Development of a split-toxin CRISPR screening platform to systematically identify regulators of human myoblast fusion.

ABSTRACT: Muscle defects are common in human developmental disorders and often cause severe functional impairment. These defects arise from intricate tissue crosstalk and rare genetic mutations, underscoring the need to systematically identify cell-autonomous mechanisms regulating human myogenesis. Here we show a rationally designed, high-throughput genetic screening platform that integrates human myoblast models, customized CRISPR libraries, and a split-toxin strategy that enables quantitative selection of fusion-defective myocytes. Leveraging this platform, our initial screen uncovers a large group of hits essential for human myoblast fusion. The majority of these hits converge into 23 protein complexes. Notably, mutations in 41 screen hits are associated with human diseases marked by abnormal ske

SUBMITTER: Zhang H 

PROVIDER: S-EPMC12808753 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature