Oncogenic YAP mediates changes in chromatin accessibility and activity that drive cell cycle gene expression and cell migration

Abstract

YAP, the key protein effector of the Hippo pathway, is a transcriptional co-activator that controls the expression of cell cycle genes, promotes cell growth and proliferation and regulates organ size. YAP modulates gene transcription by binding to distal enhancers, but the mechanisms of gene regulation by YAP-bound enhancers remain poorly understood. Here we show that constitutive active YAP5SA leads to widespread changes in chromatin accessibility in untransformed MCF10A cells. Newly accessible regions include YAP-bound enhancers that mediate activation of cycle genes regulated by the Myb-MuvB (MMB) complex. By CRISPR-interference we identify a role for YAP-bound enhancers in phosphorylation of Pol II at Ser5 at MMB-regulated promoters, extending previously published studies that suggested YAP primarily regulates the pause-release step and transcriptional elongation. YAP5SA also leads to less accessible ‘closed’ chromatin regions, which are not directly YAP-bound but which contain binding motifs for the p53 family of transcription factors. Diminished accessibility at these regions is, at least in part, a consequence of reduced expression and chromatin-binding of the p53 family member ΔNp63 resulting in downregulation of ΔNp63-target genes and promoting YAP-mediated cell migration. In summary, our studies uncover changes in chromatin accessibility and activity that contribute to the oncogenic activities of YAP.

YAP condensates are highly organized hubs

“…On the other hand, YAP still forms around 15 condensates in confluent cells when they are supposedly inactive. While previous studies have shown that YAP is still able to bind to the chromatin under inactive conditions, 54 , 55 we speculate that YAP condensates in YAP-inactive condition may bookmark the important genes and prepare them for transcriptional activation once cells are placed sparsely and YAP becomes active. This is similar to the scenario when the TF Sox2 (SRY-box 2) binds to the mitotic chromosome in mouse embryonic stem cells and prepare the cells for transcription once mitosis ends.…”

DNMT3A Cooperates with YAP/TAZ to Drive Gallbladder Cancer Metastasis

“…Deregulation of the Hippo pathway results in the dephosphorylation and nuclear localization of YAP to control the expression of cell cycle regulators and accelerate the growth of tumor cells. [ 30 ] In the present study, we showed that DNMT3A interacts with YAP/TAZ but does not modulate YAP/TAZ expression or cytoplasmic sequestration, revealing a Hippo pathway‐independent role for YAP in recruiting DNMT3A access to specific genome locations. In addition, our findings regarding the inconsistent function of DNMT3A and YAP in GBC growth led us to speculate that YAP‐induced expression of cell cycle regulators might not rely on DNMT3A‐mediated DNA methylation, which needs to be further explored.…”

Histone Modification of Osteogenesis Related Genes Triggered by Substrate Topography Promotes Human Mesenchymal Stem Cell Differentiation

“…Despite the fact that HIPPO pathway or YAP mediated alterations in chromatin accessibility have received great attention in recent studies, , it remains unclear whether active YAP can facilitate histone modifications at specific differentiation gene promoters in response to topographical or mechanical cues. − …”

“…81 The nuclear transportation and activation of YAP/TAZ can cause histone acetylation by the related lysine acetyltransferases CBP and p300. 82 Despite the fact that HIPPO pathway or YAP mediated alterations in chromatin accessibility have received great attention in recent studies, 83,84 it remains unclear whether active YAP can facilitate histone modifications at specific differentiation gene promoters in response to topographical or mechanical cues. 85−87 Here, we hypothesize that YAP, together with other nuclear proteins, may regulate histone modification and expression of differentiation related genes in the mechanotransduction processes.…”