Deciphering the transcriptional circuitry of microRNA genes expressed during human monocytic differentiation.
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.
Schmeier
Sebastian
S
South African National Bioinformatics Institute, University of the Western Cape, Modderdam Road, Bellville, South Africa. sebastian.schmeier@kaust.edu.sa
MacPherson
Cameron R
CR
Essack
Magbubah
M
Kaur
Mandeep
M
Schaefer
Ulf
U
Suzuki
Harukazu
H
Hayashizaki
Yoshihide
Y
Bajic
Vladimir B
VB
D001665:Binding Sites; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D009000:Monocytes / Q000166:cytology* / Q000276:immunology; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology; D014158:Transcription, Genetic
D035683:MicroRNAs; D014157:Transcription Factors