Dataset Information

Cell fate determination by ubiquitin-dependent regulation of ribosome function

ABSTRACT: Metazoan development depends on accurate execution of differentiation programs that allow pluripotent stem cells to adopt specific fates. Differentiation is brought about by global changes to chromatin architecture and transcriptional networks, yet whether other regulatory events support cell fate determination is less well understood. Using a human embryonic stem cell model, we identified the vertebrate-specific ubiquitin ligase Cul3KBTBD8 as an essential regulator of neural crest cell formation. Cul3KBTBD8 monoubiquitylates NOLC1 and its paralog TCOF1, whose mutation underlies the developmental disease Treacher Collins Syndrome that is characterized by a loss of cranial neural crest cells. Ubiquitylation of NOLC1 and TCOF1 drives formation of a platform that connects RNA polymerase I with ribosome modification enzymes, thereby altering the translational program of differentiating cells to support the generation of neural crest cells. We conclude that the dynamic regulation of ribosome function is an important feature of cell fate determination.

ORGANISM(S): Homo sapiens

PROVIDER: GSE62123 | GEO | 2015/09/24

SECONDARY ACCESSION(S): PRJNA263250

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Myriad of craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as ribosome biogenesis. While it is understood that many of these highly tissue-specific malformations are a consequence of defects in cranial neural crest cells (cNCCs), an embryonic cell group that gives rise to most of the facial structures during embryogenesis, the mechanism underlying cell type-selectivity of these effects remains largely unknown. Here we show that DDX21, a DEAD-box RNA helicase involved in control of both RNA polymerase (Pol) I and Pol II dependent transcriptional arms of ribosome biogenesis, is a key mediator of the nucleolar stress response. Using an in vitro model of Treacher Collins Syndrome (TCS), a craniofacial disorder caused by heterozygous mutations in components of the Pol I transcriptional machinery, we demonstrate that perturbations in ribosomal RNA (rRNA) transcription induce DDX21-mediated surveillance mechanism in cNCCs, leading to DDX21 relocalization from the nucleolus to the nucleoplasm, its eviction from Pol I and Pol II chromatin targets and inhibition of rRNA processing. Importantly, these effects are cell type-selective, cell-autonomous and involve activation of the p53 pathway. We further show that cNCCs are characterized by the inherently high reservoir of p53 mRNA and sensitivity to p53-mediated apoptosis. Remarkably, preventing the loss of DDX21 from nucleolus and chromatin can rescue both the sensitivity to apoptosis and TCS-associated craniofacial phenotypes in vivo. This mechanism is not restricted to TCS, as gene function perturbations linked to other ribosomopathies with craniofacial manifestations also lead to the activation of DDX21 surveillance. Lastly, we provide evidence that inhibition of rRNA synthesis leads to rDNA damage, and furthermore, that rDNA damage is sufficient to activate DDX21 surveillance and elicits tissue-selective and dosage-dependent effects on craniofacial development in vivo.

Dataset Information

Cell fate determination by ubiquitin-dependent regulation of ribosome function

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets