The Role of Epigenetic Mechanisms in Notch Signaling During Development

Abstract

The Notch pathway is a highly conserved cell-cell communication pathway in metazoan involved in numerous processes during embryogenesis, development, and adult organisms. Ligand-receptor interaction of Notch components on adjacent cells facilitates controlled sequential proteolytic cleavage resulting in the nuclear translocation of the intracellular domain of Notch (NICD). There it binds to the Notch effector protein RBP-J, displaces a corepressor complex and enables the induction of target genes by recruitment of coactivators in a cell-context dependent manner. Both, the gene-specific repression and the context dependent activation require an intense communication with the underlying chromatin of the regulatory regions. Since the epigenetic landscape determines the function of the genome, processes like cell fate decision, differentiation, and self-renewal depend on chromatin structure and its remodeling during development. In this review, structural features enabling the Notch pathway to read these epigenetic marks by proteins interacting with RBP-J/Notch will be discussed. Furthermore, mechanisms of the Notch pathway to write and erase chromatin marks like histone acetylation and methylation are depicted as well as ATP-dependent chromatin remodeling during the activation of target genes. An additional fine-tuning of transcriptional regulation upon Notch activation seems to be controlled by the commitment of miRNAs. Since cells within an organism have to react to environmental changes, and developmental and differentiation cues in a proper manner, different signaling pathways have to crosstalk to each other. The chromatin status may represent one major platform to integrate these different pathways including the canonical Notch signaling.

Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease

“…However, in the context of glomerular diseases, including FSGS and diabetic nephropathy, it can become reactivated, promoting podocyte dedifferentiation and accelerating glomerular damage (24,25,29). During development, chromatin remodeling provides an important means by which a cell can set, coordinate, and integrate Notch-dependent processes (41). The findings of the present study indicate that chromatin remodeling events are similarly involved in the reactivation of developmental processes during the occurrence of glomerular disease.…”

Intracellular and extracellular O-linked N-acetylglucosamine in the nervous system

“…Notch receptors mediate an evolutionarily conserved intracellular signaling process that regulates cell fate (Schwanbeck, 2015). Many studies have demonstrated the role of Notch signaling during neural development including neurogenesis, gliogenesis, neuronal morphology, synaptic plasticity, learning and memory (Pierfelice et al, 2011).…”

Opportunities lost and gained: Changes in progenitor competence during nervous system development

“…Thus, Hh signaling could only promote the specification of KA" interneurons in LFP progenitors where Notch signaling was active. 69 How Notch signaling provides competence to respond to Hh remains unknown, but Notch signaling is known to alter chromatin state, 70,71 and it a likely mechanism for altering progenitor competence in this system.…”