scholarly journals Progesterone receptor-A isoform interaction with RUNX transcription factors controls chromatin remodelling at promoters during ovulation

2021 ◽  
Author(s):  
Thao D Dinh ◽  
James Breen ◽  
Barbara Nicol ◽  
Kirsten M Smith ◽  
Matilda Nicholls ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Progesterone Receptor ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Chromatin Accessibility ◽  
Proximal Promoter ◽  
Physical Interaction ◽  
Promoter Regions ◽  
Follicle Rupture ◽  
Transcriptional Complex

Progesterone receptor (PGR) plays diverse roles in reproductive tissues and thus coordinates mammalian fertility. In the ovary, acutely induced PGR is the key determinant of ovulation through transcriptional control of a unique set of genes that culminates in follicle rupture. However, the molecular mechanisms for PGR specialised function in ovulation is poorly understood. To address this, we assembled a detailed genomic profile of PGR action through combined ATAC-seq, RNA-seq and ChIP-seq analysis in wildtype and isoform-specific PGR null mice. We demonstrated the unique action of PGR-A isoform in the ovary through a transcriptional complex involving physical interaction with RUNX and JUN/FOS transcription factors. The assembly of this unique complex directs targeting of PGR binding to proximal promoter regions and enables chromatin accessibility, leading to ovulatory gene induction. This PGR signalling mechanism is specific to ovulation and provides potential targets for infertility treatments as well as new contraceptives that block ovulation.

scholarly journals Progesterone Receptor Directly Inhibits β-Casein Gene Transcription in Mammary Epithelial Cells Through Promoting Promoter and Enhancer Repressive Chromatin Modifications

2011 ◽  
Vol 25 (6) ◽  
pp. 955-968 ◽  
Author(s):  
Adam C. Buser ◽  
Alison E. Obr ◽  
Elena B. Kabotyanski ◽  
Sandra L. Grimm ◽  
Jeffrey M. Rosen ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Progesterone Receptor ◽  
Gene Transcription ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Proximal Promoter ◽  
Physical Interaction ◽  
Chromatin Modifications ◽  
Casein Gene ◽  
Repressive Chromatin

Abstract Differentiated HC-11 cells ectopically expressing progesterone receptor (PR) were used to explore the molecular mechanisms by which progesterone suppresses β-casein gene transcription induced by prolactin (PRL) and glucocorticoids in the mammary gland. As detected by chromatin immunoprecipitation assays, treatment of cells with the progestin agonist R5020 induced a rapid recruitment (5 min) of PR to the proximal promoter (−235 bp) and distal enhancer (−6 kb upstream of transcription start site) of β-casein. PR remained bound for 4 h and was dissociated by 24 h after treatment. Despite efficient binding, the hormone agonist-occupied PR did not stimulate transcription of the β-casein gene. Recruitment of signal transducer and activator of transcription 5a, glucocorticoid receptor, and the CCAAT enhancer binding protein β to the enhancer and proximal promoter of β-casein induced by PRL and glucocorticoids was blocked by progestin cotreatment, whereas PR binding was induced under these conditions. PRL/glucocorticoid-induced histone acetylation and the recruitment of the coactivator p300 and RNA polymerase II required for gene activation were also inhibited by progestin. In addition, progestin prevented dissociation of the corepressors Yin and Yang 1 and histone deacetylase 3 from the promoter, and demethylation of lysine 9 of histone 3 induced by PRL and glucocorticoids. These studies are consistent with the conclusion that progesterone interferes with PRL/glucocorticoid induction of β-casein transcription by a physical interaction of PR with the promoter and enhancer that blocks assembly of a transcriptional activation complex and dissociation of corepressors and promotes repressive chromatin modifications. These studies define a novel mechanism of steroid receptor-mediated transcriptional repression of a physiologically important gene in mammary gland development and differentiation.

scholarly journals Control of Francisella tularensis Virulence at Gene Level: Network of Transcription Factors

