scholarly journals Conserved nuclear receptors controlling a novel trait target fast-evolving genes expressed in a single cell

2019 ◽  
Author(s):  
Bogdan Sieriebriennikov ◽  
Shuai Sun ◽  
James W. Lightfoot ◽  
Hanh Witte ◽  
Eduardo Moreno ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Developmental Plasticity ◽  
Genetic Basis ◽  
Target Genes ◽  
Gland Cell ◽  
Nuclear Hormone Receptor ◽  
Wild Type ◽  
Phenotypic Effect ◽  
Pharyngeal Gland ◽  
Gene Regulatory

AbstractEnvironment shapes development through a phenomenon called developmental plasticity. Deciphering its genetic basis has implications for understanding evolution and adaptation to novel environments, yet molecular studies are scarce. Here, we expanded the gene regulatory network controlling predatory vs. non-predatory morphology in the nematode Pristionchus pacificus. First, we isolated a mutant in the nuclear hormone receptor nhr-1 with a previously unseen phenotypic effect. It disrupts mouth-form determination and results in animals combining features of both wild-type morphs. Further, we identified common targets of NHR-1 and the previously identified nuclear hormone receptor NHR-40 through transcriptomics. Unlike their highly conserved regulators, the target genes have no orthologs in Caenorhabditis elegans and likely result from lineage-specific expansions. An array of transcriptional reporters revealed co-expression of all tested targets in the same pharyngeal gland cell. The morphological remodeling of this cell accompanied the evolution of teeth and predation, linking rapid gene turnover with morphological innovations.

Abstract P244: Transcriptional Regulation of Cardiac Gene Expression by Med13 Alters Global Energy Balance

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Chad E Grueter ◽  
Brett A Johnson ◽  
Xiaoxia Qi ◽  
John McAnally ◽  
Rhonda Bassel-Duby ◽  
...  
Keyword(s):  
Gene Expression ◽  
Energy Balance ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Cardiac Contractility ◽  
Nuclear Hormone Receptor ◽  
Mediator Complex

Aberrant cardiac metabolism is associated with obesity, type 2 diabetes and heart failure. The heart requires highly efficient metabolism to maintain the levels of ATP needed for contractility and pump function, however little is known about the role of the heart as a metabolic organ. Nuclear hormone receptors, such as thyroid hormone receptor play an important role in cardiovascular disease by significantly altering expression of genes involved in maintaining metabolic activity. The Mediator, a large multiprotein complex functions as a hub to control gene expression through association with transcriptional activators and repressors. We tested the hypothesis that Med13, a component of the Mediator complex, regulates cardiac function in a gain-of-function mouse model. Trangsenic mice overexpressing Med13 in the heart are lean, have increased energy expenditure, are resistant to high fat diet-induced obesity and have enhanced cardiac contractility. Microarray analysis and biochemical assays show that in vivo and in vitro Med13 selectively inhibits nuclear hormone receptor target genes of energy metabolism. These results implicate the Mediator complex regulates energy balance and cardiac contractility and suggests that the heart may function as a key component of mammalian energy homeostasis.

scholarly journals NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Romaric Bouveret ◽  
Ashley J Waardenberg ◽  
Nicole Schonrock ◽  
Mirana Ramialison ◽  
Tram Doan ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Regulatory Networks ◽  
Congenital Heart ◽  
Target Genes ◽  
Loss Of Function ◽  
Wild Type ◽  
Interaction Domain ◽  
Ets Proteins ◽  
Gene Regulatory

We take a functional genomics approach to congenital heart disease mechanism. We used DamID to establish a robust set of target genes for NKX2-5 wild type and disease associated NKX2-5 mutations to model loss-of-function in gene regulatory networks. NKX2-5 mutants, including those with a crippled homeodomain, bound hundreds of targets including NKX2-5 wild type targets and a unique set of "off-targets", and retained partial functionality. NKXΔHD, which lacks the homeodomain completely, could heterodimerize with NKX2-5 wild type and its cofactors, including E26 transformation-specific (ETS) family members, through a tyrosine-rich homophilic interaction domain (YRD). Off-targets of NKX2-5 mutants, but not those of an NKX2-5 YRD mutant, showed overrepresentation of ETS binding sites and were occupied by ETS proteins, as determined by DamID. Analysis of kernel transcription factor and ETS targets show that ETS proteins are highly embedded within the cardiac gene regulatory network. Our study reveals binding and activities of NKX2-5 mutations on WT target and off-targets, guided by interactions with their normal cardiac and general cofactors, and suggest a novel type of gain-of-function in congenital heart disease.

