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Genome-wide landscape of liver X receptor chromatin binding and gene regulation in human macrophages.

Pehkonen P, Welter-Stahl L, Diwo J, Ryynänen J, Wienecke-Baldacchino A, Heikkinen S, Treuter E, Steffensen KR, Carlberg C - BMC Genomics (2012)

Bottom Line: The liver X receptors (LXRs) are oxysterol sensing nuclear receptors with multiple effects on metabolism and immune cells.Our results show that LXR actions are focused on 112 genomic regions that contain up to 11 T09 target genes per region under the control of highly stringent LXR binding sites with individual constellations for each region.We could confirm that LXR controls lipid metabolism and transport and observed a strong association with apoptosis-related functions.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Medicine, Institute of Biomedicine, University of Eastern Finland, FIN-70210 Kuopio, Finland.

ABSTRACT

Background: The liver X receptors (LXRs) are oxysterol sensing nuclear receptors with multiple effects on metabolism and immune cells. However, the complete genome-wide cistrome of LXR in cells of human origin has not yet been provided.

Results: We performed ChIP-seq in phorbol myristate acetate-differentiated THP-1 cells (macrophage-type) after stimulation with the potent synthetic LXR ligand T0901317 (T09). Microarray gene expression analysis was performed in the same cellular model. We identified 1357 genome-wide LXR locations (FDR < 1%), of which 526 were observed after T09 treatment. De novo analysis of LXR binding sequences identified a DR4-type element as the major motif. On mRNA level T09 up-regulated 1258 genes and repressed 455 genes. Our results show that LXR actions are focused on 112 genomic regions that contain up to 11 T09 target genes per region under the control of highly stringent LXR binding sites with individual constellations for each region. We could confirm that LXR controls lipid metabolism and transport and observed a strong association with apoptosis-related functions.

Conclusions: This first report on genome-wide binding of LXR in a human cell line provides new insights into the transcriptional network of LXR and its target genes with their link to physiological processes, such as apoptosis.The gene expression microarray and sequence data have been submitted collectively to the NCBI Gene Expression Omnibus http://www.ncbi.nlm.nih.gov/geo under accession number GSE28319.

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Spatial genomic organization of LXR binding locations in relation to T09 target genes. The 202 LXR locations of the high stringency peak set (Figure 1A) and the 1713 T09-regulated genes with adjusted P < 0.01 in 22 + X human chromosomes are visualized. A 1 Mb sliding window was used for the density graphs. These were further segmented, in order to detect chromosomal regions enriching LXR binding locations. One hundred twelve genomic regions were identified as hotspots for LXR actions, of which those with ≥ 2 peaks and ≥ 3 regulated genes are highlighted in red.
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Figure 2: Spatial genomic organization of LXR binding locations in relation to T09 target genes. The 202 LXR locations of the high stringency peak set (Figure 1A) and the 1713 T09-regulated genes with adjusted P < 0.01 in 22 + X human chromosomes are visualized. A 1 Mb sliding window was used for the density graphs. These were further segmented, in order to detect chromosomal regions enriching LXR binding locations. One hundred twelve genomic regions were identified as hotspots for LXR actions, of which those with ≥ 2 peaks and ≥ 3 regulated genes are highlighted in red.

Mentions: The genome-wide organization of the high stringency set of 202 LXR binding locations (Figure 1A) and of the 1713 T09-regulated genes in their physical context is shown in Figure 2 using window density based visualization. This visualization shows the densities of ChIP-Seq peaks and regulated genes across the genome within 1 Mb windows. The window densities are weighted by the FEs of ChIP-Seq peaks and the log2 fold changes (FC) of the differentially expressed (DE) genes, which emphasizes high peaks or extremely differentially expressed genes. Subsequent analysis of the window density data using segmentation (for details, see Methods) to detect the exact borders of the peak-enriched regions resulted in the indicated 112 distinct genomic areas. Regions with ≥ 2 peaks and ≥ 3 T09-regulated genes are highlighted in red and listed in Table 1 (the complete list of all regions with extended information is summarized in additional file 6: Table S3).


