An insight into the sprawling microverse of microRNAs in depression pathophysiology and treatment response

Abstract

Stress-related neuropathologies are pivotal in developing major depressive disorder (MDD) and are often governed by gene-regulatory changes. Being a stress-responsive gene-regulatory factor, microRNAs (miRNAs) have tremendous biomolecular potential to define an altered gene-regulatory landscape in the MDD brain. MiRNAs' regulatory roles in the MDD brain are closely aligned with changes in plasticity, neurogenesis, and stress-axis functions. MiRNAs act at the epigenetic interface between stress-induced environmental stimuli and cellular pathologies by triggering large-scale gene expression changes in a highly coordinated fashion. The parallel changes in peripheral circulation may provide an excellent opportunity for miRNA to devise more effective treatment strategies and help explore their potential as biomarkers in treatment response. This review discusses the role of miRNAs as epigenetic modifiers in the etiopathogenesis of MDD. Concurrently, key research is highlighted to show the progress in using miRNAs as predictive biomarkers for treatment response.

Keywords: Antidepressants; Biomarker; Epigenetics; Gene regulation; Major depression; MiRNAs; Neural plasticity.

Figure 1:. Programmed biogenesis of miRNAs.

A stepwise description of mature miRNA biogenesis has been presented with a schematic diagram. The diagram shows the involvement of various ancillary protein factors and processing enzymes to support the transcription of primary miRNA transcripts and their subsequent processing through precursor miRNA to mature form. MicroRNA biogenesis following the canonical pathway begins in the nucleus. Successful transcription of primary miRNA (pri-miR) depends on the RNA polymerase II machinery in the nuclear environment. Following a canonical path, the pri-miRNA is processed by the nuclear RNase III enzyme Drosha to produce precursor miRNA (pre-miRNA). Pre-miRNA is transported to cytosolic environment with the help of Ran-GTP and Exportin5 transporter complex. In cytosol the pre-miRNA is processed by the RNase III enzyme Dicer to generate mature miRNAs. Mature miRNAs are incorporated into the RNA-induced silencing (RISC) complex, which regulates gene expression by pairing primarily to the 3′ untranslated region of protein-coding mRNAs to repress target mRNA expression. The arrest in target expression can be caused by any one of the three mechanisms: i) translational blockage by inhibiting the access of elongation factor/ribosome complex; ii) transcript degradation by decapping and exonuclease activity, and iii) transcript degradation by deadenylation. The figure was prepared using software from Biorender.com.

Figure 2:. Conceptualizing of miRNA-target feedback loop.

The diagram collectively describes the framework of miRNAs being regulated by TFs which may in turn, be recruited as direct miRNA targets. This dynamic process provides tight regulatory control and helps to achieve a bipartite relationship between miRNA and its’s cognate target(s). A) The diagram shows one such example highlighting key steps that govern the feedback mechanism for miRNA expression stabilization and destabilization process. In the nucleus, promoter-specific miRNA transcription can happen independently from a genomic locus with the recruitment of RNA polymerase II (RNA PolII), specific TF, and other transcriptional activators. B) miRNA seed sequence-specific target scanning has been shown, followed by RNA Induced Silencing Complex (RISC) recruitment. The Ago2 is one of the major components in RISC and helps drive the gene silencing process following miRNA-dependent target binding near the 3’UTR (untranslated region). In this instance, the target could be a specific set of TFs responsible for miRNA transcriptional regulation. The cellular fate of the complex enzymatic interaction leads to the destabilization of target transcripts. C) The schematic is about a 4W5N (from the protein database, PDB), which is a crystalized structure of Ago2 locking miRNA-target transcript complex near the PAZ (Piwi/Argonaute/Zwille) domain. The tight interaction in the proximity of PAZ domain determines the catabolic fate of the target transcripts or the specific TFs following their deadenylation and helps achieve a delicate balance for further regulating the miRNA transcription in the nucleus. The figure was prepared using software from Biorender.com.

Figure 3:. miRNA-target gene base network and associated gene ontology for plasticity and stress-responsive miRNAs.

A) Plasticity-associated miRNA-target-based interaction network. Predicted targets based on synaptic plasticity-associated miRNAs (listed in Table 1) were used to map a miRNA-target interaction network with square nodes showing the miRNA names and round ones as connected targets. Target prediction was based on miRTarBase version 8.0. B) Stress-associated miRNA-target-based interaction network. Predicted targets based on cognate interaction with stress-responsive miRNAs (listed in Table 1) were used to map a miRNA-target interaction network with square nodes showing the miRNA names and round ones as connected targets. Target prediction was based on miRTarBase version 8.0. C) Gene ontology analysis for biological process conducted with predicted target genes associated with plasticity-related miRNAs. Grided bubble plot showing significant enrichment of terms in various categories associated with neuronal functions. The lower to higher p values are shown on a scale of gradient color, and the circle size means the number of gene counts in each GO term. D) Gene ontology analysis for biological process conducted with predicted target genes associated with stress responsive miRNAs. Grided bubble plot showing significant enrichment of terms in various categories associated with neuronal functions. The lower to higher p values are shown on a scale of gradient color, and the circle size means the number of gene counts in each gene ontology term.

Figure 4:. Antidepressant-responsive miRNAs.

A hypothetical circular connectivity plot to highlight the key miRNAs which have been found to be consistently responsive to various antidepressant treatments. In the plot, miRNAs responsive to the respective antidepressant treatments are connected via cords (represented with different colors). Maximum number of miRNAs were found to be responsive to escitalopram treatment.