scholarly journals The Nuclear Hormone Receptor PPARγas a Therapeutic Target in Major Diseases

2010 ◽  
Vol 10 ◽  
pp. 2181-2197 ◽  
Author(s):  
Martina Victoria Schmidt ◽  
Bernhard Brüne ◽  
Andreas von Knethen
Keyword(s):  
Therapeutic Target ◽  
Hormone Receptor ◽  
Target Genes ◽  
Inflammatory Responses ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Sensitizers

The peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements (PPREs) in the promoter region of target genes. Originally, PPARγwas identified as being essential for glucose metabolism. Thus, synthetic PPARγagonists, the thiazolidinediones (TZDs), are used in type 2 diabetes therapy as insulin sensitizers. More recent evidence implied an important role for the nuclear hormone receptor PPARγin controlling various diseases based on its anti-inflammatory, cell cycle arresting, and proapoptotic properties. In this regard, expression of PPARγis not restricted to adipocytes, but is also found in immune cells, such as B and T lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. The expression of PPARγin lymphoid organs and its modulation of macrophage inflammatory responses, lymphocyte proliferation, cytokine production, and apoptosis underscore its immune regulating functions. Moreover, PPARγexpression is found in tumor cells, where its activation facilitates antitumorigenic actions. This review provides an overview about the role of PPARγas a possible therapeutic target approaching major, severe diseases, such as sepsis, cancer, and atherosclerosis.

scholarly journals The Drosophila Eip78C Gene Is Not Vital But Has a Role in Regulating Chromosome Puffs

Genetics ◽  
1996 ◽  
Vol 144 (1) ◽  
pp. 159-170 ◽  
Author(s):  
Steven R H Russell ◽  
Gertrud Heimbeck ◽  
Catherine M Goddard ◽  
Adelaide T C Carpenter ◽  
Michael Ashburner
Keyword(s):  
Heat Shock ◽  
Ligand Binding ◽  
Chromosomal Aberrations ◽  
Hormone Receptor ◽  
Normal Development ◽  
Nuclear Hormone Receptor ◽  
Wild Type ◽  
Heat Shock Promoter ◽  
Small Deletion ◽  
Early Late

Abstract We have generated a number of chromosomal aberrations that disrupt the early-late ecdysone-induced 78C puff gene (Eip78C, ecdysone-induced protein, FlyBase name for the E78 gene of Stone and Thummel 1993), which encodes the two members of the nuclear hormone receptor superfamily Eip78C-A and Eip78C-B. The aberrations include deletions of the ligand-binding/dimeriization domain of both, inversions that split Eip78C-A but retain residual Eip78C-B expression, and a small deletion specific for Eip78C-B. We find that wild-type Eip78C functions are completely dispensable for normal development under laboratory conditions. However, we show that Eip78C-B is required for the maximal puffing activity of a subset of late puffs (63E and 82F) since these puffs are reduced in size in Eip78C-B mutant backgrounds. Paradoxically the same late puffs are reduced, as well as at least one other, when the Eip78C-B cDNA is overexpressed from a heat shock promoter. These data indicate either that Eip78C function is redundant or that it plays a subtle modulating role in the regulation of chromosome puffing.

scholarly journals Marked Potentiation of the Dominant Negative Action of a Mutant Thyroid Hormone Receptor β in Mice by the Ablation of One Wild-Type β Allele

2003 ◽  
Vol 17 (5) ◽  
pp. 895-907 ◽  
Author(s):  
H. Suzuki ◽  
X.-Y. Zhang ◽  
D. Forrest ◽  
M. C. Willingham ◽  
S.-Y. Cheng
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Thyroid Function Tests ◽  
Wild Type ◽  
Hormone Response Elements ◽  
Papillary Hyperplasia

