scholarly journals The epigenetic signature of CFTR expression is co-ordinated via chromatin acetylation through a complex intronic element

2007 ◽  
Vol 408 (3) ◽  
pp. 317-326 ◽  
Author(s):  
Thankam Paul ◽  
SiDe Li ◽  
Sanjeev Khurana ◽  
Neal S. Leleiko ◽  
Martin J. Walsh
Keyword(s):  
Transcription Factors ◽  
Cultured Cells ◽  
Therapeutic Potential ◽  
Gastrointestinal Disease ◽  
Regulatory Element ◽  
Cell Types ◽  
Intestinal Cell ◽  
Enhancer Element ◽  
Histone Deacetylase Inhibition ◽  
Regulatory Factors

The CFTR (cystic fibrosis transmembrane conductance regulator) gene is a tightly regulated and differentially expressed transcript in many mucosal epithelial cell types. It appears that DNA sequence variations alone do not explain CFTR-related gastrointestinal disease patterns and that epigenetic modifiers influence CFTR expression. Our aim was to characterize the native chromatin environment in cultured cells for intestinal CFTR expression by determining the relationship between histone acetylation and occupation of CFTR by multiple transcription factors, through a common regulatory element. We used HDAC (histone deacetylase) inhibition and ChIP (chromatin immunoprecipitation) analyses to define regions associated with acute acetylation of histone at the CFTR locus. We identified a region within the first intron associated with acute acetylation of histone H4 as an epigenetic signature corresponding to an intestine-specific enhancer element for CFTR. DHS (DNase I-hypersensitivity) assays and ChIP were used to specify control elements and occupation by regulatory factors. Quantitative ChIP procedures indicate that HNF1α (hepatic nuclear factor 1α) and Cdx2 (caudal homeobox protein 2) occupy and regulate through a novel intronic enhancer element of CFTR and that Tcf4 (T-cell factor 4) overlaps the same DNA element. RNAi (RNA interference) of Tcf4 and HNF1α decreased intestinal cell CFTR expression, identifying these as positive regulatory factors and CFTR as a target for Wnt signalling. We have linked the acetylation signature of nucleosomal histones to active intestinal CFTR expression and occupation by transcription factors HNF1α, Cdx2 and Tcf4 which converge to modify chromatin architecture. These studies suggest the therapeutic potential of histone modification strategies, such as inhibition of HDAC activity, to treat CFTR-associated disease by selectively enhancing CFTR expression.

scholarly journals The intersectional genetics landscape for human

2019 ◽  
Author(s):  
Andre Macedo ◽  
Alisson M. Gontijo
Keyword(s):  
Gene Expression ◽  
Therapeutic Potential ◽  
Regulatory Element ◽  
Logic Gate ◽  
Cell Types ◽  
Boolean Logic ◽  
Interindividual Variation ◽  
Model Organisms ◽  
Cell Type ◽  
Diagnostic Potential

The human body is made up of hundreds, perhaps thousands of cell types and states, most of which are currently inaccessible genetically. Genetic accessibility carries significant diagnostic and therapeutic potential by allowing the selective delivery of genetic messages or cures to cells. Research in model organisms has shown that single regulatory element (RE) activities are seldom cell type specific, limiting their usage in genetic systems designed to restrict gene expression posteriorly to their delivery to cells. Intersectional genetic approaches can increase the number of genetically accessible cells. A typical intersectional method acts like an AND logic gate by converting the input of two or more active REs into a single synthetic output, which becomes unique for that cell. Here, we systematically assessed the intersectional genetics landscape of human using a curated subset of cells from a large RE usage atlas obtained by Cap Analysis of Gene Expression Sequencing (CAGE-Seq) of thousands of primary and cancer cells (the FANTOM5 consortium atlas). We developed the heuristics and algorithms to retrieve and quality rank AND gate intersections intra- and inter-individually. We find that >90% of the 154 primary cell types surveyed can be distinguished from each other with as little as 3 to 4 active REs, with quantifiable safety and robustness. We call these minimal intersections of active REs with cell-type diagnostic potential “Versatile Entry Codes” (VEnCodes). We show that VEnCodes could be found for 100% of the 158 cancer cell types surveyed, and that most of these are highly robust to intra- and interindividual variation. Our tools for generating and quality-ranking VEnCodes can be adapted to other RE usage databases and to other intersectional methods using alternative Boolean logic operations. Our work demonstrate the potential of intersectional approaches for future gene delivery technologies in human.

