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. This finding has implications for bone marrow transplantation in the clinic. The standard practice of using hematopoietic stem cells from an adult donor many not result in efficient 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 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. 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 is a target for mediating this switch.
| Akef, Abdalla; Muljo, Stefan A (2018) How T cells go rogue in the absence of Roquins. Noncoding RNA Investig 2: |
| Gowen, Benjamin G; Chim, Bryan; Marceau, Caleb D et al. (2015) A forward genetic screen reveals novel independent regulators of ULBP1, an activating ligand for natural killer cells. Elife 4: |
| 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 |
| 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 |
| 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 |
| Yuan, Joan; Nguyen, Cuong K; Liu, Xiuhuai et al. (2012) Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis. Science 335:1195-200 |
