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See detailModelling and global analysis of transcript profiles reveals dynamic roles for microRNAs in transcriptional networks controlling lineage commitment.
Liivrand, Maria UL

Doctoral thesis (2014)

Controlled maintenance of multipotent stem cells is a key component for the development and sustainment of complex multicellular organisms. Various signalling pathways contribute to these processes being ... [more ▼]

Controlled maintenance of multipotent stem cells is a key component for the development and sustainment of complex multicellular organisms. Various signalling pathways contribute to these processes being either lineage specific or more ubiquitously distributed over different tissue types. Transcription factors are considered as the primary propagators of signals that induce multipotent precursor cells to differentiate into specified cell types. These processes are required to revolve in a constrained and timely manner, with different cell types using variable sets of transcription factors and time scales. microRNA molecules represent an efficient and specific class of regulatory non-coding RNA molecules that efficiently constrain and specify differentiation cascades. New findings suggest that various endogenous non-coding RNA species, whose expression is governed through elaborate transcription factor networks, contribute to the regulation of genomewide transcriptional output. Here, evidence is presented of microRNA and transcription factor connectivity during differentiation cascades. First, these two classes of RNA regulatory molecules are shown to share a common target, lipoprotein lipase, and exert dynamical regulation over its expression during adipogenic differentiation. Second, investigating the genome-wide initial events of adipogenic and osteoblastic lineage commitment cascades reveals extensive transcription in non-protein-coding genomic regions. Further analysis of a select cohort of these non-coding transcripts allows for inferring transcription factor binding dynamics through enhancer-related RNA sequences as well as suggests a more wide-spread role for long non-coding RNA species in regulating transcriptional output. These findings contribute to unravelling basic transcriptional circuitry during cellular transitions. [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 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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