Home » Prof. Michal Linial - Spatial and Temporal Regulation of miRNAs

Prof. Michal Linial - Spatial and Temporal Regulation of miRNAs

In every living cell, various regulators maintain cellular equilibrium (homeostasis). When the cell is unable to correctly deal with different types of stress, disease may develop. The regulation of cell processes is performed by transcription factors that control gene expression, enzymes that perform protein modifications to regulate their function or ability to bind other proteins, and more. According to the central dogma, RNA transcribed from DNA is translated into protein. However, there is a large group of transcripts that are not translated into protein, but instead function as important regulatory factors in the cell. Only in recent years are we beginning to understand and decipher their mechanism of action. One of these types of RNA is micro-RNA or miRNA for short, a short single-stranded RNA molecule of about 22 nucleotides that binds mRNA transcripts destined for translation. This mRNA-miRNA binding inhibits the translation of the mRNA transcript and often leads to its degradation. In humans, 2,600 miRNA molecules are known that together contribute to cellular and intercellular homeostasis.
For many years, it was widely believed in the field that miRNAs, which are copied in the cell nucleus, undergo processing and maturation in the cytoplasm and act upon mRNAs only there. However, many studies from recent years indicate the presence of miRNAs inside the cell’s organelles or spatially adjacent to them, for example in the mitochondria, at the endoplasmic reticulum (ER) membrane, and in the nucleus. The composition and amount of miRNAs found in different locations maintain the cell's character: is the cell differentiated or is it a stem cell, is it dividing, etc.
An interesting example of local control by miRNAs exists in neurons. These are very polar cells that, with the help of long extensions (axons and dendrites) carry neural signals and respond to signals produced in their environment. This intercellular communication specifically occurs at synapses by releasing molecules from the sending cell to the receiving cell. An estimated 5-10% of transcripts intended for translation are transported actively through the axons to synapses, where they await local translation. Recent research suggests that certain miRNAs are also concentrated in the synaptic area, in order to control the translation of these transcripts, and to specify the growth of axons and dendrites in the brain. This level of regulation dictates key processes such as learning, memory, and synaptic plasticity.
The balance and location of miRNAs are dynamic, and change under stress conditions such as oxidative stress, heat or cold stress, or stress caused by viral infection. For example, there is tight control over miRNAs that regulate the ER stress response. In the ER, the unfolded protein response (UPR) allows the cell under stress to deal with misfolded proteins and prevent the formation of toxic protein aggregates. The miRNAs that control the UPR process are located and act at the ER membrane, one of the central locations for the translation of proteins intended for insertion into the ER. In experiments where the UPR response was activated, extensive changes were observed in the composition and amount of miRNAs located adjacent to it. From these and many other examples, we learn that miRNAs are a major factor in the control of protein translation. As such, they monitor important processes in the cell and serve as gatekeepers for the activity of various organelles.
In the review we recently published (see link) we describe the activity of miRNAs while emphasizing their location, composition, and the dynamics of their composition and level of expression. This point of view is important for the understanding of many pathological conditions and their treatment.
 

 

Graduate students Naomi Van Vijk & Keren Zohar