miR-138 is a member of the microRNA (miRNA) family, a class of small non‑coding RNA molecules, typically 20–24 nucleotides in length, that regulate gene expression post‑transcriptionally. The mature miRNA is processed from a primary transcript (pri‑miRNA) through precursor forms (pre‑miRNA) by the Drosha and Dicer ribonuclease complexes. miR-138 is encoded by two genomic loci in humans: MIR138‑1 on chromosome 3p21.33 and MIR138‑2 on chromosome 16q13.3, each giving rise to the same mature miRNA sequence.
Biogenesis and Sequence
The mature miR-138 sequence is highly conserved across vertebrates, with the seed region (nucleotides 2–8) playing a critical role in target recognition. The precursor hairpin structures of MIR138‑1 and MIR138‑2 differ in flanking sequences but share an identical stem‑loop that yields the same mature miRNA after Dicer cleavage.
Expression Patterns
miR-138 exhibits tissue‑specific expression. It is abundant in the central nervous system, particularly in neuronal cells, and is also detected in the epidermis, thymus, and certain immune cell subsets. Developmental regulation has been observed, with elevated levels during neuronal differentiation and in mature synaptic structures.
Molecular Targets and Function
Through base‑pairing with complementary sites in the 3′ untranslated regions (3′‑UTRs) of messenger RNAs, miR-138 represses translation or promotes mRNA degradation. Validated targets include:
- EZH2 – a component of the Polycomb repressive complex 2, implicated in chromatin remodeling.
- SIRT1 – a NAD⁺‑dependent deacetylase involved in cellular stress responses.
- RhoC – a small GTPase that regulates cytoskeletal dynamics.
- Vimentin (VIM) – an intermediate filament protein associated with epithelial‑mesenchymal transition (EMT).
By modulating these and other targets, miR-138 influences processes such as cell proliferation, apoptosis, migration, and differentiation.
Physiological Roles
Research has demonstrated that miR-138 contributes to:
- Neuronal development and plasticity: It regulates dendritic spine morphology and synaptic strength by targeting proteins involved in actin cytoskeleton organization.
- Immune function: miR-138 modulates T‑cell activation and cytokine production, partly through SIRT1 repression.
- Skin homeostasis: It participates in keratinocyte differentiation and wound healing.
Clinical Significance
Altered miR-138 expression has been reported in various pathological contexts:
- Cancer: Down‑regulation of miR-138 is observed in several malignancies, including glioblastoma, head‑and‑neck squamous cell carcinoma, and breast cancer, where it generally functions as a tumor suppressor by inhibiting oncogenic targets such as EZH2 and RhoC. Conversely, over‑expression in certain contexts may facilitate tumor progression by affecting EMT pathways.
- Neurological disorders: Dysregulated miR‑138 levels have been associated with neurodegenerative diseases, such as Alzheimer’s disease, and with psychiatric conditions, although causal relationships remain under investigation.
- Cardiovascular disease: Emerging evidence suggests a role for miR‑138 in cardiac hypertrophy and ischemic injury, mediated through modulation of oxidative stress pathways.
Research Tools
Experimental manipulation of miR‑138 is commonly achieved using synthetic miRNA mimics, antagomirs (miRNA inhibitors), or CRISPR‑based approaches targeting the MIR138 genomic loci. These tools have facilitated functional studies in cell lines, animal models, and primary tissues.
References
A comprehensive list of peer‑reviewed publications detailing miR‑138 biogenesis, targets, and functional studies is available in biomedical literature databases (e.g., PubMed).
