Highlights− The first atlas of human 3'QTLs: ~0.4 million genetic variants associated with alternative polyadenylation of target genes across 46 tissues from 467 individuals − 3'QTLs could alter polyA motifs and RNA-binding protein binding sites − 3'QTLs can be used to interpret ~16.1% of trait-associated variants − Many disease-associated 3'QTLs contribute to phenotype independent of gene expression .
When identifying differentially expressed genes between two conditions using human population RNA-seq samples, we found a phenomenon by permutation analysis: two popular bioinformatics methods, DESeq2 and edgeR, have unexpectedly high false discovery rates. Expanding the analysis to limma-voom, NOISeq, dearseq, and Wilcoxon rank-sum test, we found that FDR control is often failed except for the Wilcoxon rank-sum test. Particularly, the actual FDRs of DESeq2 and edgeR sometimes exceed 20% when the target FDR is 5%. Based on these results, for population-level RNA-seq studies with large sample sizes, we recommend the Wilcoxon rank-sum test.
Over their lifetime, long-term haematopoietic stem cells (HSC) are exposed to a variety of stress conditions that they must endure. Many stresses, such as infection/inflammation, reactive oxygen species, nutritional deprivation and hypoxia, activate unfolded protein response signalling, which induces either adaptive changes to resolve the stress or apoptosis to clear the damaged cell. Whether unfolded-protein-response signalling plays any role in HSC regulation remains to be established. Here, we report that the adaptive signalling of the unfolded protein response, IRE1α-XBP1, protects HSCs from endoplasmic reticulum stress-induced apoptosis. IRE1α knockout leads to reduced reconstitution of HSCs. Furthermore, we show that oncogenic N-RasG12D activates IRE1α-XBP1, through MEK-GSK3β, to promote HSC survival under endoplasmic reticulum stress. Inhibiting IRE1β-XBP1 abolished N-RasG12D-mediated survival under endoplasmic reticulum stress and diminished the competitive advantage of NrasG12D HSCs in transplant recipients. Our studies illuminate how the adaptive endoplasmic reticulum stress response is advantageous in sustaining self-renewal of HSCs and promoting pre-leukaemic clonal dominance.
Data-driven discovery of cancer driver genes, including tumor suppressor genes (TSGs) and oncogenes (OGs), is imperative for cancer prevention, diagnosis, and treatment. Although epigenetic alterations are important for tumor initiation and progression, most known driver genes were identified based on genetic alterations alone. Here, we developed an algorithm, DORGE (Discovery of Oncogenes and tumor suppressoR genes using Genetic and Epigenetic features), to identify TSGs and OGs by integrating comprehensive genetic and epigenetic data. DORGE identified histone modifications as strong predictors for TSGs, and it found missense mutations, super enhancers, and methylation differences as strong predictors for OGs. We extensively validated DORGE-predicted cancer driver genes using independent functional genomics data. We also found that DORGE-predicted dual-functional genes (both TSGs and OGs) are enriched at hubs in protein-protein interaction and drug-gene networks. Overall, our study has deepened the understanding of epigenetic mechanisms in tumorigenesis and revealed previously undetected cancer driver genes.
Stem cells need to be protected from genotoxic and proteotoxic stress to maintain a healthy pool throughout life
1
–
3
. Little is known about the proteostasis mechanism that safeguards the stem cells. Here, we report Endoplasmic Reticulum-Associated Degradation (ERAD) as a protein quality checkpoint that controls hematopoietic stem cell (HSC)-niche interaction and determines the fate of HSC. SEL1L-HRD1 complex, the most conserved branch of ERAD
4
, is highly expressed in HSC. Deletion of
Sel1l
led to niche displacement of HSC, complete loss of HSC identity, and allowed highly efficient donor-HSC engraftment without irradiation. Mechanistic studies identified MPL, the master regulator of HSC identity
5
, as a bona-fide ERAD substrate that became aggregated in the ER upon ERAD deficiency. Restoration of MPL signaling with an agonist partially rescued the number and reconstitution capacity of
Sel1l
-deficient HSCs. Our study defines ERAD as an essential proteostasis mechanism to safeguard a healthy stem cell pool through regulating the stem cell-niche interaction.
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