YAP contributes to DNA methylation remodeling upon mouse embryonic stem cell differentiation

Abstract

The Yes-associated protein YAP, one of the major effectors of the Hippo pathway together with its related protein TAZ, mediates a range of cellular processes from proliferation and death to morphogenesis. YAP and TAZ regulate a large number of target genes, acting as co-activators of DNA-binding transcription factors or as negative regulators of transcription by interacting with the nucleosome remodeling and histone deacetylase complexes. YAP is expressed in self-renewing embryonic stem cells (ESCs), although it is still debated whether it plays any crucial roles in the control of either stemness or differentiation. Here we show that the transient downregulation of YAP in mouse ESCs perturbs cellular homeostasis, leading to the inability to differentiate properly. Bisulfite genomic sequencing revealed that this transient knockdown caused a genome-wide alteration of the DNA methylation remodeling that takes place during the early steps of differentiation, suggesting that the phenotype we observed might be due to the dysregulation of some of the mechanisms involved in regulation of ESC exit from pluripotency. By gene expression analysis we identified two molecules which could have a role in the altered genome-wide methylation profile: the long non-coding RNA Ephemeron, whose rapid upregulation is crucial for ESCs transition into epiblast, and the methyltransferase-like protein Dnmt3l, which, during the embryo development, cooperates with Dnmt3a and Dnmt3b to contribute to the de novo DNA methylation that governs early steps of ESC differentiation. These data suggest a new role for YAP in the governance of the epigenetic dynamics of exit from pluripotency.

ZNF224 is a mediator of TGF-β pro-oncogenic function in melanoma

“…Chromatin immunoprecipitation was performed as previously described (7,20). Brie y, forty-eight h posttransfection with FlagZNF224 plasmid, A375 cells were cross-linked with HCHO (1%) for 10 min at room temperature, lysed, and xed chromatin was sheared using an ultrasonic liquid processor.…”

YAP and TAZ Mediators at the Crossroad between Metabolic and Cellular Reprogramming

“…In support of this notion, there is evidence indicating that blocking YAP from contributing to the TEAD/β-catenin-TCF3 complex in mouse ESCs by the tumor suppressor RASSF1A is crucial for the onset of differentiation [ 77 ]. We have contributed to the field by demonstrating that YAP silencing induces a robust deregulation of de novo methylation events that usually guide the exit of ESCs from pluripotency upon differentiation [ 78 ].…”

“…Finally, YAP/TAZ can potentially exert profound effects on cell plasticity and metabolic reprogramming by affecting other processes like epigenetic modifications to chromatin structure [ 78 , 173 ] and post-transcriptional microRNA (miRNA) processing [ 174 ]. It is noteworthy that YAP/TAZ may influence the accessibility and activity of various target genes via chromatin structure alterations in association with chromatin-remodeling complex proteins such as nucleosome remodeling and deacetylase (NuRD), Switch/sucrose non-fermentable (SWI/SNF), nuclear receptor coactivator 6 (Ncoa6), Mediator, and GAGA factor [ 173 ].…”

Regulation of Hippo, TGFβ/SMAD, Wnt/β-Catenin, JAK/STAT, and NOTCH by Long Non-Coding RNAs in Pancreatic Cancer

“…Importantly, histone methylation and DNA methylation are highly dynamic mechanisms centrally involved in the reprogramming of gene networks in wide variety of cellular processes. Different chemicals are currently being tested to inhibit polycomb repressive complexes to re-program gene networks ( 68 , 69 ). Furthermore, knockdown of MALAT1 inhibited proliferation, migration, invasion as well as the expression of genes involved in EMT.…”