Roles of RNA-binding Proteins in Programming Gene Expression in Mammals

National Institute Of Allergy And Infectious Diseases

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Abstract

A major aim of the Integrative Immunobiology Section is to decipher gene expression programs that direct cell fates in the hematopoietic and immune systems, since perturbations to their genetic program underlie many diseases such as cancer, immunodeficiency, autoimmunity, allergy and hematological diseases. We seek knowledge that will provide insights for understanding how a cell decodes its own genome in order to develop and function. In 2012, we discovered that the RNA-binding protein Lin28b is specifically expressed in fetal hematopoietic stem/progenitor cells (HSPCs) but not in adult counterparts from the bone marrow (Science 335: 1195-1200). Furthermore, this single RNA-binding protein can reprogram adult bone marrow HSPCs to attain fetal-like properties. In 2019, we reported that a second RNA-binding protein called Igf2bp3 can cooperate with Lin28b in engineering fetal-like HSPCs (Genes & Development 33: 1048-1068). This finding has implications for bone marrow transplantation in the clinic. The standard practice of using hematopoietic stem cells from an adult donor does not regenerate the immune system in layers which normally occur during natural development. As a result, in these patients, bone marrow transplantation may not result in efficient reconstitution of cell types that develop early in life such as subsets of NKT, B-1 and marginal zone B cell. Our work on Lin28b and Igf2bp3 demonstrated that in principle, it is possible to engineer fetal-like hematopoietic stem cells. Such cells could be used for in utero hematopoietic stem cell transplantation which could be used to cure sickle cell disease and beta-thalassemia as well as primary immunodeficiencies that can be diagnosed prior to birth. In addition, we hypothesized that Lin28b may be involved in the regulation of the switch from fetal to adult hemoglobin gene expression by erythroid progenitors that occurs around birth. In collaboration with Jeff Miller's lab (NIDDK), we determined that ectopic expression of LIN28B in CD34+ adult HSPCs resulted in expression of fetal hemoglobin upon erythroid differentiation in a primary cell culture system (Blood 122: 1034-41). Mechanistically, our finding is remarkable since this switch in globin gene expression during ontogeny is still not completely understood in molecular terms and now we have uncovered a new clue towards understanding it. Most studies have concentrated on transcriptional regulation of the globin gene cluster; however, we find that the RNA-binding protein, LIN28B plays a major role in fetal hemoglobin gene (HBG1 and HBG2) expression in part by inhibiting the biogenesis of the LET-7 family of microRNAs. We have preliminary evidence that IGF2BP3 also collaborates with LIN28B in this instance (unpublished data). Importantly, we believe that our finding provides a novel avenue for treating sickle cell disease and beta-thalassemia. Despite decades of intense research, we do not have a cure for these two devastating life-long diseases that affect numerous patients including children, and is a growing public health issue in Africa and Asia. It has been postulated that reactivation of fetal hemoglobin expression could cure beta-globinopathies, and LIN28B and/or IGF2BP3 may be target(s) for mediating this switch.