511 research outputs found
Epigenomic regulation of macrophage polarization: Where do the nuclear receptors belong?
Our laboratory has a long-standing research interest in understanding how lipid-activated transcription factors, nuclear hormone receptors, contribute to dendritic cell and macrophage gene expression regulation, subtype specification, and responses to a changing extra and intracellular milieu. This journey in the last more than two decades took us from identifying target genes for various RXR heterodimers to systematically mapping nuclear receptor-mediated pathways in dendritic cells to identifying hierarchies of transcription factors in alternative polarization in macrophages to broaden the role of nuclear receptors beyond strictly ligand-regulated gene expression. We detail here the milestones of the road traveled and draw conclusions regarding the unexpectedly broad role of nuclear hormone receptors as epigenomic components of dendritic cell and macrophage gene regulation as we are getting ready for the next challenges
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
Az Ojos del Salado monitoring vizsgálata: jég- és vízjelenlét a Föld legszárazabb magashegységében
Adatok a magashegyi sivatag felszíne alól - avagy víz és jég a Föld legszárazabb magashegységén, az Ojos del Saladón
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
Antifungal Activity of an Original Amino-Isocyanonaphthalene (ICAN) Compound Family: Promising Broad Spectrum Antifungals
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Optimised selenium enrichment of Artemia Sp. Feed to improve red drum (Sciaenops Ocellatus) larvae rearing
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Amyloid ß-fibrillumok nanomechanikája = Nanomechanics of amyloid ß-fibrils
Pályázatban amiloid béta (Aß) fibrillumokat, és ehhez kapcsolódóan hasonló természetű amiloid fibrillumokat és egyéb fibrilláris biomolekuláris rendszereket vizsgáltunk. A kísérletekben atomerőmikroszkóp segítségével vizsgáltuk a fibrillumok topográfiai szerkezetét és mechanikai erővezérelt szerkezeti átalakulásait. Különböző amiloid fibrillumok nanomechanikai ujjlenyomatát mértük meg. Felfedeztük, hogy az Aß peptid egy fragmentuma, az Aß25-35, trigonálisan orientált hálózatot hoz létre csillám felszínen. Ez nanotechnológiai alkalmazások lehetőségét veti fel, amellyel kapcsolatban szabadalmi bejelentést indítottunk el. Új mérési technológiákat fejesztettünk ki: térben és időben szinkronizált TIRF/AFM, illetve pásztázó próba kimográfia. A nanomechanikai módszereinket sikerrel adaptáltuk intermedier filamentumokra és miozin vastag filamentumokra. | In this grant proposal we have investigated te properties of amyloid beta (Aß) fibrils and other relevant amyoids and fibrillar biomolecular systems. In our experiments the topographical structure and mechanical force-driven structural changes of the fibrils were explored by using atomic force microscopy(AFM). We measured the nanomechanical fingerprint of various amyloid fibrils. We discovered that a toxic fragment of the full-length Aßpeptide, Aß25-35, forms a trigonally oriented network on mice. The phenomenon opens the possiblity towards nanotechnological applications. Based on this we filed a preliminary patent application (US 61/058,244). We developed novel methodologies: spatially and temporally resolved TIRF/AFM, scanning force kymography. Our nanomechanical methods were implemented on yet unexplored biomolecular systems: intermediate filaments and myosin thick filaments
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