TNF/p38α/polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration

How regeneration cues are converted into the epigenetic information that controls gene expression in adult stem cells is currently unknown. We identified an inflammation-activated signaling in muscle stem (satellite) cells, by which the polycomb repressive complex 2 (PRC2) represses Pax7 expression during muscle regeneration. TNF-activated p38α kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzymatic subunit of the complex, leading to the formation of repressive chromatin on Pax7 promoter. TNF-α antibodies stimulate satellite cell proliferation in regenerating muscles of dystrophic or normal mice. Genetic knockdown or pharmacological inhibition of the enzymatic components of the p38/PRC2 signaling--p38α and EZH2--invariably promote Pax7 expression and expansion of satellite cells that retain their differentiation potential upon signaling resumption. Genetic knockdown of Pax7 impaired satellite cell proliferation in response to p38 inhibition, thereby establishing the biological link between p38/PRC2 signaling to Pax7 and satellite cell decision to proliferate or differentiate.     

Protein kinase signaling networks in cancer

Protein kinases orchestrate the activation of signaling cascades in response to extracellular and intracellular stimuli to control cell growth, proliferation, and survival. The complexity of numerous intracellular signaling pathways is highlighted by the number of kinases encoded by the human genome (539) and the plethora of phosphorylation sites identified in phosphoproteomic studies. Perturbation of these signaling networks by mutations or abnormal protein expression underlies the cause of many diseases including cancer. Recent RNAi screens and cancer genomic sequencing studies have revealed that many more kinases than anticipated contribute to tumorigenesis and are potential targets for inhibitor drug development intervention. This review will highlight recent insights into known pathways essential for tumorigenesis and discuss exciting new pathways for therapeutic intervention.     

Central Nervous System Regeneration Inhibitors and their Intracellular Substrates

Injury to the central nervous system (CNS) initiates a cascade of responses that is inhibitory to the regeneration of neurons and full recovery. At the site of injury, glial cells conspire with an inhibitory biochemical milieu to construct both physical and chemical barriers that prevent the outgrowth of axons to or beyond the lesion site. These inhibitors include factors derived from myelin, repulsive guidance cues, and chondroitin sulfate proteoglycans. Each bind receptors on the axon surface to initiating intracellular signaling cascades that ultimately result in cytoskeletal reorganization and growth cone collapse. Here, we present an overview of the molecules, receptors, and signaling pathways that inhibit CNS regeneration, with a particular focus on the intracellular signaling machinery that may function as convergent targets for multiple inhibitory ligands.     

Signaling mechanisms for chemotaxis

Cells recognize external chemical gradients and translate these environmental cues into amplified intracellular signaling that results in elongated cell shape, actin polymerization toward the leading edge, and movement along the gradient. Mechanisms underlying chemotaxis are conserved evolutionarily from Dictyostelium amoeba to mammalian neutrophils. Recent studies have uncovered several parallel intracellular signaling pathways that crosstalk in chemotaxing cells. Here, we review these signaling mechanisms in Dictyostelium discoideum.     

An extracellular signal-regulated kinase 1- and 2-dependent program of chromatin trafficking of c-Fos and Fra-1 is required for cyclin D1 expression during cell cycle reentry

Mitogens activate cell signaling and gene expression cascades that culminate in expression of cyclin D1 during the G(0)-to-G(1) transition of the cell cycle. Using cell cycle arrest in response to oxidative stress, we have delineated a dynamic program of chromatin trafficking of c-Fos and Fra-1 required for cyclin D1 expression during cell cycle reentry. In serum-stimulated lung epithelial cells, c-Fos was expressed, recruited to chromatin, phosphorylated at extracellular signal-regulated kinase 1- and 2 (ERK1,2)-dependent sites, and degraded prior to prolonged recruitment of Fra-1 to chromatin. Immunostaining showed that expression of nuclear c-Fos and that of cyclin D1 are mutually exclusive, whereas nuclear Fra-1 and cyclin D1 are coexpressed as cells traverse G(1). Oxidative stress prolonged the accumulation of phospho-ERK1,2 and phospho-c-Fos on chromatin, inhibited entry of Fra-1 into the nucleus, and blocked cyclin D1 expression. After induction of the immediate-early gene response in the presence of oxidative stress, inhibition of ERK1,2 signaling promoted degradation of c-Fos, recruitment of Fra-1 to chromatin, and expression of cyclin D1. Our data indicate that termination of nuclear ERK1,2 signaling is required for an exchange of Fra-1 for c-Fos on chromatin and initiation of cyclin D1 expression at the G(0)-to-G(1) transition of the cell cycle.     

Dexras1: shaping the responsiveness of the circadian clock

Living organisms are endowed with an autonomous timekeeping program that not only maintains circadian rhythms of behaviour and physiology but is reset by cues from the external, cyclic environment. Intracellular signaling events that mediate entrainment of the mammalian circadian clock by photic (light) as well as non-photic inputs are only beginning to be elucidated. Dexras1 is a novel Ras-like G protein that modulates multiple signaling cascades. Genetic ablation of Dexras1 in mice (dexras1(-/-)) results in altered responsiveness of the master circadian clock to photic and non-photic cues. This review will attempt to provide mechanistic insights into the involvement of Dexras1 in biological timing processes based on its role as a modulator of signal transduction.     

染色质可及性分析的研究进展

在细胞核内,染色质可及性模式会随着外部刺激和发育线索的改变而发生动态变化。染色质可及性重构对于基因表达调控至关重要,在建立和维持细胞特性等方面发挥着重要作用。因此开展染色质可及性的研究对染色质功能上的三维解析具有十分重要的意义。近几年,随着高通量测序技术的进步以及测序成本的降低,基于高通量测序技术的染色质可及性分析方法得到了迅速发展。目前观察和分析全基因组染色质开放与否的常见技术主要有脱氧核糖核酸酶I超敏位点测序（DNase-seq）、微球菌核酸酶测序（MNase-seq）、甲醛辅助分离调控元件测序（FAIRE-seq）以及转座酶可及性测序（ATAC-seq）。本文比较了这4种染色质可及性分析技术的优缺点,详细介绍了它们的原理及主要实验流程,并简要讨论了它们的发展及相关技术的应用,期望通过这些互补的方法为染色质分析领域的未来发展提供一些借鉴和思路。