The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages

The molecular basis of signal-dependent transcriptional activation has been extensively studied in macrophage polarization, but our understanding remains limited regarding the molecular determinants of repression. Here we show that IL-4-activated STAT6 transcription factor is required for the direct transcriptional repression of a large number of genes during in vitro and in vivo alternative macrophage polarization. Repression results in decreased lineage-determining transcription factor, p300, and RNA polymerase II binding followed by reduced enhancer RNA expression, H3K27 acetylation, and chromatin accessibility. The repressor function of STAT6 is HDAC3 dependent on a subset of IL-4-repressed genes. In addition, STAT6-repressed enhancers show extensive overlap with the NF-kappaB p65 cistrome and exhibit decreased responsiveness to lipopolysaccharide after IL-4 stimulus on a subset of genes. As a consequence, macrophages exhibit diminished inflammasome activation, decreased IL-1beta production, and pyroptosis. Thus, the IL-4-STAT6 signaling pathway establishes an alternative polarization-specific epigenenomic signature resulting in dampened macrophage responsiveness to inflammatory stimuli

The IL-4/STAT6/PPARgamma signaling axis is driving the expansion of the RXR heterodimer cistrome, providing complex ligand responsiveness in macrophages

Retinoid X receptor (RXR) is an obligate heterodimeric partner of several nuclear receptors (NRs), and as such a central component of NR signaling regulating the immune and metabolic phenotype of macrophages. Importantly, the binding motifs of RXR heterodimers are enriched in the tissue-selective open chromatin regions of resident macrophages, suggesting roles in subtype specification. Recent genome-wide studies revealed that RXR binds to thousands of sites in the genome, but the mechanistic details how the cistrome is established and serves ligand-induced transcriptional activity remained elusive. Here we show that IL-4-mediated macrophage plasticity results in a greatly extended RXR cistrome via both direct and indirect actions of the transcription factor STAT6. Activation of STAT6 leads to chromatin remodeling and RXR recruitment to de novo enhancers. In addition, STAT6 triggers a secondary transcription factor wave, including PPARgamma. PPARgamma appears to be indispensable for the development of RXR-bound de novo enhancers, whose activities can be modulated by the ligands of the PPARgamma:RXR heterodimer conferring ligand selective cellular responses. Collectively, these data reveal the mechanisms leading to the dynamic extension of the RXR cistrome and identify the lipid-sensing enhancer sets responsible for the appearance of ligand-preferred gene signatures in alternatively polarized macrophages

Genotoxikus hatásra bekövetkező funkcionális és strukturális DNS változások = Functional and structural changes in DNA upon genotoxic effects

Morfológiai és biokémiai vizsgálataink arra utalnak, hogy a a genotoxikus hatások kategorizálhatók az okozott kromatin változások alapján. A kemotoxikus változások potenciális diagnosztikus jelentősége miatt vizsgáltuk a nehézfémek (elsősosrban kadmium) (Banfalvi et al., 2005), a gamma sugárzás (Nagy et al., 2004), az UVB sugárzás (Ujvárosi et al., 2007) és a carcinogén (dimetilnitrózamin) hatására bekövetkező kromatin változásokat (Trencsényi et al., 2007). Kadmium kezelés jellegzetes szakadásokat és nagy lyukakat hozott létre a sejtmagban. A gamma sugárzás preapoptotikus hatására: a. a sejtek és sejtmagok mérete megnőtt, b. DNA tartalmuk a sejtciklus minden szakaszában kisebb volt a normál kezeletlen populációhoz képest, c. a sejtciklus a korai S fázisban leállt (2,4 C értéknél), d. a kromatin kondenzálás annak fibrilláris szakaszában akadt el, e. az apoptotikus testek száma és nagysága a sejtciklus haladásávalfordítva arányos: sok apró apoptotikus testtel az S fázis elején és kevés nagy apoptotikus testtel az S fázis végén. A CHO sejtekben mért vizsgálatokat humán K562 sejteken megerősítettük. UVB sugárzás hatására a kromoszómák nem voltak láthatók, a sérülés hatására vékony összefüggő kromatin fátyol vonta be mind az interfázisos, mind a metafázisos kromoszómákat. | Morphological and biochemical studies after genotoxic treatments suggest that the consequences of various chromatin injuries can be categorized based on the assessment of injury-specific chromatin changes. Due to its diagnostic significance, we have started to determine and systematize the effects of heavy metals, primarily cadmium treatment (Banfalvi et al., 2005), gamma irradiation (Nagy et al., 2004) and UV irradiation (Ujvarosi et al., 2007). After cadmium treatment and have seen the same large extensive disruptions and holes in the nuclear membrane and sticky incompletely folded chromosomes typical for cadmium treatment (Nagy et al., 2004; Banfalvi et al., 2007). Preapoptotic changes upon γ-irradiation manifested as: (a) The cellular and nuclear sizes increased. (b) The DNA content was lower in each elutriated subpopulation of cells. (c) The progression of the cell cycle was arrested in the early S phase at 2.4 C value. (d) The chromatin condensation was blocked at its fibrillary stage. (e) The number and size of apoptotic bodies were inversely correlated with the progression of the cell cycle, with many small apoptotic bodies in early S phase and less but larger apoptotic bodies in late S phase (Nagy et al., 2004). Similar observations were made in K562 cells (Banfalvi et al., 2007). UV irradiation blocked chromatin condensation at its fibrillary stage, nuclear structures were blurred and covered with fibrillary chromatin, neither interphase nor metaphase chromosomes were visible