2020 ◽  
Vol 8 (10) ◽  
pp. 1622
Author(s):  
Petra Spidlova ◽  
Pavla Stojkova ◽  
Anders Sjöstedt ◽  
Jiri Stulik
Keyword(s):  
Transcription Factors ◽  
Francisella Tularensis ◽  
Pathogenic Bacteria ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Experimental Studies ◽  
Initial Step ◽  
Research Area ◽  
Comprehensive Overview ◽  
Complex Process

Regulation of gene transcription is the initial step in the complex process that controls gene expression within bacteria. Transcriptional control involves the joint effort of RNA polymerases and numerous other regulatory factors. Whether global or local, positive or negative, regulators play an essential role in the bacterial cell. For instance, some regulators specifically modify the transcription of virulence genes, thereby being indispensable to pathogenic bacteria. Here, we provide a comprehensive overview of important transcription factors and DNA-binding proteins described for the virulent bacterium Francisella tularensis, the causative agent of tularemia. This is an unexplored research area, and the poorly described networks of transcription factors merit additional experimental studies to help elucidate the molecular mechanisms of pathogenesis in this bacterium, and how they contribute to disease.

scholarly journals The Transcriptional Control of Lymphatic Vascular Development

Physiology ◽  
2011 ◽  
Vol 26 (3) ◽  
pp. 146-155 ◽  
Author(s):  
Mathias Francois ◽  
Natasha L. Harvey ◽  
Benjamin M. Hogan
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Developmental Process ◽  
Vascular Development ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cell ◽  
Transcriptional Networks ◽  
Genetic Manipulations

More than 100 years ago, Florence Sabin suggested that lymphatic vessels develop by sprouting from preexisting blood vessels, but it is only over the past decade that the molecular mechanisms underpinning lymphatic vascular development have begun to be elucidated. Genetic manipulations in mice have identified a transcriptional hub comprised of Prox1, CoupTFII, and Sox18 that is essential for lymphatic endothelial cell fate specification. Recent work has identified a number of additional transcription factors that regulate later stages of lymphatic vessel differentiation and maturation. This review highlights recent advances in our understanding of the transcriptional control of lymphatic vascular development and reflects on efforts to better understand the activities of transcriptional networks during this discrete developmental process. Finally, we highlight the transcription factors associated with human lymphatic vascular disorders, demonstrating the importance of understanding how the activity of these key molecules is regulated, with a view toward the development of innovative therapeutic avenues.

scholarly journals Discovery of lipotoxicity-sensitive transcription factors in non-alcoholic steatohepatitis

2021 ◽  
Author(s):  
Joaquín Pérez-Schindler ◽  
Elyzabeth Vargas-Fernández ◽  
Bettina Karrer-Cardel ◽  
Danilo Ritz ◽  
Alexander Schmidt ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Chromatin Accessibility ◽  
Alcoholic Fatty Liver ◽  
Mouse Hepatocyte ◽  
Alcoholic Steatohepatitis ◽  
Pathogenic Factors ◽  
Mouse Hepatocytes ◽  
Regulated Gene Expression

Non-alcoholic fatty liver disease is continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. Here, we integrated transcriptomic and chromatin accessibility analyses from human liver and mouse hepatocytes to identify lipotoxicity-sensitive transcription factors. We found that the transcription factors MAFK and TCF4 were activated in liver from NASH patients and by mouse hepatocyte lipotoxicity. Genetic deletion of these transcription factors protected hepatocytes against saturated fatty acid oversupply. Notably, MAFK- and TCF4-regulated gene expression linked to lipotoxicity closely correlated with transcriptional patters in fibrosis progression in NASH patients. Collectively, our findings uncovered novel molecular insights into lipotoxicity-induced NASH, revealing the relevance and therapeutic potential of MAFK and TCF4 in human disease.

