Small RNAs Play Big Roles in Hematopoietic Development

Citation

Rao, Dinesh Subba (2010) Small RNAs Play Big Roles in Hematopoietic Development. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/D6GJ-4057. https://resolver.caltech.edu/CaltechTHESIS:05142010-184014918

Abstract

The relatively recent identification of microRNAs (miRNAs) has added a new layer of complexity to our understanding of gene regulation. These small noncoding RNAs cause the downregulation of target mRNAs, leading to downstream effects. We have studied how particular miRNAs can impact hematopoietic development in mice and correlated these findings with miRNA deregulation in human disease. Specifically, we studied the role of miR-155 in myeloid cells, finding that it promoted myeloid cell expansions when induced by lipopolysaccharide and a myeloproliferative disease when constitutively expressed. Interestingly, miR-155 is overexpressed in acute myeloid leukemia, a human disease that has the proliferation of myeloid cells in common with our mouse model. miR-155 is a growth-promoting factor in cells and acts in early hematopoiesis by repressing the inositol phosphatase, SHIP1. We have also studied the role of miR-34a, a putative growth-suppressing miRNA, in hematopoietic development, finding a specific perturbation in B-cell development by gain- and loss of function analyses. In this case, the majority of the findings are attributable to repression of Foxp1, a transcription factor involved in regulation of immunoglobulin gene V(D)J recombination. Our findings show how miRNAs are integrated into developmental pathways that control hematopoiesis, and suggest that they may act as nodes of regulation during specific hematopoietic developmental processes.

Thesis Files