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-κB 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-1β 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

Synthesis of arylsulfonyl Isocyanates and sulfonylurea type herbicides via catalytic carbonylation of sulfonamide derivatives

[Synopsis] Palladium complexes are active catalysts in converting salts of N-chloroarylsulfonamides, N-(arylsulfonyl)iodoimines and N-(arylsulfonyl)selenilmines into arylsulfonyl isocyanates which are intermediates in manufacturing sulfonylurea type herbicides. Potassium N-chloroarylsulfonamidates are more advantageous starting materials that the analogous sodium derivatives. Application of acetonitrile as a solvent in the catalytic carbonylation of N-chloroarylsulfonamidates allowed to reduce the catalyst/substrate ratio and the CO pressure as compared to those used with chlorinated hydrocarbons. Palladium complexes with coordinated arylsulfonylnitrene ligands are thought to play a key role in these reactions

Synthesis of arylsulfonyl Isocyanates and sulfonylurea type herbicides via catalytic carbonylation of sulfonamide derivatives

none[Synopsis] Palladium complexes are active catalysts in converting salts of N-chloroarylsulfonamides, N-(arylsulfonyl)iodoimines and N-(arylsulfonyl)selenilmines into arylsulfonyl isocyanates which are intermediates in manufacturing sulfonylurea type herbicides. Potassium N-chloroarylsulfonamidates are more advantageous starting materials that the analogous sodium derivatives. Application of acetonitrile as a solvent in the catalytic carbonylation of N-chloroarylsulfonamidates allowed to reduce the catalyst/substrate ratio and the CO pressure as compared to those used with chlorinated hydrocarbons. Palladium complexes with coordinated arylsulfonylnitrene ligands are thought to play a key role in these reactions

RXR heterodimers orchestrate transcriptional control of neurogenesis and cell fate specification

Retinoid X Receptors (RXRs) are unique and enigmatic members of the nuclear receptor (NR) family with extensive and complex biological functions in cellular differentiation. On the one hand, RXRs through permissive heterodimerization with other NRs are able to integrate multiple lipid signaling pathways and are believed to play a central role to coordinate the development of the central nervous system. On the other hand, RXRs may have heterodimer-independent functions as well. Therefore, a more RXR-centric analysis is warranted to identify its genomic binding sites and regulated gene networks, which are orchestrating the earliest events in neuronal differentiation. Recently developed genome-wide approaches allow systematic analyses of the RXR-driven neural differentiation. Here we applied next generation sequencing-based methodology to track the dynamic redistribution of the RXR cistrome along the path of embryonic stem cell to glutamatergic neuron differentiation. We identified Retinoic Acid Receptor (RAR) and Liver X Receptor (LXR) as dominant heterodimeric partners of RXR in these cellular stages. Our data presented here characterize the RAR:RXR and LXR:RXR-mediated transcriptional program in embryonic stem cells, neural progenitors and terminally differentiated neurons. Considering the growing evidence for dysregulated RXR-mediated signaling in neurodegenerative disorders, such as Alzheimer's Disease or Amyotrophic Lateral Sclerosis, the data presented here will be also a valuable resource for the field of neuro(patho)biology

OCT4 acts as an integrator of pluripotency and signal-induced differentiation

Cell type specification relies on the capacity of undifferentiated cells to properly respond to specific differentiation-inducing signals. Using genomic approaches along with loss- and gain-of-function genetic models, we identified OCT4-dependent mechanisms that provide embryonic stem cells with the means to customize their response to external cues. OCT4 binds a large set of low-accessible genomic regions. At these sites, OCT4 is required for proper enhancer and gene activation by recruiting co-regulators and RAR:RXR or {beta}-catenin, suggesting an unexpected collaboration between the lineage-determining transcription factor and these differentiation-initiating, signal-dependent transcription factors. As a proof of concept, we demonstrate that overexpression of OCT4 in a kidney cell line is sufficient for signal-dependent activation of otherwise unresponsive genes in these cells. Our results uncover OCT4 as an integral and necessary component of signal-regulated transcriptional processes required for tissue-specific responses