TGF-β signaling to chromatin: How Smads regulate transcription during self-renewal and differentiation

Abstract

Ligands of the TGF-β superfamily (including the TGF-βs, Nodal and BMPs) play instructive roles during embryonic development. This is achieved by regulation of genes important for both maintaining pluripotency and germ layer specification and differentiation. Here we review how the TGF-β superfamily ligands signal to the chromatin to regulate transcription during development. The effectors of the pathway, the Smad transcription factors, are regulated in a combinatorial and spatiotemporal manner. This occurs via post-translational modifications affecting stability, localization and activity, as well as through interactions with other transcription factors and chromatin modifying enzymes, which occur on DNA. Expression profiling and Chromatin Immunoprecipitation have defined Smad target genes and binding sites on a genome-wide scale, which vary between cell types and differentiation stages. This has led to the insight that Smad-mediated transcriptional responses are influenced by the presence of master transcription factors, such as OCT4, SOX2 and NANOG in embryonic stem cells, interaction with other signal-induced factors, as well as by the general chromatin remodeling machinery. Interplay with transcriptional repressors and the polycomb group proteins also regulates the balance between expression of self-renewal and mesendoderm-specific genes in embryonic stem cells and during early development.

Sensing relative signal in the Tgf-β/Smad pathway

“…isoform of Smad2 does not (14). Here, we focused on Smad3 and generated a reporter C2C12 cell line stably expressing an mNeonGreen-Smad3 construct (NG-Smad3; the sequence is shown in Fig.…”

The adipocyte clock controls brown adipogenesis via TGF-β/BMP signaling pathway

“…Furthermore, in epidermal stem cells (Janich et al, 2011;Karpowicz et al, 2013) and the central clock (the suprachiasmatic nuclei; Beynon et al, 2009), a circadian pattern of TGF-b signaling activity as indicated by Smad3 phosphorylation has been reported. Given the importance of TGF-b signaling in stem cell proliferation and differentiation (Gaarenstroom and Hill, 2014), circadian modulation of this pathway might confer appropriate responses to temporal cues involved in controlling stem cell behavior and tissue homeostasis. Although our current study defines a specific role of Bmal1 in the brown fat differentiation program, its broader impact on various important TGF-b-regulated biological processes remains to be elucidated.…”

Activin/Nodal signalling before implantation: setting the stage for embryo patterning

“…Smads can also integrate the input of FGF/RTK signalling, via MAPK-mediated phosphorylation, which can, for example, promote Smad1 degradation, and reduce BMP signal transduction [12,28]. Further information on how Smads integrate input from other signalling pathways can be found in other reviews [7,10,29].…”