Abstract Mutations in the thyroid hormone receptor (TR) β gene result in resistance to thyroid hormone (RTH), characterized by reduced sensitivity of tissues to thyroid hormone. To understand which physiological TR pathways are affected by mutant receptors, we crossed mice with a dominantly negative TRβ mutation (TRβPV) with mice carrying a TRβ null mutation (TRβ−/−) to determine the consequences of the TRβPV mutation in the absence of wild-type TRβ. TRβPV/− mice are distinct from TRβ+/− mice that did not show abnormalities in thyroid function tests. TRβPV/− mice are also distinct from TRβPV/+ and TRβ−/− mice in that the latter shows mild dysfunction in the pituitary-thyroid axis, whereas the former exhibit very severe abnormalities, including extensive papillary hyperplasia of the thyroid epithelium, indistinguishable from that observed in TRβPV/PV mice. Similar to TRβPV/PV mice, TRβPV/− mice exhibited impairment in weight gain. Moreover, the abnormal regulation patterns of T3-target genes in the tissues of TRβPV/− and TRβPV/PV mice were strikingly similar. Using TR isoforms and PV-specific antibodies in gel shift assays, we found that in vivo, PV competed with TRα1 for binding to thyroid hormone response elements in TRβPV/− mice as effectively as in TRβPV/PV mice. Thus, the actions of mutant TRβ are markedly potentiated by the ablation of the second TRβ allele, suggesting that interference with wild-type TRα1-mediated gene regulation by mutant TRβ leads to severe RTH.

scholarly journals The Nuclear Hormone Receptor Coactivator NRC Is a Pleiotropic Modulator Affecting Growth, Development, Apoptosis, Reproduction, and Wound Repair

2004 ◽  
Vol 24 (11) ◽  
pp. 4994-5004 ◽  
Author(s):  
Muktar A. Mahajan ◽  
Sharmistha Das ◽  
Hong Zhu ◽  
Marjana Tomic-Canic ◽  
Herbert H. Samuels
Keyword(s):  
Hormone Receptor ◽  
Wound Repair ◽  
Hormone Receptors ◽  
Homozygous Deletion ◽  
Nuclear Hormone Receptor ◽  
High Rate ◽  
Wild Type ◽  
Postnatal Mortality ◽  
Wild Type Mefs ◽  
Interfering Rna

ABSTRACT Nuclear hormone receptor coregulator (NRC) is a 2,063-amino-acid coregulator of nuclear hormone receptors and other transcription factors (e.g., c-Fos, c-Jun, and NF-κB). We and others have generated C57BL/6-129S6 hybrid (C57/129) NRC+/− mice that appear outwardly normal and grow and reproduce. In contrast, homozygous deletion of the NRC gene is embryonic lethal. NRC−/− embryos are always smaller than NRC+/+ embryos, and NRC−/− embryos die between 8.5 and 12.5 days postcoitus (dpc), suggesting that NRC has a pleotrophic effect on growth. To study this, we derived mouse embryonic fibroblasts (MEFs) from 12.5-dpc embryos, which revealed that NRC−/− MEFs exhibit a high rate of apoptosis. Furthermore, a small interfering RNA that targets mouse NRC leads to enhanced apoptosis of wild-type MEFs. The finding that C57/129 NRC+/− mice exhibit no apparent phenotype prompted us to develop 129S6 NRC+/− mice, since the phenotype(s) of certain gene deletions may be strain dependent. In contrast with C57/129 NRC+/− females, 20% of 129S6 NRC+/− females are infertile while 80% are hypofertile. The 129S6 NRC+/− males produce offspring when crossed with wild-type 129S6 females, although fertility is reduced. The 129S6 NRC+/− mice tend to be stunted in their growth compared with their wild-type littermates and exhibit increased postnatal mortality. Lastly, both C57/129 NRC+/− and 129S6 NRC+/− mice exhibit a spontaneous wound healing defect, indicating that NRC plays an important role in that process. Our findings reveal that NRC is a coregulator that controls many cellular and physiologic processes ranging from growth and development to reproduction and wound repair.

