Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

/pdf/gene-discovery-and-polygenic-prediction-from-a-genome-wide-28jxdgwqo5.pdf

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

The mRNA-Bound Proteome and Its Global Occupancy Profile on Protein-Coding Transcripts

Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins (RBPs) that contribute to multiple aspects of nucleic acid metabolism including alternative splicing, mRNA stabilization, and transcriptional and translational regulation Many hnRNPs share general features, but differ in domain composition and functional properties This review will discuss the current knowledge about the different hnRNP family members, focusing on their structural and functional divergence Additionally, we will highlight their involvement in neurodegenerative diseases and cancer, and the potential to develop RNA-based therapies

/pdf/the-hnrnp-family-insights-into-their-role-in-health-and-1sabmin86x.pdf

The hnRNP family: insights into their role in health and disease

RNA-binding proteins (RBPs) are key players in post-transcriptional events. The combination of versatility of their RNA-binding domains with structural flexibility enables RBPs to control the metabolism of a large array of transcripts. Perturbations in RBP–RNA networks activity have been causally associated with cancer development, but the rational framework describing these contributions remains fragmented. We review here the evidence that RBPs modulate multiple cancer traits, emphasize their functional diversity, and assess future trends in the study of RBPs in cancer.

RNA-Binding Proteins in Cancer: Old Players and New Actors

Examination of the expanding pathways for the regulation of p21 expression and activity.

The p53 pathway is critical for tumor suppression, as the majority of human cancer has a faulty p53. Here, we identified RNPC1, a p53 target and a RNA-binding protein, as a critical regulator of p53 translation. We showed that ectopic expression of RNPC1 inhibited, whereas knockdown of RNPC1 increased, p53 translation under normal and stress conditions. We also showed that RNPC1 prevented cap-binding protein eIF4E from binding p53 mRNA via its C-terminal domain for physical interaction with eIF4E, and its N-terminal domain for binding p53 mRNA. Consistent with this, we found that RNPC1 directly binds to p53 59 and 39untranslated regions (UTRs). Importantly, we showed that RNPC1 inhibits ectopic expression of p53 in a dose-dependent manner via p53 59 or 39 UTR. Moreover, we showed that loss of RNPC1 in mouse embryonic fibroblasts increased the level of p53 protein, leading to enhanced premature senescence in a p53-dependent manner. Finally, to explore the clinical relevance of our finding, we showed that RNPC1 was frequently overexpressed in dog lymphomas, most of which were accompanied by decreased expression of wild-type p53. Together, we identified a novel p53–RNPC1 autoregulatory loop, and our findings suggest that RNPC1 plays a role in tumorigenesis by repressing p53 translation.

/pdf/translational-repression-of-p53-by-rnpc1-a-p53-target-1mmk7iz8mt.pdf

Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas

P21, a cyclin-dependent kinase inhibitor, plays a pivotal role in the cell-cycle regulation in response to stress stimuli. P21 expression is highly regulated through transcriptional, post-transcriptional and post-translational mechanisms. Previously, we and others showed that p21 expression is regulated through p21 mRNA stability by RNPC1, a target of the p53 family and HuR, a member of the ELAV family RNA-binding proteins. HuR carries three highly conserved RNA recognition motifs (RRMs) whereas RNPC1 carries one. Here we found that the ability of RNPC1 to regulate p21 mRNA stability is dependent on HuR. We also found that RNPC1 and HuR physically interact, and the RRM domain in RNPC1 and RRM3 in HuR are necessary for their interaction. Interestingly, we found that RNPC1 and HuR, both of which can bind AU-rich elements (AREs) in p21 3′-UTR, preferentially bind the upstream and downstream AREs, respectively. Finally, we showed that the RNA-binding activity of HuR to p21 transcript was enhanced by RNPC1 in vitro and in vivo. Together, we hypothesize that RNPC1 modulates the RNA-binding activity of, and cooperates with, HuR to regulate p21 mRNA stability.

/pdf/rnpc1-modulates-the-rna-binding-activity-of-and-cooperates-iqnnmqm2fx.pdf

RNPC1 modulates the RNA-binding activity of, and cooperates with, HuR to regulate p21 mRNA stability.

P63, a p53 family tumor suppressor, is involved in many cellular processes, including growth suppression and differentiation. Thus, p63 activity needs to be tightly controlled. Here, we found that RNPC1, a RNA-binding protein and a target of the p53 family, regulates p63 mRNA stability and consequently p63 activity. Specifically, we showed that overexpression of RNPC1 decreases, whereas knockdown of RNPC1 increases, the half-life of p63 transcript, which leads to altered p63 expression. Consistent with this, we showed that RNPC1 binds the AU-/U-rich elements in p63 3′ UTR in vitro and in vivo and the RRM domain in RNPC1 is required for binding, and regulating the stability of, p63 transcript. Furthermore, we showed that RNPC1 promotes keratinocyte differentiation by repressing p63 expression. Together, we uncovered a previously undetected mechanism by which p63 expression is regulated via mRNA stability and a novel regulatory feedback loop between RNPC1 and p63.

https://www.pnas.org/content/pnas/107/21/9614.full.pdf

RNPC1, an RNA-binding protein and a target of the p53 family, regulates p63 expression through mRNA stability.

RNA-binding proteins (RBPs) play a major role in many post-transcriptional processes, including mRNA stability, alternative splicing and translation. PCBP4, also called MCG10, is an RBP belonging to the poly(C)-binding protein family and a target of p53 tumor suppressor. Ectopic expression of PCBP4 induces cell-cycle arrest in G2 and apoptosis. To identify RNA targets regulated by PCBP4 and further decipher its function, we generated multiple cell lines in which PCBP4 is either inducibly over-expressed or knocked down. We found that PCBP4 expression decreases cyclin-dependent kinase inhibitor p21 induction in response to DNA damage. We also provided evidence that PCBP4 regulates p21 expression independently of p53. In addition, we showed that a deficiency in PCBP4 enhances p21 induction upon DNA damage. To validate PCBP4 regulation of p21, we made PCBP4-deficient mice and showed that p21 expression is markedly increased in PCBP4-deficient primary mouse embryo fibroblasts compared to that in wild-type counterparts. Finally, we uncovered that PCBP4 binds to the 3′-UTR of p21 transcript in vitro and in vivo to regulate p21 mRNA stability. Taken together, we revealed that PCBP4 regulates both basal and stress-induced p21 expression through binding p21 3′-UTR and modulating p21 mRNA stability.

/pdf/the-cyclin-dependent-kinase-inhibitor-p21-is-regulated-by-1bsis2hrc0.pdf

Seong Jun Cho

Papers

Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas

RNPC1 modulates the RNA-binding activity of, and cooperates with, HuR to regulate p21 mRNA stability.

RNPC1, an RNA-binding protein and a target of the p53 family, regulates p63 expression through mRNA stability.

The cyclin-dependent kinase inhibitor p21 is regulated by RNA-binding protein PCBP4 via mRNA stability

Mutant p53 Protein Is Targeted by Arsenic for Degradation and Plays a Role in Arsenic-mediated Growth Suppression