Transcription factor binding dynamics during human ES cell differentiation

Abstract

Pluripotent stem cells provide a powerful system to dissect the underlying molecular dynamics that regulate cell fate changes during mammalian development. Here we report the integrative analysis of genome-wide binding data for 38 transcription factors with extensive epigenome and transcriptional data across the differentiation of human embryonic stem cells to the three germ layers. We describe core regulatory dynamics and show the lineage-specific behaviour of selected factors. In addition to the orchestrated remodelling of the chromatin landscape, we find that the binding of several transcription factors is strongly associated with specific loss of DNA methylation in one germ layer, and in many cases a reciprocal gain in the other layers. Taken together, our work shows context-dependent rewiring of transcription factor binding, downstream signalling effectors, and the epigenome during human embryonic stem cell differentiation. Lineage-specific transcription factors and signalling pathways cooperate with pluripotency regulators to control the transcriptional networks that drive cell specification and exit from an embryonic stem cell state; here, we report genome-wide binding data for 38 transcription factors combined with analysis of epigenomic and gene expression data during the differentiation of human embryonic stem cells into the three germ layers. Lineage-specific transcription factors and signalling pathways cooperate with pluripotency regulators when cells exit the embryonic stem cell state and activate the transcriptional networks that control cell specification. Here, as part of the Epigenome Roadmap project, Meissner and colleagues report genome-wide binding data for 38 transcription factors — combined with analysis of epigenomic and gene expression data — during the differentiation of human embryonic stem cells into the three germ layers. They reveal the orchestrated changes in transcription factor binding during differentiation, such as key roles for GATA4 and OTX2 in the transition to mesoderm and ectoderm, respectively.