Searching for insights into normal and diseased stem cell behaviors
Characterized as the body’s raw materials, embryonic stem cells serve as the source for all other cells. While embryonic stem cells themselves are unspecialized, they divide and give rise to many cell types with specialized functions. Understanding how stem cells give rise to specialized cells is important due to their effect on normal developmental processes and pediatric cancer formation and progression. To deepen our knowledge of the role stem cells play in these normal and disease-state processes, we focus on genomic DNA organization and gene-regulation mechanisms within stem cells. Our detailed focus allows us to investigate the molecular mechanisms that drive stem cell behavior as we work to uncover the origins of disease in children.
Our laboratory seeks answers to how genomic DNA organization and gene-regulation mechanisms within stem cells affect a cell’s behavior and functional role in both normal and disease states. To study genomic DNA organization, we focus our efforts on chromatin—the structure within the nucleus of a cell that serves to package and contain a cell’s DNA. Specifically, we examine how chromatin structure and histones—the proteins that serve as building blocks of chromatin—affect gene expression.
Of all the different types of mechanisms that regulate chromatin structure, we concentrate on the modification of histone H3. This histone protein has a twenty-seventh residue, lysine (K), that can be methylated or acetylated. Our interest in H3K27 arises from the fact that, in pediatric cancers (blood, bone, brain, etc.), all the enzymes that modify H3K27 are either mutated or dysfunctional.
To analyze the normal and diseased functions of these H3K27 modifiers, we try to identify new factors and potential regulators. We study how these new factors control the stem cell models to grow or give rise to specialized neuronal cells. New knowledge from these studies enables us to uncover molecular mechanisms that regulate H3K27 modifications, chromatin structure, as well as gene expression and stem cell behavior.
In our examination of the factors that interact with H3K27 modifiers, we find these factors regulate neural stem cell growth, survival, and differentiation. Without these factors, we characterize the brain to undergo massive cell death or excessive cell proliferation to the point that the cells do not differentiate. As we try to expand our understanding of these factors, we strive to define a pathway from transcription circuitry and signaling pathways to intrinsic mechanisms that alter chromatin structure, gene expression, and stem cell behaviors. To this end, we use increasingly advanced techniques—imaging, deep sequencing, and data analysis—to profile the effects of stem cell behavior on normal and disease development in brain organoids and pediatric cancer models.