scholarly journals Learning the human chromatin network from all ENCODE ChIP-seq data

2015 ◽  
Author(s):  
Scott M. Lundberg ◽  
William B. Tu ◽  
Brian Raught ◽  
Linda Z. Penn ◽  
Michael M. Hoffman ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Protein Interactions ◽  
Graphical Model ◽  
Cell Types ◽  
Statistical Technique ◽  
Regulatory Factor ◽  
Genomic Context ◽  
Regulatory Factors ◽  
Conditional Dependence ◽  
Factor Interactions

Introduction: A cell's epigenome arises from interactions among regulatory factors --- transcription factors, histone modifications, and other DNA-associated proteins --- co-localized at particular genomic regions. Identifying the network of interactions among regulatory factors, the chromatin network, is of paramount importance in understanding epigenome regulation. Methods: We developed a novel computational approach, ChromNet, to infer the chromatin network from a set of ChIP-seq datasets. ChromNet has four key features that enable its use on large collections of ChIP-seq data. First, rather than using pairwise co-localization of factors along the genome, ChromNet identifies conditional dependence relationships that better discriminate direct and indirect interactions. Second, our novel statistical technique, the group graphical model, improves inference of conditional dependence on highly correlated datasets. Such datasets are common because some transcription factors form a complex and the same transcription factor is often assayed in different laboratories or cell types. Third, ChromNet's computationally efficient method and the group graphical model enable the learning of a joint network across all cell types, which greatly increases the scope of possible interactions. We have shown that this results in a significantly higher fold enrichment for validated protein interactions. Fourth, ChromNet provides an efficient way to identify the genomic context that drives a particular network edge, which provides a more comprehensive understanding of regulatory factor interactions. Results: We applied ChromNet to all available ChIP-seq data from the ENCODE Project, consisting of 1451 ChIP-seq datasets, which revealed previously known physical interactions better than alternative approaches. ChromNet also identified previously unreported regulatory factor interactions. We experimentally validated one of these interactions, between the MYC and HCFC1 transcription factors. Discussion: ChromNet provides a useful tool for understanding the interactions among regulatory factors and identifying novel interactions. We have provided an interactive web-based visualization of the full ENCODE chromatin network and the ability to incorporate custom datasets at http://chromnet.cs.washington.edu.

Developmental expression of the maternal protein XDCoH, the dimerization cofactor of the homeoprotein LFB1 (HNF1)

Development ◽  
1995 ◽  
Vol 121 (4) ◽  
pp. 1217-1226
Author(s):  
E. Pogge yon Strandmann ◽  
G.U. Ryffel
Keyword(s):  
Transcription Factors ◽  
Anterior Part ◽  
Regulatory Element ◽  
Cdna Probe ◽  
Cell Types ◽  
Developmental Expression ◽  
Variant Form ◽  
Cis Acting ◽  
Liver And Kidney

