References of "Heinäniemi, Merja 40000283"
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See detailThe Effects of Sequence Variation on Genome-wide NRF2 Binding––New Target Genes and Regulatory SNPs
Kuosmanen, Suvi; Viitala, Sari; Laitinen, Tuomo et al

in Nucleic Acids Research (2016), 44(4), 1760-1775

Transcription factor binding specificity is crucial for proper target gene regulation. Motif discovery algorithms identify the main features of the binding patterns, but the accuracy on the lower affinity ... [more ▼]

Transcription factor binding specificity is crucial for proper target gene regulation. Motif discovery algorithms identify the main features of the binding patterns, but the accuracy on the lower affinity sites is often poor. Nuclear factor E2-related factor 2 (NRF2) is a ubiquitous redox-activated transcription factor having a key protective role against endogenous and exogenous oxidant and electrophile stress. Herein, we decipher the effects of sequence variation on the DNA binding sequence of NRF2, in order to identify both genome-wide bind- ing sites for NRF2 and disease-associated regulatory SNPs (rSNPs) with drastic effects on NRF2 binding. Interactions between NRF2 and DNA were studied using molecular modelling, and NRF2 chromatin immunoprecipitation-sequence datasets together with protein binding microarray measurements were utilized to study binding sequence variation in detail. The binding model thus generated was used to identify genome-wide binding sites for NRF2, and genomic binding sites with rSNPs that have strong effects on NRF2 binding and reside on active regulatory elements in human cells. As a proof of concept, miR-126–3p and -5p were identified as NRF2 target microRNAs, and a rSNP (rs113067944) residing on NRF2 target gene (Ferritin, light polypeptide, FTL) promoter was experimentally verified to decrease NRF2 binding and result in decreased transcriptional activity. [less ▲]

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See detailTranscriptomics profiling of human SGBS adipogenesis
Galhardo, Mafalda Sofia UL; Sinkkonen, Lasse UL; Berninger, Philipp et al

in Genomics Data (2014), 2

Obesity is an ever-growing epidemic where tissue homeostasis is influenced by the differentiation of adipocytes that function in lipid metabolism, endocrine and inflammatory processes. While this ... [more ▼]

Obesity is an ever-growing epidemic where tissue homeostasis is influenced by the differentiation of adipocytes that function in lipid metabolism, endocrine and inflammatory processes. While this differentiation process has been well-characterized in mice, limited data is available from human cells. Applying microarray expression profiling in the human SGBS pre-adipocyte cell line, we identified genes with differential expression during differentiation in combination with constraint-based modeling of metabolic pathway activity. Here we describe the experimental design and quality controls in detail for the gene expression and related results published by Galhardo et al. in Nucleic Acids Research 2014 associated with the data uploaded to NCBI Gene Expression Omnibus (). [less ▲]

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See detailCombinatorial regulation of lipoprotein lipase by microRNAs during mouse adipogenesis
Liivrand, Maria UL; Heinäniemi, Merja UL; John, Elisabeth UL et al

in RNA Biology (2014), 11(1), 76-91

MicroRNAs (miRNAs) regulate gene expression directly through base pairing to their targets or indirectly through participating in multi-scale regulatory networks. Often miRNAs take part in feed-forward ... [more ▼]

MicroRNAs (miRNAs) regulate gene expression directly through base pairing to their targets or indirectly through participating in multi-scale regulatory networks. Often miRNAs take part in feed-forward motifs where a miRNA and a transcription factor act on shared targets to achieve accurate regulation of processes such as cell differentiation. Here we show that the expression levels of miR-27a and miR-29a inversely correlate with the mRNA levels of lipoprotein lipase (Lpl), their predicted combinatorial target, and its key transcriptional regulator peroxisome proliferator activated receptor gamma (Pparg) during 3T3-L1 adipocyte differentiation. More importantly, we show that Lpl, a key lipogenic enzyme, can be negatively regulated by the two miRNA families in a combinatorial fashion on the mRNA and functional level in maturing adipocytes. This regulation is mediated through the Lpl 3′UTR as confirmed by reporter gene assays. In addition, a small mathematical model captures the dynamics of this feed-forward motif and predicts the changes in Lpl mRNA levels upon network perturbations. The obtained results might offer an explanation to the dysregulation of LPL in diabetic conditions and could be extended to quantitative modeling of regulation of other metabolic genes under similar regulatory network motifs. [less ▲]

