South African National Bioinformatics Institute, University of the Western Cape, Modderdam Road, Bellville, South Africa.
BMC Genomics. 2009 Dec 10;10:595. doi: 10.1186/1471-2164-10-595.
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.
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.
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.
巨噬细胞是参与多种生物学过程的免疫细胞，包括宿主防御、稳态、分化和器官发生。巨噬细胞生物学的破坏与病原体感染、炎症和恶性疾病的增加有关。单核细胞分化中观察到的差异基因表达主要受相互作用的转录因子（TFs）调节。目前的研究表明，microRNAs（miRNAs）降解并抑制 mRNA 的翻译，但也可能靶向分化过程中涉及的基因。我们专注于深入了解调节单核细胞分化过程中表达的 miRNA 基因的转录电路。
我们使用体外时间过程表达数据对 TF 和 miRNA 进行计算分析，以了解单核细胞分化过程中 miRNA 基因的转录电路。从 miRNA 基因启动子区域中预测的 TF 结合位点中获得了一组 TF-->miRNA 关联。利用时间滞后表达相关性分析评估了 TF-->miRNA 关联。我们的分析确定了 12 个 TF，它们可能在整个分化过程中调节 miRNA 发挥核心作用。这 12 个 TF 中有 6 个（ATF2、E2F3、HOXA4、NFE2L1、SP3 和 YY1）以前没有被描述为对单核细胞分化很重要。其余 6 个 TF 是 CEBPB、CREB1、ELK1、NFE2L2、RUNX1 和 USF2。对于几个 miRNA（miR-21、miR-155、miR-424 和 miR-17-92），我们展示了它们推断的转录调控如何影响单核细胞分化。
该研究表明，miRNAs 及其转录调控控制是分化过程中的整体分子机制。此外，这是第一项大规模研究如何在人类单核细胞分化过程中由 TFs 控制 miRNAs 的研究。随后，我们确定了在这个分化过程中 12 个候选 miRNA 关键控制器。