scholarly journals The Nuclear Hormone Receptor NHR-40 Acts Downstream of the Sulfatase EUD-1 as Part of a Developmental Plasticity Switch in Pristionchus

2016 ◽  
Vol 26 (16) ◽  
pp. 2174-2179 ◽  
Author(s):  
Manuela R. Kieninger ◽  
Nicholas A. Ivers ◽  
Christian Rödelsperger ◽  
Gabriel V. Markov ◽  
Ralf J. Sommer ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Developmental Plasticity ◽  
Nuclear Hormone Receptor

scholarly journals Urban Renewal in the Nucleus: Is Protein Turnover by Proteasomes Absolutely Required for Nuclear Receptor-Regulated Transcription?

2004 ◽  
Vol 18 (3) ◽  
pp. 493-499 ◽  
Author(s):  
Zafar Nawaz ◽  
Bert W. O’Malley
Keyword(s):  
Protein Degradation ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Gene Transcription ◽  
Hormone Receptor ◽  
Target Genes ◽  
Nuclear Hormone Receptor ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Abstract The importance of the ubiquitin proteasome pathway in higher eukaryotes has been well established in cell cycle regulation, signal transduction, and cell differentiation, but has only recently been linked to nuclear hormone receptor-regulated gene transcription. Characterization of a number of ubiquitin proteasome pathway enzymes as coactivators and observations that several nuclear receptors are ubiquitinated and degraded in the course of their nuclear activities provide evidence that ubiquitin proteasome-mediated protein degradation plays an integral role in eukaryotic transcription. In addition to receptors, studies have revealed that coactivators are ubiquitinated and degraded via the proteasome. The notion that the ubiquitin proteasome pathway is involved in gene transcription is further strengthened by the fact that ubiquitin proteasome pathway enzymes are recruited to the promoters of target genes and that proteasome-dependent degradation of nuclear receptors is required for efficient transcriptional activity. These findings suggest that protein degradation is coupled with nuclear receptor coactivation activity. It is possible that the ubiquitin proteasome pathway modulates transcription by promoting remodeling and turnover of the nuclear receptor-transcription complex. In this review, we discus the possible role of the ubiquitin proteasome pathway in nuclear hormone receptor-regulated gene transcription.

scholarly journals INTRACISTRONIC MAPPING OF ELECTROPHORETIC SITES IN DROSOPHILA MELANOGASTER: FIDELITY OF INFORMATION TRANSFER BY GENE CONVERSION

Genetics ◽  
1974 ◽  
Vol 76 (2) ◽  
pp. 289-299
Author(s):  
Margaret McCarron ◽  
William Gelbart ◽  
Arthur Chovnick
Keyword(s):  
Drosophila Melanogaster ◽  
Information Transfer ◽  
Large Scale ◽  
Genetic Basis ◽  
Xanthine Dehydrogenase ◽  
Specific Protein ◽  
Wild Type ◽  
Electrophoretic Variation ◽  
The Stability ◽  
Recombination Experiments

ABSTRACT A convenient method is described for the intracistronic mapping of genetic sites responsible for electrophoretic variation of a specific protein in Drosophila melanogaster. A number of wild-type isoalleles of the rosy locus have been isolated which are associated with the production of electrophoretically distinguishable xanthine dehydrogenases. Large-scale recombination experiments were carried out involving null enzyme mutants induced on electrophoretically distinct wild-type isoalleles, the genetic basis for which is followed as a nonselective marker in the cross. Additionally, a large-scale recombination experiment was carried out involving null enzyme rosy mutants induced on the same wild-type isoallele. Examination of the electrophoretic character of crossover and convertant products recovered from the latter experiment revealed that all exhibited the same parental electrophoretic character. In addition to documenting the stability of the xanthine dehydrogenase electrophoretic character, this observation argues against a special mutagenesis hypothesis to explain conversions resulting from allele recombination studies.

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