Abstract
Background: Macrophages are immune cells involved in various biological processes including host defence, homeostasis, differentiation, and organogenesis. Disruption of macrophage biology has been linked to increased pathogen infection, inflammation and malignant diseases. Differential gene expression observed in monocytic differentiation is primarily regulated by interacting transcription factors (TFs). Current research suggests that microRNAs (miRNAs) degrade and repress translation of mRNA, but also may target genes involved in differentiation. We focus on getting insights into the transcriptional circuitry regulating miRNA genes expressed during monocytic differentiation. Results: We computationally analysed the transcriptional circuitry of miRNA genes during monocytic differentiation using in vitro time-course expression data for TFs and miRNAs. A set of TF→miRNA associations was derived from predicted TF binding sites in promoter regions of miRNA genes. Time-lagged expression correlation analysis was utilised to evaluate the TF→miRNA associations. Our analysis identified 12 TFs that potentially play a central role in regulating miRNAs throughout the differentiation process. Six of these 12 TFs (ATF2, E2F3, HOXA4, NFE2L1, SP3, and YY1) have not previously been described to be important for monocytic differentiation. The remaining six TFs are CEBPB, CREB1, ELK1, NFE2L2, RUNX1, and USF2. For several miRNAs (miR-21, miR-155, miR-424, and miR-17-92), we show how their inferred transcriptional regulation impacts monocytic differentiation. Conclusions: The study demonstrates that miRNAs and their transcriptional regulatory control are integral molecular mechanisms during differentiation. Furthermore, it is the first study to decipher on a large-scale, how miRNAs are controlled by TFs during human monocytic differentiation. Subsequently, we have identified 12 candidate key controllers of miRNAs during this differentiation process.
| Original language | English |
|---|---|
| Article number | 595 |
| Journal | BMC Genomics |
| Volume | 10 |
| DOIs | |
| Publication status | Published - 10 Dec 2009 |
| Externally published | Yes |
Bibliographical note
Funding Information:We thank Alistair Forrest and Mutsumi Kanamori for providing the normalized miRNA array data. SS, US and VBB were partly supported by the National Bioinformatics Network grants; ME has been supported by a Scarce Skills Scholarship from the National Research Foundation (SFH2007080600011); MK has been supported by the postdoctoral fellowship from the Claude Leon Foundation, South Africa; VBB has been partly supported by the National Research Foundation grants (61070 and 62302); CRM and VBB were partly supported by the DSTNRF Research Chair grant (64751). This study was also partly supported by a grant of the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) to YH and a Research Grant for RIKEN Omics Science Center from MEXT to YH.
