Sensing cellular states—signaling to chromatin pathways targeting Polycomb and Trithorax group function

Abstract

Cells respond to extra- and intra-cellular signals by dynamically changing their gene expression patterns. After termination of the original signal, new expression patterns are maintained by epigenetic DNA and histone modifications. This represents a powerful mechanism that enables long-term phenotypic adaptation to transient signals. Adaptation of epigenetic landscapes is important for mediating cellular differentiation during development and allows adjustment to altered environmental conditions throughout life. Work over the last decade has begun to elucidate the way that extra- and intra-cellular signals lead to changes in gene expression patterns by directly modulating the function of chromatin-associated proteins. Here, we review key signaling-to-chromatin pathways that are specifically thought to target Polycomb and Trithorax group complexes, a classic example of epigenetically acting gene silencers and activators important in development, stem cell differentiation and cancer. We discuss the influence that signals triggered by kinase cascades, metabolic fluctuations and cell-cycle dynamics have on the function of these protein complexes. Further investigation into these pathways will be important for understanding the mechanisms that maintain epigenetic stability and those that promote epigenetic plasticity.

Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

“…Recent reviews have highlighted the importance of chromatin modifications in the spatiotemporal integration of diverse signals from cellular signalling and metabolic pathways 99,100 . Cancer-relevant signalling pathways thus regulate epigenetic modifiers to indirectly destabilize cellular phenotypes during tumour development (FIG.…”

How Polycomb‐Mediated Cell Memory Deals With a Changing Environment

“…Memory is the result of a dynamic process involving learning, codification, and the ability to reproduce the acquired information in the absence of the triggering event. Cells are daily exposed to fluctuations of environmental conditions, the epigenome function is to allow phenotypic variation in terms of transcriptional programs adaptation to the changing environment and to store cell memory throughout life . In the present paragraph we will highlight some of the main aspects related to the PcG memory system and adaptation.…”

“…In mammalian cells, reactive oxygen species (ROS) or serum starvation may modulate PcG proteins localization. Following ROS stress, phosphorylation by MAPK (mitogen activated protein kinase) negatively controls Bmi‐1 triggering its detachment from chromatin . Conversely, in skeletal muscle cells, oxidative stress induces increase of intra‐nuclear Eed level driving genome‐wide activation of PCR2‐Ezh1 complex and silencing of specific muscle gene networks .…”

A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro

“…In addition, maladaptive responses in the homeostatic controls on cellular physiology may cause changes to critical metabolites involved in epigenetic functions. Important metabolic co-factors in epigenetic functions include: glutathione which is important for DNA and histone methylation reactions; ATP for histone phosphorylations; acetyl-coenzyme A for histone acetylations; flavin adenine dinucleotide (FAD) as a cofactor for the lysine-specific histone demethylase 1 (LSD1) histone demethylase; NAD+ as cofactor for the SIRTUIN family of histone deacetylases; α-ketoglutarate, as a co-factor for histone demethylases (HDMs) and for the Ten-eleven translocation (TET) protein dioxygenase family members that oxidize the methyl group of 5-methylcytosine and facilitate DNA demethylation [22,23,24]. Thus, under the Tox21 view, perturbations of the molecular pathways to the point that they extend beyond the ranges measured in model human cell cultures, or lead in new directions, to become “drivers” of cellular toxicity, are the mechanistic links between the chemical exposures at the cellular level and the toxicologically-relevant changes in cellular behaviors.…”