Genes can also be regulated by noncoding RNAs. These genomic sequences are transcribed but not translated. Although many distinct families of noncoding RNAs exist, we will discuss only two examples here: small RNA molecules called microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) (>200 nucleotides in length).

Micro-RNA miRNAs do not encode proteins; they modulate translation of target messenger RNAs (mRNAs). Posttranscriptional silencing of gene expression by miRNA is a fundamental and well-conserved mechanism of gene regulation present in all eukaryotes (plants, animals, and fungi). Even bacteria have a primitive version of the same machinery that they use to protect themselves against foreign DNA (e.g., phage and virus DNA). The profound influence of miRNAs on protein expression allows these relatively short RNAs (22 nucleotides on average) to be critical regulators of developmental pathways as well as pathologic conditions (e.g., cancer).

The human genome encodes almost 6000 miRNA genes, about 30% of the total number of protein-coding genes. Individual miRNAs can regulate multiple protein-coding genes, allowing each miRNA to coregulate entire programs of gene expression. Transcription of miRNA genes produces a primary transcript (pri-miRNA) that is processed into progressively smaller segments, including trimming by the enzyme Dicer. This generates mature single-stranded miRNAs of 21 to 30 nucleotides that associate with a multiprotein aggregate called RNA-induced silencing complex (RISC) (Fig. 1). Subsequent base pairing between the miRNA strand and its target mRNA directs the RISC to either induce mRNA cleavage or repress its translation. In this way the target mRNA is posttranscriptionally silenced.

Fig1. Generation of microRNAs (miRNAs) and their mode of action in regulating gene function. Transcription of a miRNA produces a primary miRNA (pri-miRNA), which is processed within the nucleus to form pre-miRNA composed of a single RNA strand with secondary hairpin loop structures and stretches of double-stranded RNA. After export out of the nucleus via specific transporter proteins, pre-miRNA is trimmed by the cytoplasmic Dicer enzyme to generate mature double-stranded miRNAs of 21 to 30 nucleotides. The miRNA subsequently unwinds and the single strands are incorporated into multiprotein RNA-induced silencing complexes (RISC). Base pairing between single-stranded miRNA and the targeted messenger RNA (mRNA) directs RISC to either cleave or repress translation of the mRNA, resulting in posttranscriptiontional silencing.

Small interfering RNAs (siRNAs) are short RNA sequences that can be introduced experimentally into cells where they serve as substrates for Dicer and interact with RISC, thereby reproducing endogenous miRNAs function. Synthetic siRNAs that target specific mRNA species are powerful laboratory tools to study gene function (so-called knockdown technology) and are also being studied as potential therapeutic agents to silence pathogenic genes (e.g., oncogenes that drive neoplastic transformation).

Long Noncoding RNA

Recent studies have further identified an untapped universe of lncRNAs—by some calculations, the number of lncRNAs may exceed coding mRNAs by 10-fold to 20-fold. lncRNAs modulate gene expression by several mechanisms (Fig. 2). As one example, lncRNAs can bind to chromatin and restrict RNA polymerase from accessing coding genes within that region. The best-known example is XIST, which is transcribed from the X chromosome and plays an essential role in the physiologic X chromosome inactivation that occurs in females. XIST itself escapes X inactivation but forms a repressive “cloak” on the X chromosome from which it is transcribed, resulting in gene silencing. Conversely, many enhancers are actually sites of lncRNA synthesis. In this case the lncRNAs expand transcription from gene promoters via a variety of mechanisms (see Fig. 2).

Fig2.  Roles of long noncoding RNAs (lncRNAs). (A) lncRNAs can facilitate transcription factor binding and thus promote gene activation. (B) Conversely, lncRNAs can preemptively bind transcription factors to inhibit transcription. (C) Histone and DNA modification by acetylases or methylases (or deacetylases and demethylases) may be directed by lncRNA binding. (D) In other instances, lncRNAs can act as scaffolds to stabilize secondary or tertiary structures and multisubunit complexes that influence chromatin architecture or gene activity. (Modified from Wang KC, Chang HY: Molecular mechanisms of long noncoding RNAs, Mol Cell 43:904, 2011.)

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مواضيع ذات صلة

Histone Organization

Noncoding DNA

DNA Synthesis Occurs During the S Phase of the Cell Cycle

Formation of Replication Bubbles

Initiation & Elongation of DNA Synthesis

The Exact Function of Much of the Mammalian Genome is Not Well Understood

DNA is organized into Chromosomes

Some Regions of Chromatin are “Active” & Others are “Inactive”

The Nucleosome Contains Histone & DNA

Histones Are the Most Abundant Chromatin Proteins

Specific Nucleases Digest Nucleic Acids

Directions for Future Research in Molecular Biology