Genome-wide landscape of liver X receptor chromatin binding and gene regulation in human macrophages.

Pehkonen P, Welter-Stahl L, Diwo J, Ryynänen J, Wienecke-Baldacchino A, Heikkinen S, Treuter E, Steffensen KR, Carlberg C - BMC Genomics (2012)

Spatial genomic organization of LXR binding locations in relation to T09 target genes. The 202 LXR locations of the high stringency peak set (Figure 1A) and the 1713 T09-regulated genes with adjusted P < 0.01 in 22 + X human chromosomes are visualized. A 1 Mb sliding window was used for the density graphs. These were further segmented, in order to detect chromosomal regions enriching LXR binding locations. One hundred twelve genomic regions were identified as hotspots for LXR actions, of which those with ≥ 2 peaks and ≥ 3 regulated genes are highlighted in red.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3295715&req=5

Figure 2: Spatial genomic organization of LXR binding locations in relation to T09 target genes. The 202 LXR locations of the high stringency peak set (Figure 1A) and the 1713 T09-regulated genes with adjusted P < 0.01 in 22 + X human chromosomes are visualized. A 1 Mb sliding window was used for the density graphs. These were further segmented, in order to detect chromosomal regions enriching LXR binding locations. One hundred twelve genomic regions were identified as hotspots for LXR actions, of which those with ≥ 2 peaks and ≥ 3 regulated genes are highlighted in red.
Mentions: The genome-wide organization of the high stringency set of 202 LXR binding locations (Figure 1A) and of the 1713 T09-regulated genes in their physical context is shown in Figure 2 using window density based visualization. This visualization shows the densities of ChIP-Seq peaks and regulated genes across the genome within 1 Mb windows. The window densities are weighted by the FEs of ChIP-Seq peaks and the log2 fold changes (FC) of the differentially expressed (DE) genes, which emphasizes high peaks or extremely differentially expressed genes. Subsequent analysis of the window density data using segmentation (for details, see Methods) to detect the exact borders of the peak-enriched regions resulted in the indicated 112 distinct genomic areas. Regions with ≥ 2 peaks and ≥ 3 T09-regulated genes are highlighted in red and listed in Table 1 (the complete list of all regions with extended information is summarized in additional file 6: Table S3).

Bottom Line: The liver X receptors (LXRs) are oxysterol sensing nuclear receptors with multiple effects on metabolism and immune cells.Our results show that LXR actions are focused on 112 genomic regions that contain up to 11 T09 target genes per region under the control of highly stringent LXR binding sites with individual constellations for each region.We could confirm that LXR controls lipid metabolism and transport and observed a strong association with apoptosis-related functions.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Medicine, Institute of Biomedicine, University of Eastern Finland, FIN-70210 Kuopio, Finland.

ABSTRACT

Background: The liver X receptors (LXRs) are oxysterol sensing nuclear receptors with multiple effects on metabolism and immune cells. However, the complete genome-wide cistrome of LXR in cells of human origin has not yet been provided.

Results: We performed ChIP-seq in phorbol myristate acetate-differentiated THP-1 cells (macrophage-type) after stimulation with the potent synthetic LXR ligand T0901317 (T09). Microarray gene expression analysis was performed in the same cellular model. We identified 1357 genome-wide LXR locations (FDR < 1%), of which 526 were observed after T09 treatment. De novo analysis of LXR binding sequences identified a DR4-type element as the major motif. On mRNA level T09 up-regulated 1258 genes and repressed 455 genes. Our results show that LXR actions are focused on 112 genomic regions that contain up to 11 T09 target genes per region under the control of highly stringent LXR binding sites with individual constellations for each region. We could confirm that LXR controls lipid metabolism and transport and observed a strong association with apoptosis-related functions.

Conclusions: This first report on genome-wide binding of LXR in a human cell line provides new insights into the transcriptional network of LXR and its target genes with their link to physiological processes, such as apoptosis.The gene expression microarray and sequence data have been submitted collectively to the NCBI Gene Expression Omnibus http://www.ncbi.nlm.nih.gov/geo under accession number GSE28319.

Show MeSH
Related in: MedlinePlus