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See detailIntegrated analysis of transcript-level regulation of metabolism reveals disease-relevant nodes of the human metabolic network
Galhardo, Mafalda Sofia UL; Sinkkonen, Lasse UL; Berninger, Philippe et al

in Nucleic Acids Research (2013)

Metabolic diseases and comorbidities represent an ever-growing epidemic where multiple cell types impact tissue homeostasis. Here, the link between the metabolic and gene regulatory networks was studied ... [more ▼]

Metabolic diseases and comorbidities represent an ever-growing epidemic where multiple cell types impact tissue homeostasis. Here, the link between the metabolic and gene regulatory networks was studied through experimental and computational analysis. Integrating gene regulation data with a human metabolic network prompted the establishment of an open-sourced web portal, IDARE (Integrated Data Nodes of Regulation), for visualizing various gene-related data in context of metabolic pathways. Motivated by increasing availability of deep sequencing studies, we obtained ChIP-seq data from widely studied human umbilical vein endothelial cells. Interestingly, we found that association of metabolic genes with multiple transcription factors (TFs) enriched disease-associated genes. To demonstrate further extensions enabled by examining these networks together, constraintbased modeling was applied to data from human preadipocyte differentiation. In parallel, data on gene expression, genome-wide ChIP-seq profiles for peroxisome proliferator-activated receptor (PPAR) c, CCAAT/enhancer binding protein (CEBP) a, liver X receptor (LXR) and H3K4me3 and microRNA target identification for miR-27a, miR-29a and miR-222 were collected. Disease-relevant key nodes, including mitochondrial glycerol-phosphateacyltransferase (GPAM), were exposed from metabolic pathways predicted to change activity by focusing on association with multiple regulators. In both cell types, our analysis reveals the convergence of microRNAs and TFs within the branched chain amino acid (BCAA) metabolic pathway, possibly providing an explanation for its downregulation in obese and diabetic conditions. [less ▲]

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See detailGene-pair expression signatures reveal lineage control
Heinäniemi, Merja UL; Nykter, Matti; Kramer, Roger et al

in Nature Methods (2013)

The distinct cell types of multicellular organisms arise due to constraints imposed by gene regulatory networks on the collective change of gene expression across the genome, creating self-stabilizing ... [more ▼]

The distinct cell types of multicellular organisms arise due to constraints imposed by gene regulatory networks on the collective change of gene expression across the genome, creating self-stabilizing expression states, or attractors. We compiled a resource of curated human expression data comprising 166 cell types and 2,602 transcription regulating genes and developed a data driven method built around the concept of expression reversal defined at the level of gene pairs, such as those participating in toggle switch circuits. This approach allows us to organize the cell types into their ontogenetic lineage-relationships and to reflect regulatory relationships among genes that explain their ability to function as determinants of cell fate. We show that this method identifies genes belonging to regulatory circuits that control neuronal fate, pluripotency and blood cell differentiation, thus offering a novel large-scale perspective on lineage specification. [less ▲]

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See detailDataset integration identifies transcriptional regulation of microRNA genes by PPARgamma in differentiating mouse 3T3-L1 adipocytes
John, Elisabeth UL; Wienecke-Baldacchino, Anke UL; Liivrand, Maria UL et al

in Nucleic Acids Research (2012), 40(10), 4446-4460

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a key transcription factor in mammalian adipogenesis. Genome-wide approaches have identified thousands of PPARgamma binding sites in mouse ... [more ▼]

