**4.1 Transcriptional regulation**

Similar to protein-coding genes, miRNA genes can also be regulated through transcription level. The promoters of miRNA genes are controlled by transcription factors (TFs). Many TFs regulate miRNA gene expression through positive or negative mechanism in a tissue-specific or developmental-specific manner. For instance, MYC inhibits expression of tumor suppressor miRNA-15a, which promote MYC-mediated tumorigenesis [6]. On the other hands, MYC can stimulate expression of miR-9 in neuroblastoma cells, resulting in regulation of E-cadherin and cancer metastasis [7]. It has shown that p53 enhances the expression of miR-34 and miR-107 families, which induce cell cycle arrest and apoptosis [8]. In addition to regulate by TFs, the expression of miRNA can be regulated by methylation of the promoter. Most of the miRNA promoter region has certain CpG islands. For example, promoter hypermethylation of genes such as miR-132, miR-34b/c, miR-218-1/2, and miR33b have been associated with or denote a poor prognosis of various cancers [9, 10]. In addition, the changes in DNMT1 and DNMT3b DNA methyltransferases lead to alter the miRNAs (miR-148a, miR-34b/c, miR-9 and let-7) gene promoter methylation status, resulting in regulation of their gene transcription levels [11]. Furthermore, it has reported that miR-210 is highly induced by hypoxia in various cancer cell lines [12], whose expression is not only regulated by the transcription factors hypoxia-inducible factor-1 (HIF-1), but also regulated by DNA demethylation mechanism in neural progenitor cells under both normoxia and hypoxia [12].