The tissue-specific transcription factors LFB1 (HNF1) and LFB3 (vHNF1) mainly expressed in liver, kidney and intestine are homeoproteins that interact with the regulatory element HP1. The HP1 sequence constitutes one of the most important cis-acting elements in liver-specifically expressed genes, while its function in other cell types containing LFB1 and LFB3 is not fully understood. In mammals, LFB1 activity is modulated by DCoH, a cofactor that stimulates the LFB1 transactivation significantly. Using the rat cDNA probe, we cloned the corresponding Xenopus sequence XDCoH, encoding a 104 amino acid protein, that is 85% identical to the rat protein. XDCoH enhances the LFB1-dependent transactivation potential in transfection experiments and interacts in vitro directly with LFB1 and its variant form LFB3. The protein is detectable in liver and kidney extracts of adult frogs and in small amounts also in lung and stomach, organs expressing LFB1 and/or LFB3 protein as well. To investigate the possible involvement of XDCoH in Xenopus development, we analyzed its temporal and spatial expression pattern during early embryogenesis. XDCoH is a maternal factor, although LFB1 is absent in the egg. In early cleavage stages, the protein is detectable in the cytoplasm of each blastomere and enters the nuclei of the cells as early as the zygotic transcription in the Xenopus embryo starts. The amount of XDCoH increases dramatically following neurulation, when the formation of liver, pronephros and other organs takes place. Whole-mount immunostaining demonstrates that, in the developing larvae, XDCoH is localized in the nuclei of the hepatocytes, the gut cells and the pronephric cells, tissues of mesodermal and endodermal origin known to contain LFB1 and LFB3. Surprisingly it is also present in the pigmented epithelium surrounding the eye of the embryo, which is derived from the anterior part of the ectodermal neural plates and lacks LFB1. The tissue distribution of XDCoH during embryogenesis suggests that XDCoH is involved in determination and differentiation of various unrelated cell types. It seems likely that XDCoH interaction is not only essential for the function of LFB1 and LFB3 but also for certain other transcription factors.

Lozenge is expressed in pluripotent precursor cells and patterns multiple cell types in the Drosophila eye through the control of cell-specific transcription factors

Development ◽  
1998 ◽  
Vol 125 (18) ◽  
pp. 3681-3687 ◽  
Author(s):  
G.V. Flores ◽  
A. Daga ◽  
H.R. Kalhor ◽  
U. Banerjee
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Cell Types ◽  
Cell Fates ◽  
Specific Expression ◽  
Enhancer Element ◽  
Eye Disc ◽  
Drosophila Eye ◽  
A Cell ◽  
Multiple Cell

In the developing Drosophila eye, individual cell fates are specified when general signaling mechanisms are interpreted in the context of cell-specific transcription factors. Lozenge, a Runt/AML1/CBFA1-like transcription factor, determines the fates of a number of neuronal and non-neuronal cells by regulating the expression of multiple fate-determining transcription factors. The Lozenge protein is expressed in the nuclei of the cells that it patterns and also in their undifferentiated precursors. An enhancer element located within the second intron of the lozenge gene is responsible for its eye-specific expression. Lozenge is not itself a cell-specific transcription factor, rather it prepatterns the eye disc by positioning cell-specific factors in their appropriate locations.

Therapeutic Potential of Umbilical Cord Stem Cells for Liver Regeneration

2020 ◽  
Vol 15 (3) ◽  
pp. 219-232
Author(s):  
Ifrah Anwar ◽  
Usman A. Ashfaq ◽  
Zeeshan Shokat
Keyword(s):  
Stem Cells ◽  
Umbilical Cord ◽  
Fas Ligand ◽  
Viral Infections ◽  
Therapeutic Potential ◽  
Cell Types ◽  
Low Risk ◽  
Blood Stem Cells ◽  
Umbilical Cord Stem Cells ◽  
High Regeneration

The liver is a vital organ for life and the only internal organ that is capable of natural regeneration. Although the liver has high regeneration capacity, excessive hepatocyte death can lead to liver failure. Various factors can lead to liver damage including drug abuse, some natural products, alcohol, hepatitis, and autoimmunity. Some models for studying liver injury are APAP-based model, Fas ligand (FasL), D-galactosamine/endotoxin (Gal/ET), Concanavalin A, and carbon tetrachloride-based models. The regeneration of the liver can be carried out using umbilical cord blood stem cells which have various advantages over other stem cell types used in liver transplantation. UCB-derived stem cells lack tumorigenicity, have karyotype stability and high immunomodulatory, low risk of graft versus host disease (GVHD), low risk of transmitting somatic mutations or viral infections, and low immunogenicity. They are readily available and their collection is safe and painless. This review focuses on recent development and modern trends in the use of umbilical cord stem cells for the regeneration of liver fibrosis.

scholarly journals NF-κB in Cancer Immunity: Friend or Foe?