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a key transcription factor in mammalian adipogenesis. Genome-wide approaches have identified thousands of PPARgamma binding sites in mouse adipocytes and PPARgamma upregulates hundreds of protein-coding genes during adipogenesis. However, no microRNA (miRNA) genes have been identified as primary PPARgamma-targets. By integration of four separate datasets of genome-wide PPARgamma binding sites in 3T3-L1 adipocytes we identified 98 miRNA clusters with PPARgamma binding within 50 kb from miRNA transcription start sites. Nineteen mature miRNAs were upregulated >/=2-fold during adipogenesis and for six of these miRNA loci the PPARgamma binding sites were confirmed by at least three datasets. The upregulation of five miRNA genes miR-103-1 (host gene Pank3), miR-148b (Copz1), miR-182/96/183, miR-205 and miR-378 (Ppargc1b) followed that of Pparg. The PPARgamma-dependence of four of these miRNA loci was demonstrated by PPARgamma knock-down and the loci of miR-103-1 (Pank3), miR-205 and miR-378 (Ppargc1b) were also responsive to the PPARgamma ligand rosiglitazone. Finally, chromatin immunoprecipitation analysis validated in silico predicted PPARgamma binding sites at all three loci and H3K27 acetylation was analyzed to confirm the activity of these enhancers. In conclusion, we identified 22 putative PPARgamma target miRNA genes, showed the PPARgamma dependence of four of these genes and demonstrated three as direct PPARgamma target genes in mouse adipogenesis. [less ▲]

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See detailTime-Resolved Expression Profiling of the Nuclear Receptor Superfamily in Human Adipogenesis
Lahnalampi, Mari; Heinäniemi, Merja UL; Sinkkonen, Lasse UL et al

in PLoS ONE (2010), 5(9),

Background: The differentiation of fibroblast-like pre-adipocytes to lipid-loaded adipocytes is regulated by a network of transcription factors, the most prominent one being the nuclear receptor ... [more ▼]

Background: The differentiation of fibroblast-like pre-adipocytes to lipid-loaded adipocytes is regulated by a network of transcription factors, the most prominent one being the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma. However, many of the other 47 members of the nuclear receptor superfamily have an impact on adipogenesis, which in human cells has not been investigated in detail. Methodology/Principal Findings: We analyzed by quantitative PCR all human nuclear receptors at multiple time points during differentiation of SGBS pre-adipocytes. The earliest effect was the down-regulation of the genes RARG, PPARD, REVERBA, REV-ERBB, VDR and GR followed by the up-regulation of PPARG, LXRA and AR. These observations are supported with data from 3T3-L1 mouse pre-adipocytes and primary human adipocytes. Investigation of the effects of the individual differentiation mix components in short-term treatments and of their omission from the full mix showed that the expression levels of the early-regulated nuclear receptor genes were most affected by the glucocorticoid receptor (GR) ligand cortisol and the phosophodiesterase inhibitor IBMX. Interestingly, the effects of both compounds converged to repress the genes PPARD, REV-ERBA, REV-ERBB, VDR and GR, whereas cortisol and IBMX showed antagonistic interaction for PPARG, LXRA and AR causing a time lag in their up-regulation. We hypothesize that the well-known auto-repression of GR fine-tunes the detected early responses. Consistently, chromatin immunoprecipitation experiments showed that GR association increased on the transcription start sites of the genes RARG, REV-ERBB, VDR and GR. Conclusions/Significance: Adipocyte differentiation is a process, in which many members of the nuclear receptor superfamily change their mRNA expression. The actions of cortisol and IBMX converged to repress several nuclear receptors early in differentiation, while up-regulation of other nuclear receptor genes showed a time lag due to antagonisms of the signals. Our results place GR and its ligand cortisol as central regulatory factors controlling early regulatory events in human adipogenesis that precedes the regulation of the later events by PPARG. [less ▲]

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