Human embryonic stem cells (hESCs) share an identical genome with lineage-committed cells, yet possess the remarkable properties of self-renewal and pluripotency. The diverse cellular properties in ...different cells have been attributed to their distinct epigenomes, but how much epigenomes differ remains unclear. Here, we report that epigenomic landscapes in hESCs and lineage-committed cells are drastically different. By comparing the chromatin-modification profiles and DNA methylomes in hESCs and primary fibroblasts, we find that nearly one-third of the genome differs in chromatin structure. Most changes arise from dramatic redistributions of repressive H3K9me3 and H3K27me3 marks, which form blocks that significantly expand in fibroblasts. A large number of potential regulatory sequences also exhibit a high degree of dynamics in chromatin modifications and DNA methylation. Additionally, we observe novel, context-dependent relationships between DNA methylation and chromatin modifications. Our results provide new insights into epigenetic mechanisms underlying properties of pluripotency and cell fate commitment.
► 11 histone modifications mapped in human embryonic stem cells and fibroblasts ► Dramatic redistributions of repressive H3K9me3 and H3K27me3 marks ► Context-dependent relationship between DNA methylation and chromatin modifications ► Multiple distinct modes of repression of genes important for pluripotency
Naive CD4+ T cells can differentiate into specific helper and regulatory T cell lineages in order to combat infection and disease. The correct response to cytokines and a controlled balance of these ...populations is critical for the immune system and the avoidance of autoimmune disorders. To investigate how early cell-fate commitment is regulated, we generated the first human genome-wide maps of histone modifications that reveal enhancer elements after 72 hr of in vitro polarization toward T helper 1 (Th1) and T helper 2 (Th2) cell lineages. Our analysis indicated that even at this very early time point, cell-specific gene regulation and enhancers were at work directing lineage commitment. Further examination of lineage-specific enhancers identified transcription factors (TFs) with known and unknown T cell roles as putative drivers of lineage-specific gene expression. Lastly, an integrative analysis of immunopathogenic-associated SNPs suggests a role for distal regulatory elements in disease etiology.
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•The first genome-wide maps of enhancer elements used in early Th1 and Th2 cell-lineage commitment•Lineage-specific enhancers are mapped to nucleosome-free resolution•Enhancers overlap SNPs associated with autoimmune disorders•SNPs often occur at enhancers within TF binding-site motifs
The human body is composed of diverse cell types with distinct functions. Although it is known that lineage specification depends on cell-specific gene expression, which in turn is driven by ...promoters, enhancers, insulators and other cis-regulatory DNA sequences for each gene, the relative roles of these regulatory elements in this process are not clear. We have previously developed a chromatin-immunoprecipitation-based microarray method (ChIP-chip) to locate promoters, enhancers and insulators in the human genome. Here we use the same approach to identify these elements in multiple cell types and investigate their roles in cell-type-specific gene expression. We observed that the chromatin state at promoters and CTCF-binding at insulators is largely invariant across diverse cell types. In contrast, enhancers are marked with highly cell-type-specific histone modification patterns, strongly correlate to cell-type-specific gene expression programs on a global scale, and are functionally active in a cell-type-specific manner. Our results define over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalogue of human enhancers and highlighting the role of these elements in cell-type-specific gene expression.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
More than a pore: ion channel signaling complexes Lee, Amy; Fakler, Bernd; Kaczmarek, Leonard K ...
The Journal of neuroscience,
2014-Nov-12, 2014-11-12, 20141112, Letnik:
34, Številka:
46
Journal Article
Recenzirano
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Voltage- and ligand-gated ion channels form the molecular basis of cellular excitability. With >400 members and accounting for ∼1.5% of the human genome, ion channels are some of the most well ...studied of all proteins in heterologous expression systems. Yet, ion channels often exhibit unexpected properties in vivo because of their interaction with a variety of signaling/scaffolding proteins. Such interactions can influence the function and localization of ion channels, as well as their coupling to intracellular second messengers and pathways, thus increasing the signaling potential of these ion channels in neurons. Moreover, functions have been ascribed to ion channels that are largely independent of their ion-conducting roles. Molecular and functional dissection of the ion channel proteome/interactome has yielded new insights into the composition of ion channel complexes and how their dysregulation leads to human disease.
