CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF

Abstract

Initiation and maintenance of transcriptional states are critical for controlling normal tissue homeostasis and differentiation. Cyclin Dependent Kinases CDK8/CDK19 (Mediator kinase) are regulatory components of Mediator, a highly conserved complex that orchestrates enhancer-mediated transcriptional output. While Mediator kinase has been implicated in the transcription of genes necessary for development and growth, its function in mammals has not been well defined. Using genetically defined models and pharmacological inhibitors, we showed that CDK8/19 function in a redundant manner to regulate intestinal lineage-specification in human and mouse. The Mediator kinase module bound and phosphorylated key components of the chromatin remodelling complex Switch/Sucrose Non-Fermentable (SWI/SNF) in intestinal epithelial cells (IECs). Concomitantly, SWI/SNF and MED12-Mediator co-localised at distinct lineagespecifying enhancers in a CDK8/19 dependent manner. As such, these studies revealed a transcriptional mechanism of intestinal cell specification, coordinated by the interaction between the chromatin remodelling complex SWI/SNF and Mediator kinase.

Genetically Engineered Mice Unveil In Vivo Roles of the Mediator Complex

“…Paneth cell, goblet and tuft cell counts were decreased, while the number of absorptive cells significantly increased. It was shown that CDK8 and CDK19 allowed secretory lineage differentiation by upregulating Atoh1 expression with an ARID1A-defined enhancer upon interaction with SWI/SNF [70]. Thus, this model confirms that the Mediator functions are not limited to transcription modulation, but take part in chromatin remodeling.…”

CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium

“…Indeed, there are 95 solute carriers whose expression is deregulated in CDK8/19 knockouts (Table EV2), including four inorganic anion transporters of the Slc26 family, all of which are upregulated, and which might contribute to the phenotype. While this study was still ongoing, a report was published in which, using a similar genetic approach in mice and intestinal organoids, CDK8 and CDK19 were found to be dispensable for intestinal morphology and viability but were observed to redundantly control intestinal lineage specification (Dannappel et al, 2022). In particular, a decrease in number of paneth cells, tuft cells, and goblet cells were reported in intestinal tissue lacking both kinases, a result that we do not reproduce.…”

Knockout of cyclin dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice

“…If CDK8 and CDK19 functions are redundant, DKO would show a phenotype that is not produced by the knockout of Cdk8 or Cdk19 alone. Previously described animals with conditional knockout of Cdk8 in the intestine on Cdk19 -/- background presented with a mild phenotype, moderately affecting the number of specialized secreting cells (Dannappel et al 2022). At the same time, our DKO mice had a phenotype evident at the histological level: they lacked haploid spermatids and mature spermatozoa (Fig.…”

“…Moreover, conditional Cdk8 KO is almost asymptomatic in adult mice, and the lifespan is normal. Minor differences were observed in colon epithelial differentiation [12,13] and tumorigenesis [14] as well as in osteoclastogenesis [15] after tissue specific Cdk8 knockout.…”

“…Moreover, conditional Cdk8 KO is almost asymptomatic in adult mice, and the lifespan is normal. Minor differences were observed in colon epithelial differentiation (Dannappel et al 2022; Prieto et al 2023) and tumorigenesis (McCleland et al 2015) as well as in osteoclastogenesis (Yamada et al 2022) after tissue specific Cdk8 knockout. Although two CDK8/19 inhibitors were reported to have systemic toxicity (Clarke et al 2016), this toxicity was subsequently found to be due to off-target effects of these inhibitors (Chen et al 2019), and several CDK8/19 inhibitors have reached clinical trials (clinicaltrials.gov NCT03065010, NCT04021368, NCT05052255, NCT05300438).…”