Transcription factor binding dynamics during human ES cell differentiation

Abstract

Summary 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 behavior of selected factors. In addition to the orchestrated remodeling 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 signaling effectors, and the epigenome during human embryonic stem cell differentiation.

Modeling heterogeneity in the pluripotent state: A promising strategy for improving the efficiency and fidelity of stem cell differentiation

“…The high variability in the epigenetic landscape has recently been studied at the single‐cell level in HSCs 25, in which significant chromatin reorganization in different subpopulations plays a key role during cell‐fate commitment. Similar observations have been made in human ESCs, where the dynamics of histone chromatin marks and DNA methylation is strongly associated to the binding of specific TFs, such as Sox17 , Otx2 , and Gata6 , which defines and stabilizes the phenotypes corresponding to different germ layers 13. Moreover, the acquisition of a poising state – i.e.…”

“…The TGF‐β/SMAD signaling pathway maintains self‐renewal in mESC through the BMP/SMAD signalling activation of Id family genes 52, while in hESCs is the Activin/Nodal/SMAD2/3 cascade the one responsible for promoting pluripotency 53. Interestingly, several studies have demonstrated that pluripotency regulators form intricate circuits at the transcriptional level 13, 36, 53, 54, and many of the TFs ( Essrb , Klf4 , Stat3 , Tcf3 ) in these regulatory motifs are downstream effectors of the signaling pathways regulating self‐renewal and differentiation. Although the complete spectrum of signaling pathways regulating pluripotency has not been fully described 55, these results demonstrate the confluence of different environmental signals from the microenvironment for the regulation of pluripotency.…”

“…Gene expression heterogeneity has also been studied in hematopoietic stem cells (HSCs), in which gene expression uni‐ and bimodality have been observed for different genes in different hematopoietic progenitor cells 1, 12. Interestingly, it has also been demonstrated that genes exhibiting bimodal gene expression tend to be co‐expressed, and regulators such as Rex1 , Nanog , and Esrrb display strong correlations 3, 5, which is related to the dynamics in the interplay among TFs for regulating pluripotency genes in ESCs 13. On the other hand, genes displaying sporadic expression exhibit more complex correlation patterns 5, suggesting that there exist no clear functional relationships among genes expressed in burst in some specific subpopulations.…”

Roadmap for regulation

“…Four of the papers in this issue [2][3][4][5] exploit these relationships to identify combinations of transcription factors that might define different cell types during development. Ziller et al 4 (page 355) modelled neuronal development in vitro, by generating six lineages of neuronal progenitors from embryonic stem (ES) cells, which give rise to almost every cell type of the body.…”

“…Tsankov et al 5 (page 344) studied the sets of transcription factors that bind to promoters and enhancers in the first three cell lineages that differentiate from ES cells. Sequences bound by transcription factors in one of the three lineages exhibited molecular modifications that promote gene expression, such as loss of DNA methylation.…”