BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease

Abstract

Epicardium-derived cells (EPDCs) contribute cardiovascular cell types during development and in adulthood respond to Thymosin β4 (Tβ4) and myocardial infarction (MI) by reactivating a fetal gene programme to promote neovascularization and cardiomyogenesis. The mechanism for epicardial gene (re-)activation remains elusive. Here we reveal that BRG1, the essential ATPase subunit of the SWI/SNF chromatin–remodelling complex, is required for expression of Wilms’ tumour 1 (Wt1), fetal EPDC activation and subsequent differentiation into coronary smooth muscle, and restores Wt1 activity upon MI. BRG1 physically interacts with Tβ4 and is recruited by CCAAT/enhancer-binding protein β (C/EBPβ) to discrete regulatory elements in the Wt1 locus. BRG1-Tβ4 co-operative binding promotes optimal transcription of Wt1 as the master regulator of embryonic EPDCs. Moreover, chromatin immunoprecipitation-sequencing reveals BRG1 binding at further key loci suggesting SWI/SNF activity across the fetal epicardial gene programme. These findings reveal essential functions for chromatin–remodelling in the activation of EPDCs during cardiovascular development and repair.

The ontogeny, activation and function of the epicardium during heart development and regeneration

“…The transcription factor Nfatc1 and MRTFs (myocardin-related transcription factors) are also crucial regulators of EPDC-migration into the underlying myocardium (Combs et al, 2011;Trembley et al, 2015). A recent study elucidated an epigenetic mechanism by which regulation of the Wt1 locus via the BRG1-SWI/SNF chromatin remodelling complex controls epicardial EMT (Vieira et al, 2017). The epigenetic regulator p300 has also been shown to be required for epicardial EMT; however, it is not clear if this acetyl-transferase acts in epicardial cells or noncell autonomously (Shikama et al, 2003).…”

“…Such restricted EMT and migratory potential, however, can be amplified in response to distinct biological stimuli, such as stem cell factor (Xiang et al, 2014), prokineticins (Urayama et al, 2008), modified-RNA encoding for VEGFA protein (Zangi et al, 2013) and Tβ4 (Smart et al, 2007). A mechanism explaining how Tβ4 can reactivate the adult epicardium was recently reported, demonstrating that BRG1 physically interacts with Tβ4 not only at the Wt1 locus, but also at other epicardial loci, including Raldh2, Tbx18 and Tcf21, thus establishing an embryonic gene programme underpinning the activation and migration of adult EPDCs (Vieira et al, 2017). A similar common regulatory mechanism responsible for activating various epicardial-related genes has also been found in C/EBP binding-dependent regulatory regions of Wt1 and Raldh2 (Huang et al, 2012).…”

Arid1a restrains Kras-dependent changes in acinar cell identity

“…As the SWI/SNF complex dictates chromatin accessibility by available TFs, such context dependencies might broadly relate to development or pathological cell state. Indeed, in drosophila and mammalian systems, SWI/SNF complex dependent regulation of gene expression controls cell identity and differentiation in developmental as well as regenerative contexts ( Sun et al, 2016 ; Takada et al, 2016 ; Vieira et al, 2017 ). How loss of SWI/SNF subunit function contributes to changes in cell plasticity in concert with oncogenes that drive cancer development is poorly understood.…”

Multivariate patterning of human pluripotent cells under perfusion reveals critical roles of induced paracrine factors in kidney organoid development

“…In this study, we selected three antibodies chosen for their capacity to multiplex to identify up to five distinct cell types. We must acknowledge that none of these proteins are specific to the kidney just as they are not completely specific to the putative kidney cell types that we have described an identity to here (40)(41)(42)(43). However, what our data definitively confirm is that initial renal differentiation can be perturbed to bias the patterning and cellular complexity present in these renal differentiations, highlighting evidence for clear and complex paracrine signals that can shift cellular identity, cluster morphology, and spatial interactions between distinct cell types as well as the relative ratio of cell types within each condition.…”