The interaction between MtDELLA-MtGAF1 complex and MtARF3 mediates transcriptional control of MtGA3ox1 to elaborate leaf margin formation in Medicago truncatula

2021 ◽  
Author(s):  
Lizhu Wen ◽  
Yiming Kong ◽  
Hongfeng Wang ◽  
Yiteng Xu ◽  
Zhichao Lu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Medicago Truncatula ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Leaf Shape ◽  
Critical Role ◽  
Competitive Inhibitor ◽  
Leaf Margin ◽  
Loss Of Function ◽  
Model Legume

Abstract The molecular mechanisms underlying diversity of leaf shapes have been of great interest to researchers. Leaf shape depends on the pattern of serrations and the degree of indentation of leaf margins. Multiple transcription factors and hormone signaling are involved in this process. In this study, we characterized the developmental roles of SMALL AND SERRATED LEAF (SSL) by analyzing a recessive mutant in the model legume Medicago truncatula. An ortholog of Arabidopsis thaliana GA3-oxidase 1 (GA3ox1), MtGA3ox1/SSL, is required for GA biosynthesis. Loss of function in MtGA3ox1 results in the small plant and lateral organs. The prominent phenotype of the mtga3ox1 mutant is the more pronounced leaf margin, indicating the critical role of GA level in leaf margin formation. Moreover, 35S: MtDELLA2  ΔDELLAand 35S: MtARF3 transgenic plants display leaves with the deeply wavy margin, which resembles those of mtga3ox1. Further investigations show that the MtGA3ox1 is under the control of MtDELLA1/2/3-MtGAF1 complexes-dependent feedback regulation. Meanwhile, MtARF3 behaves as a competitive inhibitor of MtDELLA2/3-MtGAF1 complexes to repress the expression of MtGA3ox1 indirectly. These findings suggest that GA feedback regulatory circuits play a fundamental role in leaf margin formation, in which the posttranslational interaction between transcription factors functions as an additional feature.

scholarly journals Distinct Promoters Mediate the Regulation of Ebf1 Gene Expression by Interleukin-7 and Pax5

2006 ◽  
Vol 27 (2) ◽  
pp. 579-594 ◽  
Author(s):  
Stephanie Roessler ◽  
Ildiko Györy ◽  
Sascha Imhof ◽  
Mikhail Spivakov ◽  
Ruth R. Williams ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Regulatory Network ◽  
Transcriptional Control ◽  
Replication Timing ◽  
Feedback Loops ◽  
Protein Isoforms ◽  
Proximal Promoter ◽  
B Lymphopoiesis ◽  
Interleukin 7 ◽  
Insight Into

ABSTRACT Early differentiation of B lymphocytes requires the function of multiple transcription factors that regulate the specification and commitment of the lineage. Loss- and gain-of-function experiments have provided important insight into the transcriptional control of B lymphopoiesis, whereby E2A was suggested to act upstream of EBF1 and Pax5 downstream of EBF1. However, this simple hierarchy cannot account for all observations, and our understanding of a presumed regulatory network, in which transcription factors and signaling pathways operate, is limited. Here, we show that the expression of the Ebf1 gene involves two promoters that are differentially regulated and generate distinct protein isoforms. We find that interleukin-7 signaling, E2A, and EBF1 activate the distal Ebf1 promoter, whereas Pax5, together with Ets1 and Pu.1, regulates the stronger proximal promoter. In the absence of Pax5, the function of the proximal Ebf1 promoter and accumulation of EBF1 protein are impaired and the replication timing and subcellular localization of the Ebf1 locus are altered. Taken together, these data suggest that the regulation of Ebf1 via distinct promoters allows for the generation of several feedback loops and the coordination of multiple determinants of B lymphopoiesis in a regulatory network.

Transcriptional Regulation of Metabolism

2006 ◽  
Vol 86 (2) ◽  
pp. 465-514 ◽  
Author(s):  
Béatrice Desvergne ◽  
Liliane Michalik ◽  
Walter Wahli
Keyword(s):  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Cholesterol Metabolism ◽  
Regulatory Pathways ◽  
Glucose And Lipid Metabolism ◽  
The Metabolic Syndrome

Our understanding of metabolism is undergoing a dramatic shift. Indeed, the efforts made towards elucidating the mechanisms controlling the major regulatory pathways are now being rewarded. At the molecular level, the crucial role of transcription factors is particularly well-illustrated by the link between alterations of their functions and the occurrence of major metabolic diseases. In addition, the possibility of manipulating the ligand-dependent activity of some of these transcription factors makes them attractive as therapeutic targets. The aim of this review is to summarize recent knowledge on the transcriptional control of metabolic homeostasis. We first review data on the transcriptional regulation of the intermediary metabolism, i.e., glucose, amino acid, lipid, and cholesterol metabolism. Then, we analyze how transcription factors integrate signals from various pathways to ensure homeostasis. One example of this coordination is the daily adaptation to the circadian fasting and feeding rhythm. This section also discusses the dysregulations causing the metabolic syndrome, which reveals the intricate nature of glucose and lipid metabolism and the role of the transcription factor PPARγ in orchestrating this association. Finally, we discuss the molecular mechanisms underlying metabolic regulations, which provide new opportunities for treating complex metabolic disorders.

