scholarly journals OR08-1 Context-Specific Chromatin Binding Properties of Progesterone Receptor and Consequential Effects on Gene Expression in Mouse Reproductive Tissues

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Thao Dinh ◽  
James Breen ◽  
Lisa Akison ◽  
Francesco DeMayo ◽  
Hannah Brown ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progesterone Receptor ◽  
Chromatin Binding ◽  
Binding Properties ◽  
Reproductive Tissues ◽  
Context Specific

scholarly journals Tissue-specific progesterone receptor-chromatin binding and the regulation of progesterone-dependent gene expression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
D. T. Dinh ◽  
J. Breen ◽  
L. K. Akison ◽  
F. J. DeMayo ◽  
H. M. Brown ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progesterone Receptor ◽  
Chromatin Binding ◽  
Tissue Specific

On the limits of active module identification

2021 ◽  
Author(s):  
Olga Lazareva ◽  
Jan Baumbach ◽  
Markus List ◽  
David B Blumenthal
Keyword(s):  
Gene Expression ◽  
Gene Expression Data ◽  
Small Diameter ◽  
Extensive Study ◽  
Biological Knowledge ◽  
Expression Data ◽  
Module Identification ◽  
Ppi Networks ◽  
Novel Algorithms ◽  
Context Specific

Abstract In network and systems medicine, active module identification methods (AMIMs) are widely used for discovering candidate molecular disease mechanisms. To this end, AMIMs combine network analysis algorithms with molecular profiling data, most commonly, by projecting gene expression data onto generic protein–protein interaction (PPI) networks. Although active module identification has led to various novel insights into complex diseases, there is increasing awareness in the field that the combination of gene expression data and PPI network is problematic because up-to-date PPI networks have a very small diameter and are subject to both technical and literature bias. In this paper, we report the results of an extensive study where we analyzed for the first time whether widely used AMIMs really benefit from using PPI networks. Our results clearly show that, except for the recently proposed AMIM DOMINO, the tested AMIMs do not produce biologically more meaningful candidate disease modules on widely used PPI networks than on random networks with the same node degrees. AMIMs hence mainly learn from the node degrees and mostly fail to exploit the biological knowledge encoded in the edges of the PPI networks. This has far-reaching consequences for the field of active module identification. In particular, we suggest that novel algorithms are needed which overcome the degree bias of most existing AMIMs and/or work with customized, context-specific networks instead of generic PPI networks.

scholarly journals The Progesterone Receptor in Human Term Amniochorion and Placenta Is Isoform C

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 687-693 ◽  
Author(s):  
Anthony H. Taylor ◽  
Penny C. McParland ◽  
David J. Taylor ◽  
Stephen C. Bell
Keyword(s):  
Progesterone Receptor ◽  
Western Blotting ◽  
Cell Types ◽  
Specific Role ◽  
Fetal Membranes ◽  
Rt Pcr ◽  
Reproductive Tissues ◽  
Pcr Techniques ◽  
Human Parturition ◽  
Extraembryonic Tissues

The mechanism that initiates human parturition has been proposed to be functional progesterone withdrawal whereby the 116-kDa B isoform of the progesterone receptor (PR-B) switches in favor of the 94-kDa A isoform (PR-A) in reproductive tissues. Recently other PR isoforms, PR-S, PR-C, and PR-M generated from the same gene have been identified and partially characterized. Using immunohistochemical, Western blotting, and RT-PCR techniques, evidence is provided that the major PR isoform present in human term fetal membranes (amnion and chorion) and syncytiotrophoblast of the placenta is neither of the classical nuclear PR-B or PR-A isoforms but is the N terminally truncated 60-kDa PR-C isoform. Evidence is also provided that the PR-C isoform resides in the cytoplasm of the expressing cell types. Data are also presented to show that PR-B, PR-A, and PR-S isoforms are essentially absent from the amnion and chorion, whereas PR isoforms A, B, C, and S are all present in the decidua, with PR-A being the major isoform. The syncytiotrophoblast of the placenta contains the cytoplasmic PR-C isoform but not PR-A, PR-B, or PR-S. The major PR isoform in the amnion, chorion, and placenta is PR-C, suggesting that the cytoplasmic PR-C isoform has a specific role in extraembryonic tissues and may be involved in the regulation of human parturition.

scholarly journals Xrp1 genetically interacts with the ALS-associated FUS orthologue caz and mediates its toxicity

2018 ◽  
Vol 217 (11) ◽  
pp. 3947-3964 ◽  
Author(s):  
Moushami Mallik ◽  
Marica Catinozzi ◽  
Clemens B. Hug ◽  
Li Zhang ◽  
Marina Wagner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Life Span ◽  
Motor Neurons ◽  
Gene Expression Regulation ◽  
Genetic Interaction ◽  
Motor Deficits ◽  
Chromatin Binding ◽  
Mutant Phenotypes ◽  
Gene Expression Dysregulation ◽  
Lateral Sclerosis

