It has been estimated that only 2 % of the mammalian genome encodes for protein products, whereas 70-90 % is extensively transcribed to produce a large transcriptome of non-coding RNA species (ncRNA). The unexpected pervasive transcription recently revealed by improved RNA-seq technologies has challenged the traditional view of RNA as merely intermediary between genes and proteins and has identified ncRNA as functional RNA species involved in the regulation of fundamental biological processes. Since their first discovery in 1993 (Wightman et al. 1993; Lee et al. 1993), the list of functional ncRNA classes is growing and to date it appears evident that microRNA (miRNA), which represent the most comprehensive and well characterized class of small ncRNA, are just the tip of the iceberg. MiRNA are a class of small evolutionary conserved ncRNA which regulate translation and stability of several target mRNA in a sequence-specific manner. They can be encoded as single miRNA or be organized in cluster of multiple miRNA. They have been identified in intergenic regions of the genome (Olena and Patton 2010), where they are transcribed as standing alone units, and in other cases at the level of annotated transcripts, located in introns of protein-coding genes; in the latter case their expression is often co-regulated with that of the host gene. They originate from a primary transcript of ∼1 kb length called primary miRNA (pri-miRNA), processed in the nucleus by the RNAse III enzyme Drosha and DGCR8 into an hairpin precursor called precursor miRNA (pre-miRNA) of about 60 nt in length. The pre-miRNA is then exported to the cytoplasm where it is cleaved by the RNAse III Dicer to generate imperfect miRNA-miRNA∗duplexes (Dueck et al. 2012). The preferential selection of one miRNA strand depends, at least in part associated with the thermodynamic instability of the mature miRNA strand (Hu et al. 2009), lead to the generation of a mature miRNA of ∼22 nt in length, incorporated into the RNA-induced silencing complex (RISC). Within the RISC, the mature miRNA interacts with members of the argonaute (Ago) proteins and drives Ago proteins and other associated factors to partially complementary target sites, mainly located in the 3′UTR of the mRNA targets (Chekulaeva and Filipowicz 2009; Filipowicz et al. 2008), leading to their post-transcriptional repression (Chekulaeva and Filipowicz 2009; Filipowicz et al. 2008). The precise mechanism of such down-regulation is not fully understood, but is largely dependent on the extent of base-pairing complementarity between the miRNA and the respective mRNA target (Lee and Shin 2012). Since the first evidence of miRNA deregulated expression in cancer cells (Calin et al. 2002), it has become apparent that miRNA are indeed key regulators of cellular functions in different aspect of cell biology, from cell development to apoptosis, cell cycle, and differentiation (Lodish et al. 2008; Bartel and Chen 2004). From the perspective of innate immunity, miRNA have been extensively studied both in physiological and pathological contexts. They are differentially expressed in immune cells and are able to target proteins involved in the modulation of panel of genes involved in myeloid cell maturation, inflammatory pathways, and macrophage polarization processes. At the molecular level mRNA targets show in most cases a relatively mild down-regulation at the protein level (O'Connell et al. 2012) (from 1.2 to 4-fold) as miRNA do not act as on-off molecular switches but rather fine tune the expression of multiple target genes involved in a common biological processes. Specific sets of miRNA have also been demonstrated to work in concert with other regulatory molecules [i.e., transcription factors and other emerging classes of ncRNAs (Pagani et al. 2013)] to affect the expression of key components of signaling pathways. The proper combination of these mechanisms results in a precise and timely modulation of cellular responses, affecting strength, location, and timing of the immune response (Bhaumik et al. 2008; Baek et al. 2008).
|Title of host publication||Macrophages: Biology and Role in the Pathology of Diseases|
|Publisher||Springer New York|
|Number of pages||11|
|ISBN (Print)||9781493913114, 1493913107, 9781493913107|
|Publication status||Published - May 1 2014|
ASJC Scopus subject areas
- Immunology and Microbiology(all)