A sportgenetikai kutatási eredmények áttekintése és gyakorlati alkalmazásuk lehetőségei = Review of Genetic Research and Testing in Sport

Az utóbbi években megerősítést nyert a fizikai teljesítmény jelentős mértékű genetikai meghatározottsága. Emellett a sportoláshoz köthető sérülésekre és betegségekre való genetikai hajlamról is egyre nagyobb ismeretanyag áll rendelkezésünkre. A teljesítményt befolyásoló génpolimorfizmusok vizsgálata lehetőséget kínál a sportági kiválasztási rendszer fejlesztésére. A sportoló genetikai profiljának ismerete a jövőben lehetővé teszi a személyre szabott edzésprogram kidolgozását és ezáltal a teljesítmény potenciális növelését. A genetikai tesztek a jövőben fontos szerepet játszhatnak a sérülések és a betegségek genetikai kockázati tényezőinek szűrésében is. There is compelling evidence for a genetic contribution to physical performance. In addition, there is an advanced scientific knowledge on the predisposition to sports-related diseases and injuries. Genetic testing of performance related polymorphisms can serve as a new opportunity for developing the process of talent selection. Sport-related genetic information may also allow for individualization of the training and improve performance. Genetic testing may also play an important role in the pre-participation screening for injuries and disease risks

A családi halmozódású petefészekrák genetikai és onkológiai ellátása = Management of hereditary ovarian cancer

A családi halmozódást mutató petefészek- és emlőrákok többségéért a BRCA1/2 gének mutációi felelősek. A rosszindulatú petefészek-daganatok hozzávetőleg 10%-a alakul ki a BRCA1/2 gének csíravonalbeli mutációja következtében. A daganatok többsége serosus és endometrioid szövettani típusú és rosszul differenciált. A mutációkat hordozó nők esetében a 40 éves életkor elérésekor vagy a családterv lezárásakor kockázatcsökkentő salpingo-oophorectomia javasolt. Napjainkban nincsen különbség a sporadikus és a herediter petefészekrákok kezelése között, bár a BRCA1/2 mutációk jelenlétekor a célzott terápia nagyobb hatékonyságát észlelték. A retrospektív tanulmányokban a mutációk fennállásakor a platinaszármazékokkal szemben érzékenyebbek voltak a daganatok, és a korai vizsgálatok szerint a mutációt hordozó, előrehaladott petefészekrákban szenvedők esetében hatékonyabb volt a poli-ADP-ribóz polimeráz gátlóival történő kezelés is. Ezeknek a szereknek a kemoprevencióban is szerepe lehet. Közleményünkben a családi halmozódású petefészekrák ellátásának elveit foglaljuk össze. Orv. Hetil., 2011, 152, 1596–1608. | Mutations in BRCA1 and BRCA2 genes account for the majority of hereditary breast and ovarian cancers. Approximately 10% of cases of ovarian cancer are due to germline mutations in BRCA1 and BRCA2. Ovarian cancer associated with BRCA1 and BRCA2 mutations has a distinct histological phenotype. This type of cancer is predominantly of serous or endometrioid histology and is high grade. Patients with BRCA1 or BRCA2 mutations should be offered risk-reducing salpingo-oophorectomy by age 40 years, or when childbearing is complete. Nowadays there are no differences between the treatments provided for sporadic and hereditary ovarian cancer, although there are indications that targeted therapy is effective in women with BRCA1/BRCA2-associated tumors. Retrospective studies reveal a high level of sensitivity to platinum agents in BRCA-associated tumors and initial trials show good efficacy and tolerability for polyADP-ribose polymerase inhibitors in mutation carriers with advanced ovarian cancers. These agents might also potentially be used in chemoprevention. Authors review the current management of hereditary ovarian cancer. Orv. Hetil., 2011, 152, 1596–1608

