The miR-181 family: Wide-ranging pathophysiological effects on cell fate and function

Abstract

MicroRNAs (miRNAs) are epigenetic regulators that can target and inhibit translation of multiple mRNAs within a given cell type. As such, a number of different pathways and networks may be modulated as a result. In fact, miRNAs are known to regulate many cellular processes including differentiation, proliferation, inflammation, and metabolism. This review focuses on the miR-181 family and provides information from the published literature on the role of miR-181 homologs in regulating a range of activities in different cell types and tissues. Of note, we have not included details on miR-181 expression and function in the context of cancer since this is a broad topic area requiring independent review. Instead, we have focused on describing the function and mechanism of miR-181 family members on differentiation toward a number of cell lineages in various non-neoplastic conditions (e.g., immune/hematopoietic cells, osteoblasts, osteoclasts, chondrocytes, adipocytes). We have also provided information on how modulation of miR-181 homologs can have positive effects on disease states such as cardiac abnormalities, pulmonary arterial hypertension, thrombosis, osteoarthritis, and vascular inflammation. In this context, we have used some examples of FDA-approved drugs that modulate miR-181 expression. We conclude by discussing some common mechanisms by which miR-181 homologs appear to regulate a number of different cellular processes and how targeting specific miR-181 family members may lead to attractive therapeutic approaches to treat a number of human disease or repair conditions, including those associated with the aging process.

Keywords: cardiovascular; cell differentiation; miR-181; miR-181 family; microRNA; musculoskeletal.

Figure 1.. Synthesis and function of microRNAs.

Left panel shows RNA polymerase II-mediated transcription of a clustered microRNA gene in the nucleus resulting in formation of primary (pri) miRNAs which are then processed to precursor (pre) miRNAs and transported to the cytoplasm. Right panel shows processing of pre-miRNAs in the cytoplasm by a Dicer-containing enzyme complex and interaction of the functional (5p) mature miRNA strand, via its seed sequence, with a complementary sequence on the 3’UTR of a target mRNA. This interaction is mediated by the RNA-induced silencing complex (RISC) containing Ago2 protein. The result of this interaction is either mRNA degradation or suppression of mRNA translation.

Figure 2.. The human miR-181 family.

The human (homo sapiens; hsa) miR-181 family is encoded for by 6 genes shown by the grey boxes located on chromosome (chr) 1, 9 and 19. The blue and orange-boxed areas represent the mature 5p and 3p strand, respectively, within each miR-181 gene. Each chromosome contains two clustered miRNA genes: miR-181a/b-1 (Chr 1), miR-181a/b-2 (Chr 9) and miR-181c/d (Chr 19). The number of nucleotides (nt) separating these clustered miRNA genes is shown. Right panel show the sequence of each mature miR-181 strand. The seed sequence (red font) is conserved between each family member. Underlined regions indicate regions that are not conserved between the family members.

Figure 3.. miR-181 regulates differentiation of many cell types.

The published literature informs us that miR-181 homologs can either enhance (+) or suppress (−) differentiation toward various cell lineages. There are also mixed reports (+/−) on whether a specific miR-181 homolog has positive or negative effects on differentiation. Some studies also report no effect (x) of a miR-181 family member on cell differentiation. See Table 1 for information about miR-181 targets in each differentiation lineage. References: [1] (Li, 2013) [2] (Ouyang, 2016) [3] (Zhang, 2019) [4] (Knarr, 2019) [5] (Chen, 2016b) [6] (Chen, 2016a) [7] (Henao-Mejia, 2013) [8] (Chen, 2004) [9] (Gabler, 2015) [10] (Lv, 2020b) [11] (Barter, 2015) [12] (Vail, 2022) [13] (Melnik, 2021) [14] (Bakhshandeh, 2012b) [15] (Zhang, 2022) [16] (Su, 2015) [17] (Li, 2012b) [18] (Naguibneva, 2006) [19] (Wei, 2016) [20] (Yuan, 2022) [21] (He, 2022) [22] (Wang, 2020) [23] (Zhao, 2019) [24] (Cichocki, 2011) [25] (Bhushan, 2013) [26] (Liu, 2020) [27] (Bakhshandeh, 2012a) [28] (Zheng, 2019) [29] (Qi, 2021) [30] (Lv, 2020a) [31] (Ma, 2020) [32] (Liu, 2021) [33] (Xie, 2018) [34] (Zhang, 2021) [35] (Shao, 2015) [36] (Shao, 2018) [37] (Fu, 2021) [38] (Han, 2020) [39] (Yu, 2021) [40] (Sun, 2019) [41] (Liu, 2008)