The molecular basis of progesterone receptor action in breast carcinogenesis

2012 ◽  
Vol 9 (2) ◽  
Author(s):  
Patricia V. Elizalde ◽  
Cecilia J. Proietti
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Progesterone Receptor ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Critical Role ◽  
Regulatory Elements ◽  
Control Of Gene Expression ◽  
Receptor Modulation

AbstractProgesterone plays an essential role in the regulation of cell proliferation and differentiation in the mammary gland. In addition, experimental and clinical evidence points to a critical role of progesterone and the nuclear progesterone receptor (PR) in controlling mammary gland tumorigenesis. However, the molecular mechanisms of progesterone action in breast cancer still remain elusive. In its classical mechanism of action, PR acts as a ligand-induced transcription factor (TF) interacting directly with specific progesterone response elements (PREs) in the promoter of target genes. In addition to its transcriptional effects, PR activates signal transduction pathways through a rapid or non-genomic mechanism. Interestingly, progestin induces the expression of key genes involved in breast cancer growth, which lack PREs in their promoters, via a non-classical PR transcriptional mechanism through PR tethering to other TFs. Recent findings on steroid hormone receptor modulation of target genes raise the most exciting possibility that progestin may also induce long-range transcriptional control of gene expression via PR binding to cis-regulatory elements (PREs or half PREs) located far upstream or downstream from the trascriptional start site. This review will focus on the involvement and interplay of the different PR actions in breast cancer.

scholarly journals Unique Transcription Factor Functions Regulate Epigenetic and Transcriptional Dynamics During Cardiac Reprogramming

2019 ◽  
Author(s):  
Nicole R. Stone ◽  
Casey A. Gifford ◽  
Reuben Thomas ◽  
Karishma J. B. Pratt ◽  
Kaitlen Samse-Knapp ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Chromatin Accessibility ◽  
Transcriptional Dynamics ◽  
Primary Driver ◽  
Gene Expression Dynamics ◽  
Direct Lineage Conversion

SUMMARYDirect lineage conversion, whereby a somatic cell assumes a new cellular identity, can be driven by ectopic expression of combinations of lineage-enriched transcription factors. To determine the molecular mechanisms by which expression of Gata4, Mef2c, and Tbx5 (GMT) induces direct reprogramming from a cardiac fibroblast toward an induced cardiomyocyte, we performed a comprehensive transcriptomic and epigenomic interrogation of the reprogramming process. Single cell RNA sequencing indicated that a reprogramming trajectory was acquired within 48 hours of GMT introduction, did not require cell division, and was limited mainly by successful expression of GMT. Evaluation of chromatin accessibility by ATAC-seq supported the expression dynamics and revealed widespread chromatin remodeling at early stages of the reprogramming process. Chromatin immunoprecipitation followed by sequencing of each factor alone or in combinations revealed that GMT bind DNA individually and in combination, and that ectopic expression of either Mef2c or Tbx5 is sufficient in some contexts to increase accessibility. We also find evidence for cooperative facilitation and refinement of each factor’s binding in a combinatorial setting. A random-forest classifier that integrated the observed gene expression dynamics with regions of dynamic chromatin accessibility suggested Tbx5 binding is a primary driver of gene expression changes and revealed additional transcription factor motifs co-segregating with reprogramming factor motifs, suggesting new factors that may be involved in the reprogramming process. These results begin to explain the mechanisms by which transcription factors normally expressed in multiple germ layers can function combinatorially to direct lineage conversion.

Sign in / Sign up

Export Citation Format

Share Document