The role of transforming growth factor-beta in Marfan syndrome

The starting point, in Marfan syndrome (MFS) appears to be the mutation of fi brillin-1 gene whose deconstructed protein product cannot bind transforming growth factor beta (TGF-b), leading to an increased TGF-b tissue level. The aim of this review is to review the already known features of the cellular signal transduction downstream to TGF-b and its impact onthe tissue homeostasis of microfibrils, and elastic fi bers. We also investigate current data onthe extracellular regulation of TGF-b level including mechanotransduction and the feedback cycles of integrin-dependent and independent activation of the latent TGF-b complex. Togetherthese factors, by the destruction of the connective tissue fi bers, may play an important role inthe development of the diverse cardiac and extracardiac manifestations of MFS and many of them could be a target of conservative treatment. We present currently investigated drugs for thetreatment of the syndrome, and explore possible avenues of research into pathogenesis of MFS in order to improve understanding of the disease

Peripheral blood derived gene panels predict response to infliximab in rheumatoid arthritis and Crohn’s disease

Background: Biological therapies have been introduced for the treatment of chronic inflammatory diseases including rheumatoid arthritis (RA) and Crohn's disease (CD). The efficacy of biologics differs from patient to patient. Moreover these therapies are rather expensive, therefore treatment of primary non-responders should be avoided. Method: We addressed this issue by combining gene expression profiling and biostatistical approaches. We performed peripheral blood global gene expression profiling in order to filter the genome for target genes in cohorts of 20 CD and 19 RA patients. Then RT-quantitative PCR validation was performed, followed by multivariate analyses of genes in independent cohorts of 20 CD and 15 RA patients, in order to identify sets ofinterrelated genes that can separate responders from non-responders to the humanized chimeric anti-TNFalpha antibody infliximab at baseline. Results: Gene panels separating responders from non-responders were identified using leave-one-out cross-validation test, and a pool of genes that should be tested on larger cohorts was created in both conditions. Conclusions: Our data show that peripheral blood gene expression profiles are suitable for determining gene panels with high discriminatory power to differentiate responders from non-responders in infliximab therapy at baseline in CD and RA, which could be cross-validated successfully. Biostatistical analysis of peripheral blood gene expression data leads to the identification of gene panels that can help predict responsiveness of therapy and support the clinical decision-making process

Az apolipoprotein E genotípusok összefüggése cardiovascularis betegségek kialakulásával = Connections Between Apolipoprotein E Genotypes and the Development of Cardiovascular Diseases

Elevated plasma lipid level is one of the main risk factors for cardiovascular diseases, which are considered to be pimary causes of death. Apolipoprotein E plays a part in the lipid transport in the blood, thus polimophisms of that affect the lipid composition of the plasma. The three most common alleles of apolipoprotein E are e2, e3, e4. Out of the two non-wild type alleles, the e2 and e4, the latter was shown to play a role in the development of cardiovascular diseases and Alzheimer’s disease. Some studies mention the e2/e2 homozygote genotype as one of the causes of hyperlipoproteinemia type III. Besides lipid metabolism, apolipoprotein E also influences the manifestation of cardiovascular diseases through other biochemical pathways, therefore it is essential to explore the molecular background of these metabolic pathways. Orv. Hetil., 2012, 153, 2070–2076.</jats:p

Phase Structure and Compactness

In order to study the influence of compactness on low-energy properties, we compare the phase structures of the compact and non-compact two-dimensional multi-frequency sine-Gordon models. It is shown that the high-energy scaling of the compact and non-compact models coincides, but their low-energy behaviors differ. The critical frequency $\beta^2 = 8\pi$ at which the sine-Gordon model undergoes a topological phase transition is found to be unaffected by the compactness of the field since it is determined by high-energy scaling laws. However, the compact two-frequency sine-Gordon model has first and second order phase transitions determined by the low-energy scaling: we show that these are absent in the non-compact model.Comment: 21 pages, 5 figures, minor changes, final version, accepted for publication in JHE