RBPs as Targets
Examining How Defects in Protein-RNA Complexes Lead to Human Disease
Defects in RNA regulation in the nervous system lead to neurodevelopmental dysfunction (e.g. autism) and neurodegenerative diseases (e.g. ALS).
The mechanisms by which RBPs cause neurological disease are diverse, and in several cases the molecular details continue to remain elusive.
Until recently, the overwhelming majority of biological conclusions about mechanisms of RNA processing and transcriptomic diversity are derived from bulk populations of cells or tissues. However, the multitude of cell-types in heterogeneous mixtures in vivo and even in vitro during differentiation of PSCs, coupled with stochastic control of gene expression have been largely ignored. The transcriptomic composition of individual cells is lost in conventional sequencing projects, which typically analyze RNA extracted from pooled populations of cells and variations that specify individual cell-types are largely hidden in the bulk signal. Advances in the techniques for the isolation of single cells coupled with next-generation sequencing (NGS) devices have revealed new insights in specific “bimodal” gene expression patterns within a population of cells (Shalek et al., 2013), allele specific expression (Deng et al., 2014) and transcriptional programs in single cells from human and mouse embryos (Xue et al., 2013; Yan et al., 2013).
In ongoing research, my lab has developed novel experimental and computational analytical tools to isolate and analyze hundreds to thousands of individual cells.