Large-scale discovery of neural enhancers for cis-regulation therapies.

ABSTRACT: CRISPR-based gene activation (CRISPRa) has emerged as a promising therapeutic approach for neurodevelopmental disorders (NDD) caused by haploinsufficiency. However, scaling this cis-regulatory therapy (CRT) paradigm requires pinpointing which candidate cis-regulatory elements (cCREs) are active in human neurons, and which can be targeted with CRISPRa to yield specific and therapeutic levels of target gene upregulation. Here, we combine Massively Parallel Reporter Assays (MPRAs) and a multiplex single cell CRISPRa screen to discover functional human neural enhancers whose CRISPRa targeting yields specific upregulation of NDD risk genes. First, we tested 5,425 candidate neuronal enhancers with MPRA, identifying 2,422 that are active in human neurons. Selected cCREs also display

SUBMITTER: McDiarmid TA 

PROVIDER: S-EPMC12637570 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature