibition limited Ly6C(high) monocytosis through interference with GM-CSF/IL-3 stimulated myelopoiesis, attenuated cell adhesion to the intimal surface, and blocked M-CSF stimulated monocyte to macrophage differentiation. In Apoe(-/-) mice with established atherosclerosis, however, fostamatinib treatment did not limit macrophage accumulation or lesion progression despite a significant reduction in blood monocyte counts, as lesional macrophages continued to proliferate. Thus, inhibition of hypercholesterolemia-associated monocytosis, monocyte infiltration, and differentiation by SYK antagonism attenuates early atherogenesis but not established disease when local macrophage proliferation dominates lesion progression.
MeSH term(s)	Animals ; Atherosclerosis/drug therapy ; Atherosclerosis/immunology ; Atherosclerosis/prevention & control ; Cell Adhesion/drug effects ; Cells, Cultured ; Disease Progression ; Drug Evaluation, Preclinical ; Female ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Macrophages/drug effects ; Mice ; Monocytes/drug effects ; Myelopoiesis/drug effects ; Oxazines/pharmacology ; Oxazines/therapeutic use ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Pyridines/pharmacology ; Pyridines/therapeutic use ; Random Allocation ; Syk Kinase
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Oxazines ; Pyridines ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Syk Kinase (EC 2.7.10.2) ; Syk protein, mouse (EC 2.7.10.2) ; fostamatinib (SQ8A3S5101)
Language	English
Publishing date	2016-03
Publishing country	Germany
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	189755-x
ISSN	1435-1803 ; 0300-8428 ; 0175-9418
ISSN (online)	1435-1803
ISSN	0300-8428 ; 0175-9418
DOI	10.1007/s00395-016-0535-8
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Article ; Online: P2Y6 deficiency limits vascular inflammation and atherosclerosis in mice.

Stachon, Peter / Peikert, Alexander / Michel, Nathaly Anto / Hergeth, Sonja / Marchini, Timoteo / Wolf, Dennis / Dufner, Bianca / Hoppe, Natalie / Ayata, Cemil Korcan / Grimm, Melanie / Cicko, Sanja / Schulte, Lisa / Reinöhl, Jochen / von zur Muhlen, Constantin / Bode, Christoph / Idzko, Marco / Zirlik, Andreas

Arteriosclerosis, thrombosis, and vascular biology

2014 Volume 34, Issue 10, Page(s) 2237–2245

Abstract: Objective: Nucleotides such as ATP, ADP, UTP, and UDP serve as proinflammatory danger signals via purinergic receptors on their release to the extracellular space by activated or dying cells. UDP binds to the purinergic receptor Y6 (P2Y6) and propagates ...

Abstract	Objective: Nucleotides such as ATP, ADP, UTP, and UDP serve as proinflammatory danger signals via purinergic receptors on their release to the extracellular space by activated or dying cells. UDP binds to the purinergic receptor Y6 (P2Y6) and propagates vascular inflammation by inducing the expression of chemokines such as monocyte chemoattractant protein 1, interleukin-8, or its mouse homologsCCL1 (chemokine [C-C motif] ligand 1)/keratinocyte chemokine, CXCL2 (chemokine [C-X-C motif] ligand 2)/macrophage inflammatory protein 2, and CXCL5 (chemokine [C-X-C motif] ligand 5)/LIX, and adhesion molecules such as vascular cell adhesion molecule 1 and intercellular cell adhesion molecule 1. Thus, P2Y6 contributes to leukocyte recruitment and inflammation in conditions such as allergic asthma or sepsis. Because atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the vessel wall, we hypothesized a role of P2Y6 in atherogenesis. Approach and results: Intraperitoneal stimulation of wild-type mice with UDP induced rolling and adhesion of leukocytes to the vessel wall as assessed by intravital microscopy. This effect was not present in P2Y6-deficient mice. Atherosclerotic aortas of low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks expressed significantly more transcripts and protein of P2Y6 than respective controls. Finally, P2Y6 (-/-)/low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks developed significantly smaller atherosclerotic lesions compared with P2Y6 (+/+)/low-density lipoprotein receptor-deficient mice. Bone marrow transplantation identified a crucial role of P2Y6 on vascular resident cells, most likely endothelial cells, on leukocyte recruitment and atherogenesis. Atherosclerotic lesions of P2Y6-deficient mice contained fewer macrophages and fewer lipids as determined by immunohistochemistry. Mechanistically, RNA expression of vascular cell adhesion molecule 1 and interleukin-6 was decreased in these lesions and P2Y6-deficient macrophages took up less modified low-density lipoprotein cholesterol. Conclusions: We show for the first time that P2Y6 deficiency limits atherosclerosis and plaque inflammation in mice.
MeSH term(s)	Animals ; Aorta/immunology ; Aorta/metabolism ; Aorta/pathology ; Aortic Diseases/genetics ; Aortic Diseases/immunology ; Aortic Diseases/metabolism ; Aortic Diseases/prevention & control ; Atherosclerosis/genetics ; Atherosclerosis/immunology ; Atherosclerosis/metabolism ; Atherosclerosis/prevention & control ; Bone Marrow Transplantation ; Cholesterol, Dietary ; Disease Models, Animal ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/prevention & control ; Inflammation Mediators/metabolism ; Leukocyte Rolling ; Macrophages/immunology ; Macrophages/metabolism ; Mice ; Mice, Knockout ; Plaque, Atherosclerotic ; Receptors, LDL/deficiency ; Receptors, LDL/genetics ; Receptors, Purinergic P2/deficiency ; Receptors, Purinergic P2/genetics ; Signal Transduction ; Time Factors ; Transendothelial and Transepithelial Migration ; Uridine Diphosphate/metabolism
Chemical Substances	Cholesterol, Dietary ; Inflammation Mediators ; Receptors, LDL ; Receptors, Purinergic P2 ; purinoceptor P2Y6 ; Uridine Diphosphate (58-98-0)
Language	English
Publishing date	2014-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.114.303585
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Article ; Online: Histone H1 variant-specific lysine methylation by G9a/KMT1C and Glp1/KMT1D.

Weiss, Thomas / Hergeth, Sonja / Zeissler, Ulrike / Izzo, Annalisa / Tropberger, Philipp / Zee, Barry M / Dundr, Miroslav / Garcia, Benjamin A / Daujat, Sylvain / Schneider, Robert

Epigenetics & chromatin

2010 Volume 3, Issue 1, Page(s) 7

Abstract: Background: The linker histone H1 has a key role in establishing and maintaining higher order chromatin structure and in regulating gene expression. Mammals express up to 11 different H1 variants, with H1.2 and H1.4 being the predominant ones in most ... ...

Abstract	Background: The linker histone H1 has a key role in establishing and maintaining higher order chromatin structure and in regulating gene expression. Mammals express up to 11 different H1 variants, with H1.2 and H1.4 being the predominant ones in most somatic cells. Like core histones, H1 has high levels of covalent modifications; however, the full set of modifications and their biological role are largely unknown. Results: In this study, we used a candidate screen to identify enzymes that methylate H1 and to map their corresponding methylation sites. We found that the histone lysine methyltransferases G9a/KMT1C and Glp1/KMT1D methylate H1.2 in vitro and in vivo, and we mapped this novel site to lysine 187 (H1.2K187) in the C-terminus of H1. This H1.2K187 methylation is variant-specific. The main target for methylation by G9a in H1.2, H1.3, H1.5 and H1.0 is in the C-terminus, whereas H1.4 is preferentially methylated at K26 (H1.4K26me) in the N-terminus. We found that the readout of these marks is different; H1.4K26me can recruit HP1, but H1.2K187me cannot. Likewise, JMJD2D/KDM4 only reverses H1.4K26 methylation, clearly distinguishing these two methylation sites. Further, in contrast to C-terminal H1 phosphorylation, H1.2K187 methylation level is steady throughout the cell cycle. Conclusions: We have characterised a novel methylation site in the C-terminus of H1 that is the target of G9a/Glp1 both in vitro and in vivo. To our knowledge, this is the first demonstration of variant-specific histone methylation by the same methyltransferases, but with differing downstream readers, thereby supporting the hypothesis of H1 variants having specific functions.
Language	English
Publishing date	2010-03-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2462129-8
ISSN	1756-8935 ; 1756-8935
ISSN (online)	1756-8935
ISSN	1756-8935
DOI	10.1186/1756-8935-3-7
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Article ; Online: Coinhibitory suppression of T cell activation by CD40 protects against obesity and adipose tissue inflammation in mice.

Wolf, Dennis / Jehle, Felix / Michel, Nathaly Anto / Bukosza, Eva Nora / Rivera, Jennifer / Chen, Yung Chih / Hoppe, Natalie / Dufner, Bianca / Rodriguez, Alexandra Ortiz / Colberg, Christian / Nieto, Leandro / Rupprecht, Benjamin / Wiedemann, Ansgar / Schulte, Lisa / Peikert, Alexander / Bassler, Nicole / Lozhkin, Andrey / Hergeth, Sonja Patricia / Stachon, Peter /

Hilgendorf, Ingo / Willecke, Florian / von Zur Mühlen, Constantin / von Elverfeldt, Dominik / Binder, Christoph J / Aichele, Peter / Varo, Nerea / Febbraio, Mark A / Libby, Peter / Bode, Christoph / Peter, Karlheinz / Zirlik, Andreas

Circulation

2014 Volume 129, Issue 23, Page(s) 2414–2425

Abstract: Background: Costimulatory cascades such as the CD40L-CD40 dyad enhance immune cell activation and inflammation during atherosclerosis. Here, we tested the hypothesis that CD40 directly modulates traits of the metabolic syndrome in diet-induced obesity ... ...

Abstract	Background: Costimulatory cascades such as the CD40L-CD40 dyad enhance immune cell activation and inflammation during atherosclerosis. Here, we tested the hypothesis that CD40 directly modulates traits of the metabolic syndrome in diet-induced obesity in mice. Methods and results: To induce the metabolic syndrome, wild-type or CD40(-/-) mice consumed a high-fat diet for 20 weeks. Unexpectedly, CD40(-/-) mice exhibited increased weight gain, impaired insulin secretion, augmented accumulation of inflammatory cells in adipose tissue, and enhanced proinflammatory gene expression. This proinflammatory and adverse metabolic phenotype could be transplanted into wild-type mice by reconstitution with CD40-deficient lymphocytes, indicating a major role for CD40 in T or B cells in this context. Conversely, therapeutic activation of CD40 signaling by the stimulating antibody FGK45 abolished further weight gain during the study, lowered glucose levels, improved insulin sensitivity, and suppressed adipose tissue inflammation. Mechanistically, CD40 activation decreased the expression of proinflammatory cytokines in T cells but not in B cells or macrophages. Finally, repopulation of lymphocyte-free Rag1(-/-) mice with CD40(-/-) T cells provoked dysmetabolism and inflammation, corroborating a protective role of CD40 on T cells in the metabolic syndrome. Finally, levels of soluble CD40 showed a positive association with obesity in humans, suggesting clinical relevance of our findings. Conclusions: We present the surprising finding that CD40 deficiency on T cells aggravates whereas activation of CD40 signaling improves adipose tissue inflammation and its metabolic complications. Therefore, positive modulation of the CD40 pathway might describe a novel therapeutic concept against cardiometabolic disease.
MeSH term(s)	Adipocytes/immunology ; Adipocytes/metabolism ; Adipose Tissue/immunology ; Adoptive Transfer ; Animals ; Atherosclerosis/genetics ; Atherosclerosis/immunology ; Atherosclerosis/metabolism ; CD40 Antigens/genetics ; CD40 Antigens/immunology ; CD40 Ligand/immunology ; CD40 Ligand/metabolism ; Humans ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/metabolism ; Insulin Resistance/genetics ; Insulin Resistance/immunology ; Lymphocyte Activation/immunology ; Male ; Metabolic Syndrome/genetics ; Metabolic Syndrome/immunology ; Metabolic Syndrome/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Obesity/genetics ; Obesity/immunology ; Obesity/metabolism ; Signal Transduction/immunology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	CD40 Antigens ; CD40 Ligand (147205-72-9)
Language	English
Publishing date	2014-06-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.113.008055
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Article: Interruption of classic CD40L-CD40 signalling but not of the novel CD40L-Mac-1 interaction limits arterial neointima formation in mice

Thrombosis and Haemostasis

2014 Volume 111, Issue 08, Page(s) 379–389

Abstract: The co-stimulatory immune molecule CD40L figures prominently in a variety of inflammatory conditions including arterial disease. Recently, we made the surprising finding that CD40L mediates atherogenesis independently of its classic receptor CD40 via a ... ...

Abstract	The co-stimulatory immune molecule CD40L figures prominently in a variety of inflammatory conditions including arterial disease. Recently, we made the surprising finding that CD40L mediates atherogenesis independently of its classic receptor CD40 via a novel interaction with the leukocyte integrin Mac-1. Here, we hypothesised that selective blockade of the CD40L-Mac-1 interaction may also retard restenosis. We induced neointima formation in C57/BL6 mice by ligation of the left carotid artery. Mice were randomised to daily intraperitoneal injections of either cM7, a small peptide selectively inhibiting the CD40L-Mac-1 interaction, scM7, a scrambled control peptide, or saline for 28 days. Interestingly, cM7-treated mice developed neointima of similar size compared with mice receiving the control peptide or saline as assessed by computer-assisted analysis of histological cross sections. These data demonstrate that the CD40L-Mac-1 interaction is not required for the development of restenosis. In contrast, CD40-deficient mice subjected to carotid ligation in parallel, developed significantly reduced neointimal lesions compared with respective wild-type controls (2872 ± 843 µm² vs 35469 ± 11870 µm²). Flow cytometry in CD40-deficient mice revealed reduced formation of platelet-granulocyte and platelet-inflammatory monocyte-aggregates. In vitro, supernatants of CD40-deficient platelet-leukocyte aggregates attenuated proliferation and increased apoptosis of smooth muscle cells. Unlike in the setting of atherosclerosis, CD40L mediates neointima formation via its classic receptor CD40 rather than via its recently described novel interaction with Mac-1. Therefore, selective targeting of CD40L-Mac-1 binding does not appear to be a favorable strategy to fight restenosis.
Keywords	Inflammation ; CD40L ; CD40 ; Mac-1 ; restenosis ; neointima formation ; mice
Language	English
Publishing date	2014-01-01
Publisher	Schattauer GmbH
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1160/TH13-08-0653
Database	Thieme publisher's database

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Article ; Online: Histone H1 variant-specific lysine methylation by G9a/KMT1C and Glp1/KMT1D

Weiss Thomas / Hergeth Sonja / Zeissler Ulrike / Izzo Annalisa / Tropberger Philipp / Zee Barry M / Dundr Miroslav / Garcia Benjamin A / Daujat Sylvain / Schneider Robert

Epigenetics & Chromatin, Vol 3, Iss 1, p

2010 Volume 7

Abstract: Abstract Background The linker histone H1 has a key role in establishing and maintaining higher order chromatin structure and in regulating gene expression. Mammals express up to 11 different H1 variants, with H1.2 and H1.4 being the predominant ones in ... ...

Abstract	Abstract Background The linker histone H1 has a key role in establishing and maintaining higher order chromatin structure and in regulating gene expression. Mammals express up to 11 different H1 variants, with H1.2 and H1.4 being the predominant ones in most somatic cells. Like core histones, H1 has high levels of covalent modifications; however, the full set of modifications and their biological role are largely unknown. Results In this study, we used a candidate screen to identify enzymes that methylate H1 and to map their corresponding methylation sites. We found that the histone lysine methyltransferases G9a/KMT1C and Glp1/KMT1D methylate H1.2 in vitro and in vivo , and we mapped this novel site to lysine 187 (H1.2K187) in the C-terminus of H1. This H1.2K187 methylation is variant-specific. The main target for methylation by G9a in H1.2, H1.3, H1.5 and H1.0 is in the C-terminus, whereas H1.4 is preferentially methylated at K26 (H1.4K26me) in the N-terminus. We found that the readout of these marks is different; H1.4K26me can recruit HP1, but H1.2K187me cannot. Likewise, JMJD2D/KDM4 only reverses H1.4K26 methylation, clearly distinguishing these two methylation sites. Further, in contrast to C-terminal H1 phosphorylation, H1.2K187 methylation level is steady throughout the cell cycle. Conclusions We have characterised a novel methylation site in the C-terminus of H1 that is the target of G9a/Glp1 both in vitro and in vivo . To our knowledge, this is the first demonstration of variant-specific histone methylation by the same methyltransferases, but with differing downstream readers, thereby supporting the hypothesis of H1 variants having specific functions.
Keywords	Genetics ; QH426-470 ; Biology (General) ; QH301-705.5 ; Science ; Q ; DOAJ:Genetics ; DOAJ:Biology ; DOAJ:Biology and Life Sciences
Subject code	570
Language	English
Publishing date	2010-03-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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