Nathan Boles, Ph.D.
The long-term goal of Dr. Boles’ research is to address the following question: How and why do stem cells differentiate? His main approach to this issue has been to investigate the changes in the expression profile of stem cells during differentiation. He has made several contributions to the field, including a database of changes in gene expression across the hematopoietic tree (as a graduate student in Peggy Goodell’s lab) and across a human model of corticogenesis (as a postdoctoral fellow in Sally Temple’s lab). During these projects, he developed multiple algorithms to analyze expression profiles, including a method to easily determine the developmental time of a cortical differentiation making it simpler to compare across differentiations and pluripotent stem cell lines. Since establishing his group at the Neural Stem Cell Institute, he has focused on using his expertise in bioinformatics and stem cells to help characterize the retinal pigmented epithelium stem cell, brain development, and stem cell aging.
Dr. Boles’ Contributions to Science
Dr. Boles created a timeline of gene expression changes in human corticogenesis. The prefrontal cortex is the focus of several psychiatric diseases and degenerates in some early-onset dementias. Consequently, the developmental processes underlying human prefrontal cortex development are of major interest. Dr. Boles and his collaborators developed a protocol generating prefrontal cortex from human pluripotent stem cells (hPSC), performed a temporal transcriptome analysis using RNA-seq, and created a database of gene expression changes during human corticogenesis (1). Using a systems biology approach in combination with R programming, he identified vital pathways and potential regulators of each stage of corticogenesis. In addition to providing new targets for understanding the development of the cortex, this database can potentially provide a reference for comparison of patient-derived iPSCs to identify changes occurring in cortical disease. This database has been highly accessed in its first year (~30,000 page views). Using this database, they proceeded to develop new bioinformatic techniques to analyze transcriptomic data over a developmental time course (2) and a simple method to identify the developmental time of a cortical differentiation compatible with a high throughput neurotoxin screen (3).
Dr. Boles identified drivers of differentiation into multiple lineages in the hematopoietic tree and developed an algorithm to examine the status of chromatin. Hematopoietic stem cells (HSC) give rise to a set of cells with vastly divergent functions and morphologies. In order to better characterize the HSC and its progeny and to uncover potential regulators of hematopoietic differentiation, Nathan and colleagues undertook expression profiling of purified HSC and the terminally differentiated cells of the hematopoietic system (4). Using R, they identified potential regulators of hematopoiesis and demonstrated that overexpression of specific regulators was sufficient to drive HSC to a particular lineage. Furthermore, he provided support to the hypothesis that adult stem cells have a more open or permissive chromatin state than their progeny by using R to develop an algorithm that created and compared chromosomal expression maps of each cell type. Overall, in addition to giving rise to multiple projects (5,6), this work has been widely accessed and cited.
Dr. Boles characterized the roles of CD48 and interferon-gamma (Ifng) in the hematopoietic stem cell niche. Maintaining stem cell homeostasis requires a balance of signaling from both the niche and downstream progeny of the HSC. Dr. Boles and his collaborators established a role for Ifng in promoting long-term HSC proliferation and activity in both normal hematopoiesis and in response to infection (7). We also demonstrated that mice with defective components controlling the IFNg signaling apparatus show severe defects in HSC activity (8,9). Additionally, he revealed a role for CD48 as an environmental sensor that interacts with short-term hematopoietic progenitors to modulate cytokine production, especially Ifng (9). Overall, this work outlined a role for inflammatory molecules contributing to stem cell homeostasis in the hematopoietic system.