Cabeza (caz) is the single Drosophila melanogaster orthologue of the human FET proteins FUS, TAF15, and EWSR1, which have been implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we identified Xrp1, a nuclear chromatin-binding protein, as a key modifier of caz mutant phenotypes. Xrp1 expression was strongly up-regulated in caz mutants, and Xrp1 heterozygosity rescued their motor defects and life span. Interestingly, selective neuronal Xrp1 knockdown was sufficient to rescue, and neuronal Xrp1 overexpression phenocopied caz mutant phenotypes. The caz/Xrp1 genetic interaction depended on the functionality of the AT-hook DNA-binding domain in Xrp1, and the majority of Xrp1-interacting proteins are involved in gene expression regulation. Consistently, caz mutants displayed gene expression dysregulation, which was mitigated by Xrp1 heterozygosity. Finally, Xrp1 knockdown substantially rescued the motor deficits and life span of flies expressing ALS mutant FUS in motor neurons, implicating gene expression dysregulation in ALS-FUS pathogenesis.

scholarly journals Phosphorylation-dependent mitotic SUMOylation drives nuclear envelope–chromatin interactions

2021 ◽  
Vol 220 (12) ◽  
Author(s):  
Christopher Ptak ◽  
Natasha O. Saik ◽  
Ashwini Premashankar ◽  
Diego L. Lapetina ◽  
John D. Aitchison ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Envelope ◽  
Spatial Organization ◽  
G1 Phase ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Chromatin Binding ◽  
Chromatin Interactions ◽  
Sumo Ligase ◽  
Pore Complexes

In eukaryotes, chromatin binding to the inner nuclear membrane (INM) and nuclear pore complexes (NPCs) contributes to spatial organization of the genome and epigenetic programs important for gene expression. In mitosis, chromatin–nuclear envelope (NE) interactions are lost and then formed again as sister chromosomes segregate to postmitotic nuclei. Investigating these processes in S. cerevisiae, we identified temporally and spatially controlled phosphorylation-dependent SUMOylation events that positively regulate postmetaphase chromatin association with the NE. Our work establishes a phosphorylation-mediated targeting mechanism of the SUMO ligase Siz2 to the INM during mitosis, where Siz2 binds to and SUMOylates the VAP protein Scs2. The recruitment of Siz2 through Scs2 is further responsible for a wave of SUMOylation along the INM that supports the assembly and anchorage of subtelomeric chromatin at the INM and localization of an active gene (INO1) to NPCs during the later stages of mitosis and into G1-phase.

IDENTIFYING RELEVANT PATHWAYS AND BIOMARKERS IN CROHN’S DISEASE USING CONTEXTUALIZED METABOLIC NETWORK MODEL

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S9-S10
Author(s):  
Brooklyn McGrew ◽  
Aman Shrivastava ◽  
Philip Fernandes ◽  
Lubaina Ehsan ◽  
Yash Sharma ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Fatty Acid ◽  
Crohn's Disease ◽  
Fatty Acid Synthesis ◽  
Metabolic Pathway ◽  
Metabolic Pathways ◽  
Acid Synthesis ◽  
Transcriptomic Data ◽  
Context Specific

Abstract Background Candidate markers for Crohn’s Disease (CD) may be identified via gene expression-based construction of metabolic networks (MN). These can computationally describe gene-protein-reaction associations for entire tissues and also predict the flux of reactions (rate of turnover of specific molecules via a metabolic pathway). Recon3D is the most comprehensive human MN to date. We used publicly available CD transcriptomic data along with Recon3D to identify metabolites as potential diagnostic and prognostic biomarkers. Methods Terminal ileal gene expression profiles (36,372 genes; 218 CD. 42 controls) from the RISK cohort (Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn’s Disease) and their transcriptomic abundances were used. Recon3D was pruned to only include RISK dataset transcripts which determined metabolic reaction linkage with transcriptionally active genes. Flux balance analysis (FBA) was then run using RiPTiDe with context specific transcriptomic data to further constrain genes (Figure 1). RiPTiDe was independently run on transcriptomic data from both CD and controls. From the pruned and constricted MN obtained, reactions were extracted for further analysis. Results After applying the necessary constraints to modify Recon3D, 527 CD and 537 control reactions were obtained. Reaction comparison with a publicly available list of healthy small intestinal epithelial reactions (n=1282) showed an overlap of 80 CD and 84 control reactions. These were then further grouped based on their metabolic pathways. RiPTiDe identified context specific metabolic pathway activity without supervision and the percentage of forward, backward, and balanced reactions for each metabolic pathway (Figure 2). The metabolite concentrations in the small intestine was altered among CD patients. Notably, the citric acid cycle and malate-aspartate shuttle were affected, highlighting changes in mitochondrial metabolic pathways. This is illustrated by changes in the number of reactions at equilibrium between CD and control. Conclusions The results are relevant as cytosolic acetyl-CoA is needed for fatty acid synthesis and is obtained by removing citrate from the citric acid cycle. An intermediate removal from the cycle has significant cataplerotic effects. The malate-aspartate shuttle also allows electrons to move across the impermeable membrane in the mitochondria (fatty acid synthesis location). These findings are reported by previously published studies where gene expression for fatty acid synthesis is altered in CD patients along with mitochondrial metabolic pathway changes, resulting in altered cell homeostasis. In-depth analysis is currently underway with our work supporting the utility of potential metabolic biomarkers for CD diagnosis, management and improved care.

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