Natural language processing (NLP) is an effective tool for generating structured information from unstructured data, the one that is commonly found in clinical trial texts. Such interdisciplinary ...research has gradually grown into a flourishing research field with accumulated scientific outputs available. In this study, bibliographical data collected from Web of Science, PubMed, and Scopus databases from 2001 to 2018 had been investigated with the use of three prominent methods, including performance analysis, science mapping, and, particularly, an automatic text analysis approach named structural topic modeling. Topical trend visualization and test analysis were further employed to quantify the effects of the year of publication on topic proportions. Topical diverse distributions across prolific countries/regions and institutions were also visualized and compared. In addition, scientific collaborations between countries/regions, institutions, and authors were also explored using social network analysis. The findings obtained were essential for facilitating the development of the NLP-enhanced clinical trial texts processing, boosting scientific and technological NLP-enhanced clinical trial research, and facilitating inter-country/region and inter-institution collaborations.
With the growing availability and popularity of sentiment-rich resources like blogs and online reviews, new opportunities and challenges have emerged regarding the identification, extraction, and ...organization of sentiments from user-generated documents or sentences. Recently, many studies have exploited lexicon-based methods or supervised learning algorithms to conduct sentiment analysis tasks separately; however, the former approaches ignore contextual information of sentences and the latter ones do not take sentiment information embedded in sentiment words into consideration. To tackle these limitations, we propose a new model named Sentiment Convolutional Neural Network (SentiCNN) to analyze the sentiments of sentences with both contextual and sentiment information of sentiment words, in which, contextual information is captured from word embeddings and sentiment information is identified using existing lexicons. We incorporate a Highway Network into our model to adaptively combine sentiment and contextual information from sentences by strengthening the connection between features of both sentences and their sentiment words. Furthermore, we propose three lexicon-based attention mechanisms (LBAMs) for our SentiCNN model to find the most important indicators of sentiments and make predictions more effectively. Experiments over two well-known datasets indicate that sentiment words, the Highway Network, and LBAMs contribute to sentiment analysis.
Pluripotency, the ability of a cell to differentiate and give rise to all embryonic lineages, defines a small number of mammalian cell types such as embryonic stem （ES） cells. While it has been ...generally held that pluripotency is the product of a transcriptional regulatory network that activates and maintains the expression of key stem cell genes, accumulating evidence is pointing to a critical role for epigenetic processes in establishing and safeguarding the pluri-potency of ES cells, as well as maintaining the identity of differentiated cell types. In order to better understand the role of epigenetic mechanisms in pluripotency, we have examined the dynamics of chromatin modifications genome- wide in human ES cells （hESCs） undergoing differentiation into a mesendodermal lineage. We found that chromatin modifications at promoters remain largely invariant during differentiation, except at a small number of promoters where a dynamic switch between acetylation and methylation at H3K27 marks the transition between activation and silencing of gene expression, suggesting a hierarchy in cell fate commitment over most differentially expressed genes. We also mapped over 50 000 potential enhancers, and observed much greater dynamics in chromatin modifications, especially H3K4mel and H3K27ac, which correlate with expression of their potential target genes. Further analysis of these enhancers revealed potentially key transcriptional regulators of pluripotency and a chromatin signature indicative of a poised state that may confer developmental competence in hESCs. Our results provide new evidence supporting the role of chromatin modifications in defining enhancers and plnripotency.
