Integration of Signaling Pathways with the Epigenetic Machinery in the Maintenance of Stem Cells.

Luca Fagnocchi,Stefania Mazzoleni,Alessio Zippo

doi:10.1155/2016/8652748

Luca Fagnocchi, Stefania Mazzoleni + Show 1 more

Open Access

https://doi.org/10.1155/2016/8652748

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Abstract

Stem cells balance their self-renewal and differentiation potential by integrating environmental signals with the transcriptional regulatory network. The maintenance of cell identity and/or cell lineage commitment relies on the interplay of multiple factors including signaling pathways, transcription factors, and the epigenetic machinery. These regulatory modules are strongly interconnected and they influence the pattern of gene expression of stem cells, thus guiding their cellular fate. Embryonic stem cells (ESCs) represent an invaluable tool to study this interplay, being able to indefinitely self-renew and to differentiate towards all three embryonic germ layers in response to developmental cues. In this review, we highlight those mechanisms of signaling to chromatin, which regulate chromatin modifying enzymes, histone modifications, and nucleosome occupancy. In addition, we report the molecular mechanisms through which signaling pathways affect both the epigenetic and the transcriptional state of ESCs, thereby influencing their cell identity. We propose that the dynamic nature of oscillating signaling and the different regulatory network topologies through which those signals are encoded determine specific gene expression programs, leading to the fluctuation of ESCs among multiple pluripotent states or to the establishment of the necessary conditions to exit pluripotency.

Highlights

Stem cells balance their self-renewal and differentiation potential by integrating environmental signals with the transcriptional regulatory network (TRN) [1,2,3,4]
We provide multiple evidences, demonstrating how different pluripotent stem cells rely on specific extrinsic cues, which converge on transcriptional and epigenetic networks, thereby determining their cell fate (Figures 1 and 2)
This concept is supported by both the heterogeneous expression profile of pluripotency factors registered between Embryonic stem cells (ESCs) subpopulations and the fact that we can capture in vitro multiple pluripotent states, hanging on different regulatory networks

Summary

Introduction

Stem cells balance their self-renewal and differentiation potential by integrating environmental signals with the transcriptional regulatory network (TRN) [1,2,3,4]. Signaling pathways crosstalk fine-tunes the correct pattern and timing of gene expression by modulating downstream effectors such as transcription factors (TFs), cofactors, and histones modifiers These modulations are achieved through different mechanisms including differential DNA binding affinities, protein shuttling, posttranslational modifications, and protein-protein interactions. The combinatorial DNA binding action of cell type-specific TFs and signal effectors on cis-regulatory elements is strongly influenced by the chromatin landscape of a given cell, resulting in the establishment of multiple transcriptional programs. In this regard, the dynamic interplay between signaling pathways, TFs, and epigenetic machinery plays a major role in integrating multiple inputs and switching a transient signaling event into a long-lasting phenotypic change. We would underline the critical role of these regulatory circuits to control the cell identity and how their misregulation may initiate pathological events such as tumorigenesis

Mechanisms of Signaling to Chromatin

Conclusions and Future Perspectives