Haigh, J. L. | bioRxiv Science

bioRxiv2025

Prioritising Functional Noncoding Variants via eRNA Post-transcriptional Interaction Maps in Human Samples

Noncoding variants and mutations outnumber their coding counterparts but remain challenging to interpret functionally. We present TranCi, a method that prioritises human genetic variations by integrating enhancer RNA (eRNA) expression with eRNA-mRNA interactome maps. By linking variant-associated changes in eRNA to downstream gene regulation, TranCi captures functional effects missed by sequence-based or chromatin-centric approaches. In esophageal squamous cell cancer, TranCi identifies noncoding mutations with roles in disease initiation and progression. A personalised mode enables analysis at single-patient resolution, uncovering potential individual-specific regulatory variants. TranCi thus provides a mechanistic framework for interpreting noncoding variations and uniquely identifies their downstream targets, where standard methods often fall short. TranCi is available as a module within the eRNAkit R package (https://github.com/AneneLab/eRNAkit), leveraging its database of eRNA expression and interactions for functional variant interpretation.

genomics↗

bioRxiv2019

Deletion of a non-canonical promoter regulatory element causes loss of Scn1a expression and epileptic phenotypes in mice

Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the NaV1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet Syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency, however putative causal non-coding promoter mutations have been identified. To determine the functional role of one of these potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. Mice harboring a deletion of the extended evolutionarily-conserved 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and NaV1.1 expression in brain with accompanying electroencephalographic seizures and behavioral deficits. This work identified the 1b region as a critical disease-relevant regulatory element and provides evidence that non-canonical and seemingly redundant promoters can have essential function.

neuroscience↗