Dynamic Analysis of Gene Expression and Genome-wide Transcription Factor Binding during Lineage Specification of Multipotent Progenitors

Gillian May,Shamit Soneji,Alex J Tipping,Jose Teles,Simon J Mcgowan,Mengchu Wu,Yanping Guo,Cristina Fugazza,John Brown,Göran Karlsson,Cristina Pina,Victor Olariu,Stephen Taylor,Daniel G Tenen,Carsten Peterson,Tariq Enver

doi:10.1016/j.stem.2013.09.003

Abstract

SummaryWe used the paradigmatic GATA-PU.1 axis to explore, at the systems level, dynamic relationships between transcription factor (TF) binding and global gene expression programs as multipotent cells differentiate. We combined global ChIP-seq of GATA1, GATA2, and PU.1 with expression profiling during differentiation to erythroid and neutrophil lineages. Our analysis reveals (1) differential complexity of sequence motifs bound by GATA1, GATA2, and PU.1; (2) the scope and interplay of GATA1 and GATA2 programs within, and during transitions between, different cell compartments, and the extent of their hard-wiring by DNA motifs; (3) the potential to predict gene expression trajectories based on global associations between TF-binding data and target gene expression; and (4) how dynamic modeling of DNA-binding and gene expression data can be used to infer regulatory logic of TF circuitry. This rubric exemplifies the utility of this cross-platform resource for deconvoluting the complexity of transcriptional programs controlling stem/progenitor cell fate in hematopoiesis.

Highlights

Transcription factors (TFs) are key regulators of stem and progenitor cell fates
ChIPseq allows genome-wide mapping of TF binding and provides ‘‘hard-wiring’’ of transcriptional networks, but unambiguous linkage of genome-wide TF binding to global gene expression has not yet been achieved
This reflects the complexity observed, with individual genes being regulated by multiple TFs at multiple regulatory elements and differential regulation in different cell compartments

Summary

Introduction

Hematopoiesis provides a model to study TF-mediated regulation of cell fate (Orkin and Zon, 2008), with enforced expression of TFs in both multipotent and lineagecommitted progenitors demonstrating their capacity to influence, instruct, or redirect cell fate. ChIPseq allows genome-wide mapping of TF binding and provides ‘‘hard-wiring’’ of transcriptional networks, but unambiguous linkage of genome-wide TF binding to global gene expression has not yet been achieved. This reflects the complexity observed, with individual genes being regulated by multiple TFs at multiple regulatory elements and differential regulation in different cell compartments

Results

Discussion

Conclusion