Hematopoietic tissues are particularly sensitive to changes in the cellular protein synthesis machinery. Mutations in the translational apparatus, including enzymes involved in the modification and processing of ribosomal RNA (rRNA), ribosome assembly factors, and ribosomal proteins, cause specific blood phenotypes despite the ubiquitous expression of the affected genes. These human syndromes have collectively been labeled “ribosomopathies” and represent a paradigm to study the mechanisms by which perturbation of ribosome activity and translation control cause specific pathologies including high predisposition to hematological malignancies. Furthermore, recent studies also demonstrate a need for tight regulation of overall protein synthesis in hematopoietic stem cells. It remains unclear why ribosome defects lead to anemia and predisposition to hematopoietic disorders. New advances in novel organismal models to study translation control in hematopoiesis, as well as genome-wide translational profiling, may offer new insights into these questions.

Dr. Ingolia will discuss recent studies of translation in highly specialized, terminally differentiated blood lineages. Blood cells include the most prominent examples of anucleate cells in the body, platelets and erythrocytes, which cannot synthesize new RNA, but inherit a pool of mRNA and ribosomes that perform ongoing protein synthesis. We investigated the translational landscape of human platelets and identified surprising specialization of the protein synthesis apparatus in these cells that stabilizes irreplaceable mRNAs at the cost of reduced quality control in translation.

Dr. Ruggero will discuss novel mechanisms by which mRNA translational control provides an important level of regulation to erythropoiesis. This research helps to close a large gap in our understanding of how mutations in the translation machinery underlie hematopoietic disorders, collectively known as “ribosomopathies”. In particular, he will discuss surprising findings of dynamic regulation in the activity of core translation factors during erythroid differentiation. In addition, he will discuss how employing state-of-the-art proteomics of erythroid cells has revealed that translational regulation supports rapid cell differentiation and mature red cell production as a mechanism to faithfully integrate extracellular signals.