Abstract
Pluripotent stem cells (PSCs) hold great clinical potential, as they possess the capacity to differentiate into fully specialised tissues such as pancreas, liver, neurons and cardiac muscle. However, the molecular mechanisms that coordinate pluripotent exit with lineage specification remain poorly understood. To address this question, we perform a small molecule screen to systematically identify novel regulators of the Smad2 signalling network, a key determinant of PSC fate. We reveal an essential function for BET family bromodomain proteins in Smad2 activation, distinct from the role of Brd4 in pluripotency maintenance. Mechanistically, BET proteins specifically engage Nodal gene regulatory elements (NREs) to promote Nodal signalling and Smad2 developmental responses. In pluripotent cells, Brd2‐Brd4 occupy NREs, but only Brd4 is required for pluripotency gene expression. Brd4 downregulation facilitates pluripotent exit and drives enhanced Brd2 NRE occupancy, thereby unveiling a specific function for Brd2 in differentiative Nodal‐Smad2 signalling. Therefore, distinct BET functionalities and Brd4‐Brd2 isoform switching at NREs coordinate pluripotent exit with lineage specification.
Highlights
Embryonic/pluripotent stem cells (ESCs/Pluripotent stem cells (PSCs)) have the developmental capacity to differentiate into any cell type within the adult body, including terminally differentiated tissues such as pancreas, liver, neurons and cardiac muscle [1]
We find that bromodomain and extra-terminal (BET) family members Brd2 and Brd4 directly engage Nodal gene regulatory elements (NREs) to drive autocrine Nodal expression
Using quantitative proteomics to explore BET family expression dynamics during differentiation, we show that Brd4 suppression facilitates pluripotent exit and drives increased Brd2 recruitment to NREs
Summary
Embryonic/pluripotent stem cells (ESCs/PSCs) have the developmental capacity to differentiate into any cell type within the adult body, including terminally differentiated tissues such as pancreas, liver, neurons and cardiac muscle [1]. Transforming growth factor (TGF)-b signalling plays a prominent role both in maintaining pluripotency and in mesendoderm (ME) specification [3,4,5], which is a developmentally and therapeutically significant population [2]. The TGFb superfamily consists of TGFb isoforms and Activin/Nodal ligands, which selectively engage TGFbII receptors. This leads to TGFbI receptor activation, Smad2/3 recruitment and phosphorylation, and Smad2/ 3-dependent gene expression in complex with Smad4 [3,4,5]. In PSCs, autocrine Nodal activates Smad signalling [6] to maintain expression of pluripotency factors [7,8]. In contrast to our detailed understanding of the core Nodal-Smad pathway and transcriptional targets, we remain poorly informed about the molecular mechanisms by which Smad signalling is established and maintained in diverse developmental contexts
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