"Protein lysine methylation in mitochondria"
Jedrzej Mieczyslaw Malecki (Researcher, Rafal Ciosk Laboratory, BMB)
Many proteins are modified by post-translational methylation, introduced by a
number of methyltransferases (MTases). Protein methylation plays important roles in
modulating protein function, and thus in optimizing and regulating cellular and
physiological processes. Research has mainly focused on nuclear and cytosolic
protein methylation, but it has been known for many years that also mitochondrial
proteins are methylated. During the last decade, significant progress has been made
on identifying the MTases responsible for mitochondrial protein methylation and
addressing its functional significance. In particular, several novel human MTases have
been uncovered that methylate lysine in various mitochondrial proteins that are key
components of the bioenergetics machinery, including citrate synthase and the ATP
synthase. I will present data that led to those recent discoveries and discuss the
functional significance of mitochondrial protein methylation.
"Wnt and Notch signaling regulation in pre-hemogenic endothelium control hematopoietic stem and progenitor cells heterogeneity"
Joey Ghersi (Postdoctoral Fellow, Yale Cardiovascular Research Center, Stefania Nicoli Laboratory)
Hematopoietic stem/progenitor cells (HSPCs) are produced from a specialized population of endothelial cells in the embryonic aorta called hemogenic endothelial cells. This process, called the endothelial-to-hematopoietic transition (EHT), is conserved across vertebrates, and is followed by HSPC differentiation to blood lineages. Single-cell methods discovered substantial heterogeneity in lineage priming within nascent HSPCs, however it is unknown how this diverse differentiation capacity is conferred. We found that microRNA-128 (miR-128) loss-of-function zebrafish mutant, increased EHT, resulting in supernumerary lymphoid and erythroid primed HSPCs and relative mature cells. Correlatively, miR-128-deficient endothelium derived from human pluripotent stem cells have defective EHT, supporting miR-128’s functional conservation in human. Transcriptomic analysis and Single cell RNA sequencing revealed that miR-128 target cskn1a and jag1b, involved in the inhibition of Wnt and Notch signaling, specifically in pre-hemogenic endothelium. Chemical inhibition of Wnt or de-repression of cskn1a promoted HSPCs with erythroid lineage commitment, while lymphoid cell number increased after de-repression of jag1b or blockage of Notch activity only at the onset of EHT. This study sheds light on how the HSPC heterogeneity in lineage priming is programmed prior to endothelial trans-differentiation by miR-128 co-regulation of Wnt and Notch which has important ramifications for bone marrow transplantation.