A major aim of the Integrative Immunobiology Unit 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. This finding has implications for bone marrow transplantation. The standard practice of using hematopoietic stem cells from an adult donor many not result in reconstitution of NKT, B-1 and marginal zone B cells in patients. 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 Lin28 in CD34+ adult HSPCs resulted in expression of fetal hemoglobin upon erythroid differentiation in a primary cell culture system (Blood, in press). From a basic mechanism perspective, our finding is remarkable since this switch in globin gene expression during ontogeny is still not completely understood in molecular terms. Most studies have been on transcriptional regulation of the globin gene cluster;however, we find that the RNA-binding protein, Lin28b plays a major role in this process by inhibiting the biogenesis of the let-7 family of microRNAs. 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 diseases that affect numerous infants and 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 Lin28 is a strong candidate for mediating this switch.

Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2013
Total Cost
$235,751
Indirect Cost
City
State
Country
Zip Code
Escobar, Thelma M; Kanellopoulou, Chrysi; Kugler, David G et al. (2014) miR-155 activates cytokine gene expression in Th17 cells by regulating the DNA-binding protein Jarid2 to relieve polycomb-mediated repression. Immunity 40:865-79
Yuan, Joan; Muljo, Stefan A (2013) Exploring the RNA world in hematopoietic cells through the lens of RNA-binding proteins. Immunol Rev 253:290-303
Lee, Y Terry; de Vasconcellos, Jaira F; Yuan, Joan et al. (2013) LIN28B-mediated expression of fetal hemoglobin and production of fetal-like erythrocytes from adult human erythroblasts ex vivo. Blood 122:1034-41
Brady, Brenna L; Muljo, Stefan A (2013) RNA decay tolerizes: MCPIP1 (Zc3h12a) keeps inflammation in check by cleaving 3' UTRs. Immunol Cell Biol 91:331-2