The RNA binding protein HuR determines the differential translation of autism-associated FoxP subfamily members in the developing neocortex

Popovitchenko, Tatiana; Thompson, Kevin J.; Viljetić, Barbara; Jiao, Xuan; Kontonyiannis, D. L.; Kiledjian, Megerditch; Hart, Ronald P.; Rašin, Mladen-Roko

doi:10.1038/srep28998

Cited by 33 publications

(46 citation statements)

References 44 publications

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“…Computational processing might have been facilitated by some of the changes presented here, at least in some of the circuits that have expanded in our lineage (Mars et al 2018), since subtle maturational differences early in development(Dubois et al 2016) may have had a considerable impact on the phenotype. In this context, it is worth mentioning that in our dataset, several genes carrying HHMCs and associated with basal ganglia functions (critical for language and cognition) stand out, like SLITRK1(Abelson et al 2005) and NOVA1(Jelen et al 2010;Konopka et al 2012;Alsiö et al 2013;Zhou et al 2015;Popovitchenko et al 2016) (Supplementary Information 4). Finally, in the broader context of cognition, we find an enrichment of HHMCs in genes associated to "Alzheimer's disease (cognitive decline)" and "Cognitive decline(age-related)", with seven associated genes (COX7B2, BCAS3, DMXL1, LIPC, PLEKHG1, TTLL2 and VIT).…”

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confidence: 97%

A catalog of single nucleotide changes distinguishing modern humans from archaic hominins

Kuhlwilm

Boeckx

2018

Preprint

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10Throughout the past decade, studying ancient genomes provided unique insights into human 11 prehistory, and differences between modern humans and other branches like Neanderthals can 12 enrich our understanding of the molecular basis of the human condition. Modern human variation 13 and the interactions between different hominin lineages are now well studied, making it reasonable 14 to explore changes that are observed at high frequency in present-day humans, but do not reach 15 fixation. Here, we put forward interpretation of putative single nucleotide changes in recent modern 16 human history, focusing on 571 genes with non-synonymous changes at high frequency. We 17 suggest that molecular mechanisms in cell division and networks affecting cellular features of 18 neurons were prominently modified by these changes. Complex phenotypes in brain growth 19 trajectory and cognitive traits are likely influenced by these networks and other changes presented 20here. We propose that at least some of these changes contributed to uniquely human traits.

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confidence: 97%

A catalog of single nucleotide changes distinguishing modern humans from archaic hominins

Kuhlwilm

Boeckx

2018

Preprint

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“…Developmental titration of FOXP1 levels can be regulated through numerous mechanisms. There is evidence that this is accomplished, in part, by post-transcriptional regulation of FOXP1 mRNA through critical cis regulatory elements (CREs) (Huelga et al, 2012;Jangi & Sharp, 2014;Liu et al, 2014) and microRNAs (miRNAs) in UTRs of the gene (Otaegi, Pollock, Hong, & Sun, 2011;Popovitchenko et al, 2016). Bioinformatic analysis revealed that the variants observed were near the binding sites of mRNA-486-5p (mi-croRNA.org).…”

Section: Discussionmentioning

confidence: 99%

Identification of a de novo FOXP1 mutation and incidental discovery of inherited genetic variants contributing to a case of autism spectrum disorder and epilepsy

Jay

Mitra

Harding

et al. 2019

Molec Gen & Gen Med

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Background Autism spectrum disorder is commonly co‐diagnosed intellectual disability, language disorder, anxiety, and epilepsy, however, symptom management is difficult due to the complex genetic nature of ASD. Methods We present a next‐generation sequencing‐based case study with both de novo and inherited genetic variants and highlight the impact of structural variants on post‐translational regulation of protein expression. Since management of symptoms has classically been through pharmaceutical therapies, a pharmacogenomics screen was also utilized to determine possible drug/gene interactions. Results A de novo variant was identified within the FOXP1 3′ untranslated regulatory region using exome sequencing. Additionally, inherited variants that likely contribute to the current and potential future traits were identified within the COMT, SLC6A4 , CYP2C19, and CYP2D6 genes. Conclusion This study aims to elucidate how a collection of variant genotypes could potentially impact neural development resulting in a unique phenotype including ASD and epilepsy. Each gene's contribution to neural development is assessed, and the interplay of these genotypes is discussed. The results highlight the utility of exome sequencing in conjunction with pharmacogenomics screening when evaluating possible causes of and therapeutic treatments for ASD‐related symptoms.

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“…However, the mechanism underlying the effects of suramin in ASD is unclear. HuR regulated the translation of mRNA transcribed from autism‐associated genes, Foxp1 and Foxp2 . Suramin may have improved ASD by inhibiting HuR‐ Foxp1 and/or HuR‐ Foxp2 binding.…”

Section: Discussionmentioning

confidence: 99%

Suramin, screened from an approved drug library, inhibits HuR functions and attenuates malignant phenotype of oral cancer cells

et al. 2018

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AU‐rich elements (ARE) exist in the 3′‐untranslated regions of the mRNA transcribed from cell growth‐related genes such as proto‐oncogenes, cyclin‐related genes, and growth factors. HuR binds and stabilizes ARE‐mRNA. HuR is expressed abundantly in cancer cells and related malignant phenotypes. HuR knockdown attenuates the malignant phenotype of oral cancer cells. In this study, we screened 1570 compounds in the approved drug library by differential scanning fluorimetry (DSF) to discover a HuR‐targeted compound. Firstly, 55 compounds were selected by DSF. Then, 8 compounds that showed a shift in the melting temperature value in a concentration‐dependent manner were selected by DSF. Of them, suramin, an anti‐trypanosomal drug, binds to HuR, exhibiting fast‐on and fast‐off kinetic behavior on surface plasmon resonance (SPR). We confirmed that suramin significantly decreased mRNA and protein expression of cyclin A2 and cyclin B1. The cyclin A2 and cyclin B1 mRNAs were destabilized by suramin. Furthermore, the motile and invasive activities of a tongue carcinoma cell line treated with suramin were markedly lower than those of control cells. The above findings suggest that suramin binds to HuR and inhibits its function. We also showed that the anticancer effects of suramin were caused by the inhibition of HuR function, indicating its potential as a novel therapeutic agent in the treatment of oral cancer. Our results suggest that suramin, via its different mechanism, may effectively suppress progressive oral cancer that cannot be controlled using other anticancer agents.

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The RNA binding protein HuR determines the differential translation of autism-associated FoxP subfamily members in the developing neocortex

Cited by 33 publications

References 44 publications

A catalog of single nucleotide changes distinguishing modern humans from archaic hominins

A catalog of single nucleotide changes distinguishing modern humans from archaic hominins

Identification of a de novo FOXP1 mutation and incidental discovery of inherited genetic variants contributing to a case of autism spectrum disorder and epilepsy

Suramin, screened from an approved drug library, inhibits HuR functions and attenuates malignant phenotype of oral cancer cells

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