NamiRNAs are a type of

miRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miR ...

s present in the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

, which can activate

gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. ...

by binding to the enhancer, and therefore were named nuclear activating miRNAs (NamiRNAs), such as miR-24-1 and miR-26. These miRNAs loci are enriched with epigenetic markers that display enhancer activity like

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn ar ...

H3K27ac H3K27ac is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates acetylation of the lysine residue at N-terminal position 27 of the histone H3 protein. H3K27ac is associated with the higher activation o ...

, P300/CBP, and

DNaseI Deoxyribonuclease I (usually called DNase I), is an endonuclease of the DNase family coded by the human gene DNASE1. DNase I is a nuclease that cleaves DNA preferentially at phosphodiester linkages adjacent to a pyrimidine nucleotide, yielding ...

high-sensitivity loci. These NamiRNAs are able to activate the related enhancers and co-work with them to up-regulate the expression of neighboring genes. NamiRNAs are able to promote global gene transcription by binding their targeted enhancers in whole genome level. Canonically, miRNAs silence gene expression through binding to the complementary sequences of their targeted mRNAs that are often located in the 3’UTR in the cytoplasm since the first miRNA lin-4 has been found by Ambros Victor. As so far, most studies of miRNAs have focused on those in the cytoplasm. Other than the classical theory that miRNAs down-regulate target genes by binding to the 3’UTR of mRNA, it has also been shown that miRNAs could upregulate gene expression in certain cases, just like RNAa phenomenon, which describes a picture that miRNAs can bind to the promoter of the target genes to facilitate gene transcriptions. Moreover, Vasudevan S. et al. held that miRNAs display a pattern of up-regulation on gene transcription together with

AGO2 The Argonaute protein family, first discovered for its evolutionarily conserved stem cell function, plays a central role in RNA silencing processes as essential components of the RNA-induced silencing complex (RISC). RISC is responsible for the ...

and

FXR1 Fragile X mental retardation syndrome-related protein 1 is a protein that in humans is encoded by the ''FXR1'' gene. The protein encoded by this gene is an RNA binding protein that interacts with the functionally similar proteins FMR1 and FXR2. Th ...

. The discovery of NamiRNAs showcases a complementary regulatory mechanism of miRNAs, demonstrating their different roles in the nucleus and cytoplasm.

Molecular mechanism

The classical theory of miRNAs is that genomic DNA first transcribes into pri-miRNAs. Next, pri-miRNAs were cleaved into pre-miRNAs by Drosha in the nucleus. Then, pre-miRNAs are transported into the cytoplasm via Exportin5, and are cut again by Dicer to form mature miRNAs. However, this theory cannot explain the distribution of miRNAs in the nucleus. One possible explanation is that miRNAs in cytoplasm can be carried back into the nucleus by some transport proteins. However, there is no direct evidence to support it. Another reasonable explanation is that pre-miRNAs could form mature miRNAs directly in the nucleus by Dicer cleavage. This is a simpler and more energy-efficient method. Yet, the molecular mechanism of NamiRNAs is still not fully understood. NamiRNA is overlapped within the enhancer regions and it is also activated when it positively regulates its corresponding enhancers. Thus, the crosstalk between NamiRNA and enhancer will further promote a series of genes transcription. We can say that NamiRNA and enhancer mutually affect each other to form a positive feedback network and together play regulatory functions on gene expression.

Functions

NamiRNAs could interact with the corresponding enhancer, enhance the enrichment of active enhancer markers like

and

H3K4me1 H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono- methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers. Nomenclature H3K4m ...

, and change

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...

status within the enhancer regions, thus promoting the cognate gene transcription at genome-wide scale.

Perspectives on the role

Traditional theory holds that miRNAs play inhibitory functions in the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

by binding the

3’ UTR In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...

of targeted

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

and downregulate

gene transcription Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...

. The discovery of NamiRNAs provides a brand-new idea that miRNAs can also play positive roles on gene expression in transcriptional level in the nucleus. To summarize, miRNAs have dual functions in gene regulation in the cytoplasm and the nucleus. That is, miRNAs play an inhibitory function in the cytoplasm and an activating function for the gene expression in the nucleus, respectively. Meanwhile, a functional network between NamiRNAs and enhancers is put forward to illustrate their roles for the positive regulation of their targeted gene transcription. NamiRNA enhancer target gene activation network demonstrates the new function of miRNA located in the nucleus.

Molecular mechanism

Functions

Perspectives on the role

References

Further reading