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 355
Author(s):  
Guilhem Lalle ◽  
Julie Twardowski ◽  
Yenkel Grinberg-Bleyer
Keyword(s):  
Immune Responses ◽  
Therapeutic Potential ◽  
Cell Types ◽  
Transcriptional Activators ◽  
New Class ◽  
Complex Interactions ◽  
Cancer Immunity ◽  
Distinct Cell ◽  
Cancer Initiation ◽  
Cancer Outcome

The emergence of immunotherapies has definitely proven the tight relationship between malignant and immune cells, its impact on cancer outcome and its therapeutic potential. In this context, it is undoubtedly critical to decipher the transcriptional regulation of these complex interactions. Following early observations demonstrating the roles of NF-κB in cancer initiation and progression, a series of studies converge to establish NF-κB as a master regulator of immune responses to cancer. Importantly, NF-κB is a family of transcriptional activators and repressors that can act at different stages of cancer immunity. In this review, we provide an overview of the selective cell-intrinsic contributions of NF-κB to the distinct cell types that compose the tumor immune environment. We also propose a new view of NF-κB targeting drugs as a new class of immunotherapies for cancer.

The paracaspase MALT1 in psoriasis

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Stephan Hailfinger ◽  
Klaus Schulze-Osthoff
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Transcription Factors ◽  
Skin Disease ◽  
Cell Types ◽  
Cytokine Receptors ◽  
Molecular Scaffold ◽  
Therapeutic Implications ◽  
Stimulation Of

Abstract Psoriasis is a frequent autoimmune-related skin disease, which involves various cell types such as T cells, keratinocytes and dendritic cells. Genetic variations, such as mutations of CARD14, can promote the development of the disease. CARD14 mutations as well as the stimulation of immune and cytokine receptors activate the paracaspase MALT1, a potent activator of the transcription factors NF-κB and AP-1. The disease-promoting role of MALT1 for psoriasis is mediated by both its protease activity as well as its molecular scaffold function. Here, we review the importance of MALT1-mediated signaling and its therapeutic implications in psoriasis.

scholarly journals The Impact of Anthocyanins and Iridoids on Transcription Factors Crucial for Lipid and Cholesterol Homeostasis

2021 ◽  
Vol 22 (11) ◽  
pp. 6074
Author(s):  
Maciej Danielewski ◽  
Agnieszka Matuszewska ◽  
Adam Szeląg ◽  
Tomasz Sozański
Keyword(s):  
Transcription Factors ◽  
Cholesterol Metabolism ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Homeostasis ◽  
Lipid Lowering ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cell Functions ◽  
The Impact

Nutrition determines our health, both directly and indirectly. Consumed foods affect the functioning of individual organs as well as entire systems, e.g., the cardiovascular system. There are many different diets, but universal guidelines for proper nutrition are provided in the WHO healthy eating pyramid. According to the latest version, plant products should form the basis of our diet. Many groups of plant compounds with a beneficial effect on human health have been described. Such groups include anthocyanins and iridoids, for which it has been proven that their consumption may lead to, inter alia, antioxidant, cholesterol and lipid-lowering, anti-obesity and anti-diabetic effects. Transcription factors directly affect a number of parameters of cell functions and cellular metabolism. In the context of lipid and cholesterol metabolism, five particularly important transcription factors can be distinguished: liver X receptor (LXR), peroxisome proliferator-activated receptor-α (PPAR-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer binding protein α (C/EBPα) and sterol regulatory element-binding protein 1c (SREBP-1c). Both anthocyanins and iridoids may alter the expression of these transcription factors. The aim of this review is to collect and systematize knowledge about the impact of anthocyanins and iridoids on transcription factors crucial for lipid and cholesterol homeostasis.

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