POST-TRANSCRIPTIONAL REGULATION
POST-TRANSCRIPTIONAL REGULATION IN PLURIPOTENT STEM CELL BIOLOGY AND PLURIPOTENT STATE TRANSITION
We show that the microRNA-dependent regulation of Profilin-2 by miR-290/302 controls many aspects of pluripotent stem cell biology.
We define an axis of post-transcriptional control, endocytosis, and signal transduction that is essential for stem cell growth, cell cycle control, and early differentiation.
MICRORNA FUNCTION IN CELLULAR IRON HOMEOSTASIS
Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin (PLoS Genetics 2013)
cited in selected review(s): A Red Carpet for Iron Metabolism (Cell 2017), Ironing out ferroportin (Cell Metabolism 2015), MicroRNAs: the fine modulators of liver development and function (Liver International 2014)
Cellular iron homeostasis is maintained by a sophisticated system that responds to iron levels and coordinates the expression of targets important for balancing iron export and uptake with intracellular storage and utilization. Ferroportin is the only known cellular iron exporter in mammalian cells and plays a critical role in both cellular and systemic iron balance.
The ability to regulate cellular iron export is of great interest in the search for therapeutic strategies to target:
*conditions affected or regulated by cellular iron concentrations such as infection and immunity in any organ system (pathogen entry and anatimicrobial resistance), mammalian development (effects of dysregulated maternal and/or embryonic iron), and specific organ-based issues (chronic liver disease, liver regeneration, heart disease)
During iron deprivation, repression of ferroportin levels reduces iron export and preserves cellular iron. Although ferroportin translation is known to be repressed by iron regulatory proteins that bind to the 5′UTR (untranslated region), alternative mechanisms that can post-transcriptionally regulate ferroportin had not been previously reported.
*We found that the microRNA miR-485-3p is induced during iron deficiency in human primary cells and cell lines and represses ferroportin by directly targeting its 3′UTR.
*This experimental evidence introduced a new regulatory model in which both iron regulatory proteins and microRNAs are post-transcriptional regulators of ferroportin.
*These findings described a new role for microRNAs in the cellular response to iron.
MICRORNA FUNCTION IN CELLULAR STRESS RESPONSE
MicroRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease. (Blood 2010)
cited in selected review(s): Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism (Cell. Mol. Life Sci. 2016) Erythrocyte microRNAs: a tiny magic bullet with great potential for sickle cell disease therapy (Ann Hemat 2021)
MicroRNAs are essential for fine-tuning physiological functions and responding to changing environments and stress conditions. We demonstrate a role for microRNA in the regulation of oxidative stress response in erythroid cells and the functional consequences of dysregulated microRNA expression in Sickle Cell Disease pathobiology.
Homozygous Sickle Cell (HbSS) erythrocytes are known to have reduced tolerance for oxidative stress, yet the basis for this phenotype has remained unknown. Here we used erythrocyte microRNA expression profiles to identify a subset of HbSS patients with higher miR-144 expression and more severe anemia. In our study we revealed that in human K562 erythroid cells and primary erythroid progenitor cells, miR-144 directly regulates NRF2, a transcription factor and central regulator of cellular response to oxidative stress, and modulates the oxidative stress response.
We further showed that increased miR-144 is associated with the reduced NRF2 levels, decreased glutathione regeneration, and attenuated antioxidant capacity found in HbSS erythroid progenitor cells, thereby revealing a mechanism for the reduced oxidative stress tolerance and increased anemia severity seen in HbSS patients.
We used these new tools and findings to touch off an area of translational research still under investigation!
