ATRX safeguards cellular identity during C. elegans development
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1237240 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32732700_1.fastq.gz | Fastqsanger.gz | |||
| SRR32732700_2.fastq.gz | Fastqsanger.gz | |||
| SRR32732701_1.fastq.gz | Fastqsanger.gz | |||
| SRR32732701_2.fastq.gz | Fastqsanger.gz | |||
| SRR32732702_1.fastq.gz | Fastqsanger.gz |
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Project description:ATRX is a member of the SWI/SNF family of ATP-dependent chromatin remodellers. In humans, loss of ATRX function in leads to ATRX syndrome, a neurodevelopmental disorder. ATRX mutation in human cell lines is associated with multiple phenotypes including activation of the alternative lengthening of telomere (ALT) pathway, upregulation of retrotransposons and increased sensitivity to replication stress. However, the principal role of ATRX and the reason why its mutation causes such diverse phenotypes is currently unclear. To address this, we studied the role of ATRX in the model organism Caenorhabditis elegans. We find that loss of XNP-1, the C. elegans homologue of ATRX, recapitulates many human phenotypes. In addition, XNP-1 is required to repress the inappropriate activation of germline genes. Importantly, this germline misexpression correlates with most of the phenotypes observed in xnp-1 animals. Seemingly distinct xnp-1 phenotypes such as developmental abnormalities and telomeric defects are both suppressed by mutation of the germline transcription factor gsox-1. These findings suggest that the majority of XNP-1-dependent phenotypes stem from its role in maintaining proper cellular identity, offering insights into the functions of ATRX in humans.
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Project description:The establishment and maintenance of cellular identity rely upon the precise coordination of regulatory pathways culminating to the proper execution of cell type-specific gene expression programs. Generation of induced pluripotent stem cells (iPSCs) from highly specialized cell types provides an excellent model system to study how cells maintain their stability through the functional interplay of transcription factors and chromatin structure, and how they can change identity, especially in the context of disease. Previous studies have shown that chromatin structure safeguards cell identity by acting as a barrier to reprogramming. Here, we investigated the mechanisms of how the histone variant macroH2A inhibits reprogramming by interfering with the mesenchyme to epithelial transition, a step that is a prerequisite for reprogramming of mouse embryonic fibroblasts. We found that each of the macroH2A isoforms regulates the expression of defined sets of genes, whose overall function is to stabilize the mesenchyme phenotype, thus resisting reprogramming. We identified a novel gene network (MSCN, mesenchyme network) composed of 63 macroH2A-regulated genes encoding proteins of the extracellular matrix, cell membrane, cytoplasmic signal integrators and the transcriptional regulators Id2 and Snai2, all of which can function as key controllers of the mesenchyme phenotype. Functional studies including ChIP-seq and KD experiments using any one of the individual macroH2A isoforms revealed an isoform-specific combinatorial targeting of the genes that reconstruct the MSCN. Our findings established that the combinatorial macroH2A targeting of the MSCN components safeguards cell identity and demonstrated its pivotal role in maintaining the differentiated cell phenotype by generating robustness in gene expression programs to resist cellular reprogramming.
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Project description:Purpose: the chromatin-remodeler ATRX is frequently mutated in a range of human malignancies including pediatric and adult gliomas, and its loss underlies induction of alternative lengthening of telomeres (ALT) pathway for chromosome-end maintenance. But how ATRX exters its glioma suppresor role remains unclear. Here, we combine RNAi and somatic deletion approaches to demonstrate ATRX as a glioma suppressor controlling neural differentiation. Loss of ATRX promotes gliomagenesis by blocking neuronal progenitors from undergoing terminal maturation. Our findings provide the molecular and cellular mechanism underline ATRX's function in gliomagenesis.
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