Decoding lineage-specific gene regulation across hematopoiesis

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Sickle cell disease (SCD) and thalassemia are most common genetic disorders worldwide and cause early mortality and suffering. Reversal of the developmental hemoglobin switch to increase levels of fetal hemoglobin, encoded by HBG, reduces SCD complications. Previous work over several decades has elucidated several key transcription factors required to repress HBG expression, but they have proven difficult to target therapeutically with small molecules. Therefore, a deeper understanding of how cell type and context-specific gene expression programs are coordinated throughout development is essential to design therapies that reactivate HBG selectively while sparing other blood cell lineages. While transcription factor recruitment is considered a key control point for gene specificity, less is known about the selectivity of co-regulatory complexes. This proposal focuses on one such transcriptional co-activator complex, SAGA, and aims to disentangle its functions throughout human hematopoiesis. My overarching hypothesis is that despite its ubiquitous expression, SAGA has gene- and cell type-specific functions across hematopoiesis. Aim 1 elucidates its gene-specific roles using precision base editing approaches and functional genomics. I will fine-map SAGA subunit functions both genome-wide and on globin gene regulation during erythroid development and differentiation. Aim 2 investigates the distinct roles of SAGA amongst human blood cell lineages using both in vitro and in vivo xenograft model systems. The proposed research builds on my expertise in developmental hematology, genomics, and genome editing and provides a generalizable framework to dissect the functions of multi-subunit complexes and gene pathways. Through this detailed molecular mapping of the SAGA complex, I will examine how SAGA impacts specific loci in primary hematopoietic cells across both lineage and developmental state. While targeting ubiquitous factors has been viewed as therapeutically undesirable, this proposal revisits this concept by focusing on SAGA to discover new context-specific functions that could direct future precision therapies for SCD and other blood disorders.