Global Analysis of Dynamic Epigenetic Marking and Transcriptional Regulation Underlying T-Cell Lineage Commitment

Citation

Zhang, Jingli A. (2012) Global Analysis of Dynamic Epigenetic Marking and Transcriptional Regulation Underlying T-Cell Lineage Commitment. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/9Q4G-E674. https://resolver.caltech.edu/CaltechTHESIS:01262012-055600494

Abstract

T-cell lineage specification and commitment success depends on precise temporal induction of T-lineage specific genes, as well as repression of lineage-inappropriate programs. After entry into the thymus, T-cell progenitors still retain inherited lineage plasticity, reflected by the mixed-lineage pattern of gene expression and the abilities to give rise to alternative lineages. Although Notch-Delta signaling is an essential force to trigger and sustain T-lineage differentiation, it does not appear to be the only requirement for this process. Successful commitment also depends on additional transcription factors, which often cooperatively interact with Notch-Delta signaling. However, the molecular mechanism by which pro-T cells are advanced to become committed T cells, in particular how the alternative lineage potentials are eliminated, is not fully understood. Using the genome-wide high-throughput sequencing, we track global shifts in gene expression pattern and transcriptional activity associated histone modifications in five successive stages of T-cell differentiation that span the commitment process. Our results show that T-lineage commitment is defined by the surprisingly complex downregulation of progenitor- and/or alternative lineage-associated programs, with relatively few regulatory genes are substantially upregulated. Rather than being silenced by a single global repression event, progenitor- and/or alternative lineage-associated genes are regulated by individual gene-specific mechanisms, indicated by the unsynchronized epigenetic transformations at discrete cis-elements of genes loci linked to progenitor and/or alternative lineage programs. We also investigate the genome-wide occupancies of PU.1 and GATA-3, two regulatory factors that have critical but complementary roles in early T-cell development. Binding sites choices of these two factors imply that transcriptional regulation by one particular factor is developmental context as well as dosage dependent. Furthermore, We combine this genome-wide approach with gene perturbation to study the function of Bcl11b, a transcription factor required for the completion of T-cell lineage commitment. Our analyses reveal that, in part through directly or indirectly regulation of Notch1 and GATA-3, Bcl11b mediates the modulation of T-cell lineage specification and commitment.

Thesis Files