TBL1XR1 mutations bias germinal center B-cells towards a pro-tumorigenic memory fate
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA580268 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10360845.fastq.gz | Fastqsanger.gz | |||
| SRR10360846.fastq.gz | Fastqsanger.gz | |||
| SRR10360847.fastq.gz | Fastqsanger.gz | |||
| SRR10360848.fastq.gz | Fastqsanger.gz | |||
| SRR10360849.fastq.gz | Fastqsanger.gz |
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Project description:TBL1XR1 gene is associated with multiple developmental disorders presenting several neurological aspects. The relative protein is involved in regulation of important cellular pathways and master regulators of transcriptional output including nuclear receptor repressors, Wnt signaling, and MECP2 protein. However, TBL1XR1 mutations (including complete loss of its functions) have not been experimentally studied in neurological context, leaving a lack of knowledge in the mechanisms at the basis of the diseases. We show that Tbl1xr1 knock-out mice exhibit behavioral and neuronal abnormalities. Either the absence of TBL1XR1, or point mutations interfering with stability/regulation of NCOR complex induced decreased proliferation and increased differentiation in neural progenitors. We suggest that this developmental unbalance is due to the failure in the regulation of MAPK cascade. Together, our results broaden the molecular and functional aftermath of TBL1XR1 deficiency associated with human disorders.
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Project description:Several recent studies have suggested that genes that are over 100 kb in length are particularly likely to be misregulated in neurological diseases associated with synaptic dysfunction, such as autism, Fragile X syndrome, and Rett syndrome. These length-dependent transcriptional changes seem to be modest, but, given the low sensitivity of high-throughput transcriptome profiling technology, the statistical significance of these results needs to be reevaluated. Here we show that transcriptional changes reflected in microarray and RNA-Sequencing benchmark datasets from the SEQC Consortium show a bias toward genes of greater length, even in the comparison of technical replicates. We hypothesized that PCR amplification, which is used in both microarray and RNA-Seq technologies, could be introducing this bias. We found that, when the fold-change values are small, PCR amplification in microarray and RNA-Seq technologies does produce a bias toward longer genes; we found no similar bias with nCounter technology, which is not based on PCR amplification. We provide an approach to more rigorously assess length-dependent changes that begins with comparing randomized control samples to estimate baseline gene length dependency and evaluate the statistical significance of gene length regulation.
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