Biology subjects

Bahn, J. H.

Publications and source records attributed to Bahn, J. H..

5 recordsLinked to original sources

bioRxiv2026

Allele-specific splicing modulates protein isoforms and Alzheimer's risk

Despite growing catalogs of genetic variation linked to human traits and diseases, the functional impact of most genetic variants remains poorly understood. Alternative splicing, particularly in the human brain, represents a key layer of post-transcriptional regulation that may mediate genetic effects on gene expression and protein diversity. In this study, we systematically map allele-specific alternative splicing (ASAS) events in postmortem brain tissues from the Mount Sinai Brain Bank cohort, identifying hundreds of genetically regulated splicing events across four brain regions. Using a concordance-based method, we nominate over 500 putative functional SNPs associated with ASAS, many of which overlap splicing QTLs (sQTLs), RNA-binding protein binding sites, and GWAS loci for Alzheimers disease (AD), brain traits, and immune phenotypes. ASAS events are enriched in genes involved in mitochondrial function and frequently occur in 5' untranslated regions (5' UTRs), where they are associated with protein quantitative trait loci (pQTLs), alternative start codons, and isoform-specific domain changes - highlighting an underappreciated mechanism through which noncoding variants can influence translation and proteome complexity. Importantly, we also identify a subset of ASAS events exhibiting disease-specific splicing patterns in AD brains, including functional SNPs with opposing splicing effects between AD and control groups in genes implicated in mitochondrial function and neuronal signaling. Together, our results provide a brain-specific, splicing-resolved map of regulatory variation and uncover novel mechanisms linking genetic variation to transcript and protein-level changes in AD. This work highlights the importance of allele-specific splicing analysis for interpreting noncoding variation in complex human disorders.

genomics↗

bioRxiv2020

Allele-specific alternative splicing in human tissues

Alternative splicing is an RNA processing mechanism that affects most genes in human, contributing to disease mechanisms and phenotypic diversity. The regulation of splicing involves an intricate network of cis-regulatory elements and trans-acting factors. Due to their high sequence specificity, cis-regulation of splicing can be altered by genetic variants, significantly affecting splicing outcomes. Recently, multiple methods have been applied to understanding the regulatory effects of genetic variants on splicing. However, it is still challenging to go beyond apparent association to pinpoint functional variants. To fill in this gap, we utilized large-scale datasets of the Genotype-Tissue Expression (GTEx) project to study genetically-modulated alternative splicing (GMAS) via identification of allele-specific splicing events. We demonstrate that GMAS events are shared across tissues and individuals more often than expected by chance, consistent with their genetically driven nature. Moreover, although the allelic bias of GMAS exons varies across samples, the degree of variation is similar across tissues vs. individuals. Thus, genetic background drives the GMAS pattern to a similar degree as tissue-specific splicing mechanisms. Leveraging the genetically driven nature of GMAS, we developed a new method to predict functional splicing-altering variants, built upon a genotype-phenotype concordance model across samples. Complemented by experimental validations, this method predicted >1000 functional variants, many of which may alter RNA-protein interactions. Lastly, 72% of GMAS-associated SNPs were in linkage disequilibrium with GWAS-reported SNPs, and such association was enriched in tissues of relevance for specific traits/diseases. Our study enables a comprehensive view of genetically driven splicing variations in human tissues.

genomics↗

bioRxiv2020

Differential RNA editing between epithelial and mesenchymal tumors impacts mRNA abundance in immune response pathways

Recent studies revealed global shifts in RNA editing, the modification of RNA sequences, across many cancers. Besides a few sites implicated in tumorigenesis or metastasis, most tumor-associated sites, predominantly in noncoding regions, have unknown function. Here, we characterize editing profiles between epithelial (E) and mesenchymal (M) phenotypes in seven cancer types, as epithelial-mesenchymal transition (EMT) is a key paradigm for metastasis. We observe distinct editing patterns between E and M tumors and EMT induction upon loss of ADAR enzymes in cultured cells. E-M differential sites are highly enriched in genes involved in immune and viral processes, some of which regulate mRNA abundance of their respective genes. We identify a novel mechanism in which ILF3 preferentially stabilizes edited transcripts. Among editing-dependent ILF3 targets is the transcript encoding PKR, a crucial player in immune response. Our study demonstrates the broad impact of RNA editing in cancer and relevance of editing to cancer-related immune pathways.

cancer biology↗

bioRxiv2018

Widespread RNA editing dysregulation in Autism Spectrum Disorders

Autism spectrum disorder (ASD) is a genetically complex, clinically heterogeneous neurodevelopmental disease. Recently, our understanding of the molecular abnormalities in ASD has been expanded through transcriptomic analyses of postmortem brains. However, a crucial molecular pathway involved in synaptic development, RNA editing, has not yet been studied on a genome-wide scale. Here, we profiled the global patterns of adenosine-to-inosine (A-to-I) editing in a large cohort of post-mortem ASD brains. Strikingly, we observed a global bias of hypo-editing in ASD brains, common to different brain regions and involving many genes with known neurobiological functions. Through genome-wide protein-RNA binding analyses and detailed molecular assays, we show that the Fragile X proteins, FMRP and FXR1P, interact with ADAR proteins and modulate A-to-I editing. Furthermore, we observed convergent patterns of RNA editing alterations in ASD and Fragile X syndrome, thus establishing RNA editing as a molecular link underlying these two highly related diseases. Our findings support a role for RNA editing dysregulation in ASD and highlight novel mechanisms for RNA editing regulation.

neuroscience↗

bioRxiv2018

Allele-specific binding of RNA-binding proteins reveals functional genetic variants in the RNA

Allele-specific protein-RNA binding is an essential aspect that may reveal functional genetic variants influencing RNA processing and gene expression phenotypes. Recently, genome-wide detection of in vivo binding sites of RNA binding proteins (RBPs) is greatly facilitated by the enhanced UV crosslinking and immunoprecipitation (eCLIP) protocol. Hundreds of eCLIP-Seq data sets were generated from HepG2 and K562 cells during the ENCODE3 phase. These data afford a valuable opportunity to examine allele-specific binding (ASB) of RBPs. To this end, we developed a new computational algorithm, called BEAPR (Binding Estimation of Allele-specific Protein-RNA interaction). In identifying statistically significant ASB sites, BEAPR takes into account UV cross-linking induced sequence propensity and technical variations between replicated experiments. Using simulated data and actual eCLIP-Seq data, we show that BEAPR largely outperforms often-used methods Chi-Squared test and Fishers Exact test. Importantly, BEAPR overcomes the inherent over-dispersion problem of the other methods. Complemented by experimental validations, we demonstrate that ASB events are significantly associated with genetic regulation of splicing and mRNA abundance, supporting the usage of this method to pinpoint functional genetic variants in post-transcriptional gene regulation. Many variants with ASB patterns of RBPs were found as genetic variants with cancer or other disease relevance. About 38% of ASB variants were in linkage disequilibrium with single nucleotide polymorphisms from genome-wide association studies. Overall, our results suggest that BEAPR is an effective method to reveal ASB patterns in eCLIP and can inform functional interpretation of disease-related genetic variants.

bioinformatics↗