Brain microRNAs and insights into biological functions and therapeutic potential of brain enriched miRNA-128

Abstract

MicroRNAs, the non-coding single-stranded RNA of 19-25 nucleotides are emerging as robust players of gene regulation. Plethora of evidences support that the ability of microRNAs to regulate several genes of a pathway or even multiple cross talking pathways have significant impact on a complex regulatory network and ultimately the physiological processes and diseases. Brain being a complex organ with several cell types, expresses more distinct miRNAs than any other tissues. This review aims to discuss about the microRNAs in brain development, function and their dysfunction in brain tumors. We also provide a comprehensive summary of targets of brain specific and brain enriched miRNAs that contribute to the diversity and plasticity of the brain. In particular, we uncover recent findings on miRNA-128, a brain-enriched microRNA that is induced during neuronal differentiation and whose aberrant expression has been reported in several cancers. This review describes the wide spectrum of targets of miRNA-128 that have been identified till date with potential roles in apoptosis, angiogenesis, proliferation, cholesterol metabolism, self renewal, invasion and cancer progression and how this knowledge might be exploited for the development of future miRNA-128 based therapies for the treatment of cancer as well as metabolic diseases.

Figure 1

miRNA biogenesis pathway and function: miRNAs are transcribed in the nucleus either from introns or exons of protein-coding genes or introns of long non-coding RNAs into primary transcripts (pri-miRNAs). Pri-miRNAs are then processed in two steps in the nucleus and cytoplasm, catalyzed by the RNase III type endonucleases Drosha and Dicer, in complexes with dsRNA-binding domain proteins, DGCR8 and TRBP respectively. In the canonical pathway, Drosha-DGCR8 processes the transcript to a stem loop-hairpin precursor (pre-miRNA). Intron derived miRNAs, called miRtrons, evade canonical pathway and processed by the spliceosome and the debranching enzyme into pre-miRNAs. Both canonical miRNAs and miRtrons are exported to the cytoplasm via Exportin 5, where they are further processed by Dicer-TRBP or by Ago2 to yield 20-25-bp miRNA duplexes. Dicer processing adds 5′ phosphate groups and two-nucleotide overhangs at the 3′ ends of the mature strands. The duplex produced by either Dicer or Ago2 is loaded onto an Argonaute protein of RISC where one strand is selected to function as mature miRNA while the partner miRNA* strand is preferentially degraded. The mature miRNA produced by these two mechanisms leads to translational repression or mRNA degradation.

Figure 2

Roles of miRNA-128 in different cellular processes: The role of miRNA-128 in the different biological processes and multistep events that lead to cancer are shown. The experimentally validated target genes of miRNA-128 are depicted along with the respective biological processes.

Figure 3

Strategy for filtering common genes among nine species: Total targets of miRNA-128 have been extracted using TargetScan 5 program for nine species (Human, Mouse, Chimpanzee, Rhesus, Cow, Chicken, Frog, Rat, Opossum). Data was arranged in a tabular format where the union of all genes from the mentioned species were represented as first column in each row (row head). The subsequent columns in first row had species names in them (column head). For every gene, 1 was written under the species where it was found to be present and zero otherwise. This way, a matrix of 1 and zeroes was populated for every gene where 1 means presence and zero means absence. In the last column, sum across the row was taken to count the number of species in which a particular gene was present. We chose only those genes with presence in all nine species. This led to a list of ninety genes which we called high confidence set and were conserved among these species. The total green area specifies ninety common targets whereas red specifies the absence of a particular target in a particular species out of nine species.

Figure 4

Biological relevance of miRNA-128 as revealed by bioinformatic analysis: The biological pathways affected by miRNA-128 were revealed by the PANTHER and Gene Codis analysis using the list of common ninet y targets as input. Insulin signaling pathway and chemokine signaling pathway were the enriched categories in both PANTHER and GeneCodis analysis (p-value < 0.05).

Figure 5

GO biological processes by PANTHER analysis: The highest rated biological process being affected by miRNA-128 came out to be metabolic process with maximum number of genes during PANTHER analysis.