Discovery of the TGCB microprotein translated from the lncRNA CHASERR

Abstract

Long noncoding RNAs (lncRNAs) are key regulators of gene expression, and an increasing number have been found to contain small open reading frames (smORFs) that can be translated into functional microproteins. CHASERR is a conserved cis-regulatory lncRNA positioned upstream of CHD2, where it fine-tunes CHD2 dosage. Deletions spanning the CHASERR gene were recently identified in children with a syndromic, early-onset neurodevelopmental disorder, underscoring the clinical importance of this regulatory locus. Here, we report that CHASERR is not strictly noncoding but encodes a previously unannotated 41-amino-acid microprotein, which we name TGCB. Integrative analyses of bulk and single-cell transcriptomics, 47 public Ribo-seq datasets, coding-potential predictors, and multispecies alignments support active translation and evolutionary constraint of the TGCB smORF. Public mass-spectrometry data provide reproducible peptide-spectrum matches corresponding to its N-terminal region, and immunofluorescence confirms nuclear and cytoplasmic localization. Structural prediction reveals a compact -helical microdomain flanked by intrinsically disordered regions, characteristic of regulatory microproteins. Notably, all pathogenic deletions affecting the CHASERR-CHD2 region remove the entire TGCB coding sequence, raising the possibility that loss of this microprotein contributes to the associated neurodevelopmental phenotypes. These findings position CHASERR as a bifunctional transcript and uncover a conserved microprotein embedded within a clinically relevant regulatory locus.