Guide Nuclear Receptors: Current Concepts and Future Challenges: 8 (Proteins and Cell Regulation)

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In the first quarter of the 20th century the identification vitamin D3 and its sunlight driven production in skin paved the way to the elimination of rickets as a major medical problem. Twenty years or so later Sir Vincent Wigglesworth established the endocrine basis of developmental moulting in insects, arguably the most commonly performed animal behaviour on Planet Earth.

A paradigm that would unify these disparate observations arose between in and beginning with the identification of the glucocorticoid receptor and the nuclear receptor super-family. What follows is a timely and positive manifestation of the capacity, productivity and value of international human scientific endeavour.

Based on intrigue, lively competition and cooperation a global effort has rapidly fostered a school of biology with widespread ramifications for the understanding of metazoan animals, the human condition and the state of the planet. This book is the first this century to try and capture the spirit of this endeavour, to depict where the field is now and to identify some of the challenges and opportunities for the future. SlideShare Explore Search You.

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We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime. Upcoming SlideShare. Like this presentation? Statistical Methods For Experimental Biological Innovations That Built Empty Brain A Happy Landschaften Beobachten, Nutzen Und With no known ligand and few proposed binding sites in mouse and human cell lines [ 16 — 19 ], the function of the TR4 orphan nuclear receptor was largely unknown when we began these studies. To further elucidate biological roles for TR4, we set out to identify in vivo TR4 binding sites throughout the entire human genome using chromatin immunoprecipitation followed by high throughput sequencing ChIP-seq.

We wanted to compare its binding profiles in cells derived from different tissue types.

Nuclear Receptors: Current Concepts and Future Challenges

By characterizing its binding in these cell lines, we could compare TR4 binding sites with other transcription factor binding sites and histone marks determined by other ENCODE groups examining these same cell types. We first validated the presence of TR4 protein in these cell lines by Western Blot analysis see Additional file 1.

We began our ChIP experiments using the hematopoietic cell line K and the liver cell line HepG2, but were unable to confirm TR4 enrichment at targets previously published in the specialized and differentiated hematopoietic cells. Therefore, we initially proceeded without having positive controls for the ChIP assays. We prepared sequencing libraries from ChIP experiments from two independently grown batches of HepG2 cells. Only sequences that uniquely matched those in the human genome were retained for analysis. Using the Sole-search peak calling program with default settings FDR 0.

This overlap demonstrates good reproducibility between biological replicates. To obtain the final list of 2, TR4 binding sites in HepG2 cells, all reads ChIP-seq libraries were then prepared from two biological replicates using the TR4 antibody resulting in 23 million sequence reads for HeLa cells, 30 million for GM cells and 16 million for K cells see Additional file 4 for a summary of the data analysis.

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Comparison of TR4 targets in 4 different cell types. The number of tags reflecting the ChIP enrichments is plotted on the y axis and chromosomal coordinates hg18 are shown on the x axis. The position to which a transcription factor binds relative to the start site of transcription can provide insight into how the factor regulates transcription. For example, E2F family members bind to core promoter regions and are thought to stimulate transcription by interaction with the basal transcription machinery [ 22 , 23 ].

In contrast, other transcription factors, such as GATA1 or TCF4 TCF7L2 , show significant binding to sites often located more than 10 kb away from the gene that they regulate [ 21 , 24 ], suggesting that these factors may regulate transcription by looping mechanisms. Although the number of TR4 binding sites varied among the different cell types, location analysis revealed that TR4 preferentially binds close to the transcription start sites of its target genes.

To further characterize TR4 binding sites, TR4 ChIP-seq reads were organized into bp bins relative to the start site of transcription. The distribution of TR4 peaks relative to the transcription start site demonstrated that the majority of TR4 binding occurs between 1 kb upstream and 1 kb downstream of a TSS Figure 2C. For the rest of our studies, we therefore focused on the targets found within 1 kb of a TSS.

