UTR sequence regulation of mRNA survival is essential for proper hematopoietic differentiation. The best example of this is globin syn thesis, where the mRNA is very stable because of its UTR sequences. This long half-life meets the needs of reticulocytes to synthesize glo bin for up to 2 days after terminally mature erythroblasts lose the nucleus and the ability to make new mRNA.
Some of the elements contained in UTRs form a characteristic secondary structure that alters the survival of the mRNA transcript, exemplified by the prothrombin 3′ UTR. This mRNA is constitutively polyadenylated at seven or more alternative positions, and the 3′ UTR folds into at least two distinct stem-loop conformations.20 These alternate structures expose a consensus binding site for trans-acting factors, such as heterogeneous nuclear ribonucleoprotein 1 (hnRNP-I), polypyrimidine tract-binding protein-1 (PTB-1), and nucleolin, with translational regulatory properties. Another type of 3′ UTR regulatory sequence involves selenocysteine insertion sequence (SECIS) elements. These represent another stem-loop RNA structure found in mRNA transcripts and serve as protein-binding sites on UTR segments that direct the ribosome to translate the codon UGA as selenocysteine rather than as a stop codon. An example of this regulation can be found in selenoprotein P in plasma. Bacteria contain another class of these mRNA elements, the riboswitches, that directly bind the small molecules that their mRNAs encode thereby directly regulating their own activity in response to the concentrations of their effector molecules. Bacterial riboswitches are relevant to hematopoiesis since the mRNAs for several enzymes in the cobalamine pathway in intestinal bacteria have riboswitches; these bind adenosylcobalamine that in turn regulates the survival and translation of these mRNAs and finetunes cobalamine synthesis.21 Riboswitches are promising new drug targets, for now against bacteria, exemplifying the opportunities in RNA therapeutics.
Another class of UTR functional sequences affecting the stability of the mRNA is the AU-rich element (ARE). AREs are stretches of mRNA consisting mostly of adenine and uracil nucleotides. These sequences destabilize their transcripts through the action of riboendonucleases that stimulate poly(A) tail removal. Loss of the poly(A) tail is thought to promote mRNA degradation by facilitating attack by both the exosome complex and the decapping complex. Rapid mRNA degradation via AREs is a critical mechanism for preventing the overproduction of potent cytokines such as tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). AREs also regulate the synthesis of mRNA for protooncogenic transcription factors such as c-Jun and c-Fos. The AU elements in the mRNA of these genes mediate destruction of their transcripts in quiescent cells, preventing inappropriate cell proliferation that would occur if Fos/Jun were still active.
Besides transcript stability, the efficiency of translation can be regulated by cellular factors that bind mRNA in a sequence specific manner. Iron metabolism is an excellent example of how cells coordinate uptake and sequestration of an essential metabolite in response to availability. Transferrin is a plasma protein that carries iron. Receptors for transferrin (TfR) are expressed on cells requiring iron for maturation, such as erythroid progenitor cells. They mediate internalization of transferrin loaded with iron into the cytoplasm through receptor-mediated endocytosis. When a cell becomes iron deficient, iron-responsive element–binding proteins (IRE-BPs) can bind to iron-responsive elements (IREs) in the UTR of transferrin receptor (TfR) mRNA (Fig. 1). UTR binding leads to stabilization of the TfR mRNA transcript and in increased protein expression. However, when a cell has sufficient iron, as iron binds to more and more IRE-BPs, they change shape and unbind the TfR mRNA. The TfR mRNA becomes unstable and is rapidly degraded (see Fig. 1). Therefore, in that situation, TfR receptor expression is low and the fewer receptors import lessiron.
Fig1. CONTROL OF TRANSFERRIN RECEPTOR EXPRESSION BY RNA STABILITY. The transferrin receptor messenger RNA (mRNA) has five RNA iron-responsive elements (IRE) in the 3′ untranslated region (3′UTR). Upper panel: when the iron concentration is low, the IRE-binding proteins (IRE-BPs) bind to the IRE elements and stabilize the mRNA, reading to increased protein expression. When the iron concentration is high (Fe), IRE-BPs are inactive and the transferrin receptor transcript is susceptible to degradation by endonucleases, leading to decreased protein expression. CDS, Coding sequence.
References
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[1] Liu X, Jiang Y, Russell JE. A potential regulatory role for mRNA secondary structures within the prothrombin 3′UTR. Thromb Res. 2010;126(2): 130–136.
[2] Polaski JT, Holmstrom ED, Nesbitt DJ, Batey RT. Mechanistic insights into cofactor-dependent coupling of RNA folding and mRNA transcription/ translation by a cobalamin riboswitch. Cell Rep. 2016;15(5):1100–1110.