Understanding mechanisms underlying titin regulation in cardiac muscle function is of critical importance given recent compelling evidence that highlight titin mutations as major determinants of ...human cardiomyopathy. We previously identified a cardiac biomechanical stress-regulated complex at the cardiac-specific N2B region of titin that includes four-and-a-half LIM domain protein-1 (Fhl1) and components of the mitogen-activated protein signaling cascade, which impacted muscle compliance in Fhl1 knock-out cardiac muscle. However, direct regulation of these molecular components in mediating titin N2B function remained unresolved. Here we identify Fhl1 as a novel negative regulator of titin N2B levels and phosphorylation-mediated mechanics. We specifically identify titin N2B as a novel substrate of extracellular signal regulated-kinase-2 (Erk2) and demonstrate that Fhl1 directly interferes with Erk2-mediated titin-N2B phosphorylation. We highlight the critical region in titin-N2B that interacts with Fhl1 and residues that are dependent on Erk2-mediated phosphorylation in situ. We also propose a potential mechanism for a known titin-N2B cardiomyopathy-causing mutation that involves this regulatory complex. These studies shed light on a novel mechanism regulating titin-N2B mechano-signaling as well as suggest that dysfunction of these pathways could be important in cardiac disease states affecting muscle compliance.
Background: Titin is critical for cardiac muscle function; however, limited knowledge exists of mechanisms important for its regulation.
Results: A four-and-a-half LIM domain protein-1/extracellular signal-regulated kinase-2-associated complex modulates titin-N2B levels, phosphorylation, and mechanics.
Conclusion: We reveal new mechanisms underlying titin mechano-signaling.
Significance: We advance our understanding of how titin-associated complexes/mutations can impact cardiac muscle function and disease.
The widely reported effects of oxytocin (OT) on CNS function has generated considerable interest in the therapeutic potential for targeting this system for a variety of human psychiatric diseases, ...including anxiety disorders, autism, schizophrenia, and depression. The utility of synthetic OT, as both a research tool and neurotherapeutic, is limited by the physiochemical properties inherent in most neuropeptides, notably its short half-life and poor blood brain barrier penetration. Subsequently, the discovery and development of non-peptide molecules that act as selective agonists of the oxytocin receptor (OTR) has been an important goal of the field. In this study, we report the receptor and behavioral pharmacology of WAY-267464, a first generation small-molecule OTR agonist. WAY-267464 is a high-affinity, potent, and selective (vs. V1a, V2, V1b) agonist of the OTR. In assays measuring both behavioral (four-plate test, elevated zero maze) and autonomic (stress-induced hyperthermia) parameters of the anxiety response, WAY-267464 exhibits an anxiolytic-like profile similar to OT. We have demonstrated that the anxiolytic-like profile of WAY-267464 is mediated through central sites of action. WAY-267464 also significantly reverses disruption in prepulse inhibition of the acoustic startle reflex induced by either MK-801 or amphetamine, similar to the antipsychotic-like effects previously reported for OT. Interestingly, in the mouse tail suspension test, WAY-267464 failed to produce changes in immobility that are seen with OT, raising the question of whether the antidepressant-like activity of OT may be working independently of the OTR. A selective OTR antagonist also failed to block the effects of OT on immobility in the TST. The significance of these findings for shaping the clinical development of OTR agonists is discussed.
The carboxyl-terminus of the type 1 angiotensin II receptor (AT1A) regulates receptor activation/deactivation and the amphipathic Helix 8 within the carboxyl-terminus is a high affinity interaction ...motif for plasma membrane lipids. We have used dual polarisation interferometry (DPI) to examine the role of phosphatidylinositdes in the specific recognition of Helix 8 in the AT1A receptor. A synthetic peptide corresponding to Leu(305) to Lys(325) (Helix 8 AT1A) discriminated between PIPs and different charges on lipid membranes. Peptide binding to PtdIns(4)P-containing bilayers caused a dramatic change in the birefringence (a measure of membrane order) of the bilayer. Kinetic modelling showed that PtdIns(4)P is held above the bilayer until the mass of bound peptide reaches a threshold, after which the peptides insert further into the bilayer. This suggests that Helix 8 can respond to the presence of PI(4)P by withdrawing from the bilayer, resulting in a functional conformational change in the receptor.
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