202308041446
References
from Mahmoudi & Cairns, 2017:
What is it?
MiR-137 is a 23-nt miRNA that has a significant role in cellular biology, localized on human chromosome 1p22 within the gene for the non-protein-coding RNA AK094607.
MiR-137 has a critical regulatory role in brain function, where it is involved in proliferation and differentiation during development.
Brain-enriched in mouse and humans with high expression in cortical brain regions & hippocampus, with low expression in cerebellum and brain stem.
Genetics
- Classic 23-nt miRNA within a long non-coding host gene, MIR137HG
- Transcriptional unit on chromosome 1 is over 62 kb long and produces four splice variants ranging from over 2.5 kb to below 1 kb.
- 15-bp variable tandem repeat localized in primary transcript of miR-137, 5’ to the pre-miR-137
- Changes posttranscriptional processing of miR-137 through alteration of secondary structure
Genomic location, transcripts and sequence of miR-137 in human. The gene is 61 kb long situated in short arm of chromosome 1 producing four transcripts. The pri-miR is 102 nt in length which is cleaved to a 23-nt mature miRNA (miR-137).
Why is it important?
MiR-137 is associated with the etiology of many psychiatric disorders, including schizophrenia and bipolar disorder. It’s also involved in cancer.
Function
Context-dependent role in modulation of differentiation and proliferation of embryonic/adult stem cells
- MiR-137 regulates cell proliferation and differentiation in both embryonic and adult brain.
- Promotes cell differentiation while inhibiting proliferation of embryonic neuronal stem cell (NSCs) through downregulation of LSD1 gene through regulatory loop with transcriptional co-repressor TLX.
- MiR-137 increased upon differentiation, directly targets Jarid1b (AKA KDM5b) resulting in differentiation of mouse embryonic stem cells (ESCs).
- Opposite effect in adult neural stem cells (aNSCs): miR-137 enhances proliferation and inhibits differentiation through posttranscriptional regulation of Ezh2
- Mib1 is negatively modulated by miR-137 which affects dendritic morphogenesis, phenotypic maturation, and spine development in adult hippocampus
- Embryonic development is dependent on at least one functional allele of MIR137
The impact of miR-137 on neural differentiation, proliferation and maturation in ESCs and newborn neurons. (a) Upregulation of miR-137 can suppress target mRNAs such as TLX, LSD1, KDM5B and Tbx3 resulting in the neural stem cell move to cell differentiation, whereas low levels of this miRNA cause an increase in target genes expression that lead to cell proliferation.28,38,39 (b) MiR-137 regulate dendritic complexity and spine numbers by targeting Mib1 gene in newborn neurons.41 ESC, embryonic stem cells; miRNA, microRNA.
Expression
- Highly expressed in mitotic phase of cell cycle, highly upregulated during differentiation of ESCs into neural cells.
- Upregulation → repression of two ES cell transcription factors Klf4 and Tbx3 (direct targets of MiR-137)
Targets
Experimentally validated target genes of miR-137. Approximately 50 genes have been identified to be directly regulated by miR-137 and most confirmed by luciferase assay and western blot. The target genes of miR-137 are involved in different biological pathways mainly cell cycle, proliferation and differentiation.
Regulation
- MIR137 gene is highly regulated by large CpG island embedded in upstream promoter region on chromosome 1p22.
- Modified by DNA-hypermethylating agents → suppression of miR-137 transcription
- In aNSCs, miR-137 is regulated epigenetically by DNA methyl-CpG-binding protein MeCP2 and transcription factor Sox2.
- Directly binds to regulatory region of miR-137 in 2.5kb upstream region
- Directly involved in epigenetic pathways
- Modulates levels of Ezh2 directly in aNSCs.
- Targets histone lysine-specific demethylase 1 (LSD1)
- Important in TLX signalling — can induce feedback repression of miR-137 through recruitment of LSD1 to miRNA genes promoter.
Psychiatric Disorders
- MIR137 host gene (MIR137HG) implicated as a susceptibility locus through proximity to associated tag single-nucleotide polymorphism (SNP) rs1625579.
- Replicated in cohort of Han Chinese and Europeans
- TCF4, CACNA1C, CSMD1, C10orf26: other associated target genes
- Convergent pathways linked by miRNA may contribute to schizophrenia
- rs1625579, rs1198588, rs1702294 all significantly associated with SCZ risk
- Risk allele associated with lower P300 amplitude
- Less positive symptoms and more cognitive deficits involving episodic memory, attentional control in cohort of schizophrenia, schizoaffective, bipolar affective
- Carriers considered high risk had reduced response in right posterior medical frontal gyrus region in fMRI
- SZ high-risk group had differential activation in left amygdala & left pre/postcentral gyrus, suggesting susceptibility allele may affect SZ more specifically