Location analysis of TR4 binding sites in HeLa cells. A Shown is a pie chart indicating the distribution of called TR4 peaks. B Distribution of peaks found within genes.

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C Histogram showing the distribution of peak distances relative to the transcription start site TSS of the nearest gene. Peaks were combined in bp bins.

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A significant fraction of TR4 binding sites was shared among cell types Figure 1B. We next matched the TR4 peaks to the nearest gene. In some cases more than one peak matched to a given gene. As a consequence, the number of TR4 binding sites is slightly higher than the number of target genes. While blood cells shared most of their TR4 targets, liver cells contained the largest number of unique target genes.

TR4 may regulate genes important for basic biological processes shared in multiple cell types, while it may play an additional role in regulating cell type specific genes. Overlap of TR4 target genes in 4 cell types. A target gene is defined as the nearest gene to a ChIP-seq peak. In some cases a target gene was contained more than one peak. As shown above, the majority of TR4 targets are shared between different cell types. All Entrez Genes were used as background to determine the significance of over-representation. Categories of TR4 target genes are highly enriched in fundamental biological processes, such as RNA metabolism and protein translation ribosome Figure 4A.

In addition, TR4 may also regulate cell type-specific genes. To test this hypothesis, we performed gene ontology analysis on genes found in only one cell type. The number of unique target genes in K, HeLa, and GM cells was not sufficient to perform meaningful gene ontology analysis. However when TR4 target genes specific to HepG2 cells were analyzed, we found some unique functional categories Figure 4B. HepG2 specific target genes were significantly enriched for ubiquitin cycle, nucleosome, chromatin assembly and metabolic processes, particularly those involving organic acid, carbohydrates, and lipids.

Interestingly, a few previous studies have suggested a role for TR4 in gluconeogenesis [ 16 ]. Furthermore, TR4 may exert its function by sensing lipids and the presence of fatty acids was found to enhance cofactor recruitment to TR4 [ 26 ] suggesting an important role for lipids in TR4 function. Functional enrichment analysis of TR4 target genes. A Targets common to all 4 cell types and B targets unique to HepG2 cells. Significantly enriched gene ontology terms for biological processes are shown on the y axis; the x axis represents p-values for each enriched category.

In recent years it has become evident that transcription factors often play dual roles, affecting activation as well as repression of target genes. Previous studies have implicated TR4 in both activation and repression of cellular target genes [ 7 ].

Recently, a global atlas for transcription factor networks has been assembled based on physical protein-protein interactions using mammalian two hybrid data [ 28 ]. NRIP1 may function as a corepressor or coactivator depending on the interacting protein [ 29 ]. Furthermore, post translational modifications of TR4 influence its interaction with cofactors [ 30 ].

We wanted to determine whether TR4 target genes are expressed or silenced. The median expression value of TR4 target genes in HeLa and HepG2 cells median expression value and , respectively is higher than the median expression value of all genes from the HepG2 expression array median expression value TR4 target genes are also expressed at higher levels than a set of randomly selected genes from the HepG2 expression array median expression value Expression analysis of TR4 target genes.


Box-and-whisker diagrams show the range of expression values of TR4 bound genes in HeLa and HepG2 cells in comparison to expression values of all genes present on the HepG2 expression array and to the set of randomly selected genes. Expression values are plotted on the y axis. The central line in the box-and-whisker plots shows the position of the median, the upper and lower boundaries of the box represent the location of the upper 75th percentile and the lower 25th percentile quartiles, respectively.

Data outliers are not shown. The correlation between TR4 binding and expression of target genes suggests that TR4 binds to open accessible chromatin regions. To test this hypothesis, we examined the epigenetic signature at TR4 binding sites using ChIP-seq data of various histone marks in K cells. A distance of base pairs between peaks was allowed to take nucleosome positioning into account. A remarkable of the TR4 target sites in K cells were also occupied by H3K4me3, which is a mark for accessible chromatin.