The CAF-1 complex couples Hippo pathway target gene expression and DNA replication

Abstract

The Hippo signaling pathway regulates tissue growth and organ development in many animals, including humans. Pathway activity leads to inactivation of Yorkie (Yki), a transcriptional coactivator that drives expression of growth-promoting genes. In addition, Yki has been shown to recruit chromatin modifiers that enhance chromatin accessibility and thereby enhance Yki function. Here, we asked whether changes in chromatin accessibility that occur during DNA replication could also affect Yki function. We found that depletion of the chromatin assembly complex-1 (CAF-1) complex, a histone chaperone that is required for nucleosome assembly after DNA replication, in the wing imaginal epithelium leads to increased Hippo pathway target gene expression but does not affect expression of other genes. Yki shows greater association with target sites when CAF-1 is depleted and misregulation of target gene expression is Yki-dependent, suggesting that nucleosome assembly competes with Yki for pathway targets post-DNA replication. Consistent with this idea, increased target gene expression is DNA replication dependent and newly replicated chromatin at target sites shows marked nucleosome depletion when CAF-1 function is reduced. These observations suggest a connection between cell cycle progression and Hippo pathway target expression, providing insights into functions of the Hippo pathway in normal and abnormal tissue growth.

Negative feedback couples Hippo pathway activation with Kibra degradation independent of Yorkie-mediated transcription

“…A notable feature of the Hpo pathway is that its upstream components Kib, Ex, and Mer are upregulated by Yki transcriptional activity in a negative feedback loop ( Hamaratoglu et al, 2006 ; Genevet et al, 2010 ; Yee et al, 2019 ). In particular, Kib levels were previously shown to be significantly elevated in double-mutant Mer ; ex somatic mosaic clones, consistent with the transcriptional feedback regulation of kibra by Yki ( Genevet et al, 2010 ).…”

“…One way that cells modulate signaling output is by controlling the levels of signaling components. Within the Hpo pathway, transcription of Ex, Kib, and Mer is positively regulated by Yki activity in a negative feedback loop ( Hamaratoglu et al, 2006 ; Genevet et al, 2010 ; Yee et al, 2019 ). Multiple Hpo pathway components are also regulated post-translationally.…”

Yorkie-independent negative feedback couples Hippo pathway activation with Kibra degradation

“…A notable feature of the Hippo pathway is that its upstream components Kib, Ex, and Mer are upregulated by Yki transcriptional activity in a negative feedback loop (Hamaratoglu et al, 2006;Genevet et al, 2010;Yee et al, 2019). In particular, Kib levels were previously shown to be significantly elevated in double-mutant Mer; ex somatic mosaic clones, consistent with the transcriptional feedback regulation of kibra by Yki (Genevet et al, 2010).…”

“…One way that cells modulate signaling output is by controlling the levels of signaling components. Within the Hippo pathway, the transcription of Ex, Kib, and Mer is positively regulated by Yki activity to form a negative feedback loop (Hamaratoglu et al, 2006;Genevet et al, 2010;Yee et al, 2019). Multiple Hippo pathway components are also regulated post-translationally.…”

Mitotic Inheritance of PRC2-Mediated Silencing: Mechanistic Insights and Developmental Perspectives

“…Loss of CAF-1 induces strong developmental abnormalities including homeotic transformations in Drosophila that are reminiscent of the phenotypic defects observed in mutants lacking PRC2 activity (Anderson et al, 2011), defects in cell identity maintenance in both mouse embryonic stem cells (ESCs) and Arabidopsis meristems (Kaya et al, 2001;Clémot et al, 2018) as well as increased reprogramming abilities in mouse cells (Cheloufi et al, 2015;Cheloufi and Hochedlinger, 2017). In addition, lack of CAF-1 in Drosophila imaginal discs is associated with a massive decrease of H3K27me3 levels (Anderson et al, 2011;Yee et al, 2019), suggesting that CAF-1 activity is required for the inheritance of H3K27me3 in vivo.…”