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

Summary

We 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

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  Cross-platform resource for TF-network regulation of multipotent blood cell fate

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  DNA motif dependence and changing specificity of GATA factors in lineage choice

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  Modeling-based inference identifies GATA2 repression of PU.1 in multipotent cells

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  Priming, recruitment, and switching modes of GATA interplay during differentiation

Abstract

A systems-level resource of the GATA-PU.1 axis provides insight into the dynamics of transcriptional programs during hematopoietic lineage commitment and differentiation.