Peer Review Report For: lncRNA CHASERR Integrates Transcriptional and Post-Transcriptional Gene Regulation [version 1; peer review: 1 not approved]

Long non-coding RNAs (lncRNAs) are critical regulators of chromatin and gene expression, yet their precise molecular mechanisms are often undefined. CHASERR exemplifies this challenge: haploinsufficiency of this locus causes a severe neurodevelopmental syndrome, positioning it as a master epigenetic regulator, but its physical interactors and modes of action remain unknown. Here, we define the CHASERR interactome to uncover its core mechanism. By combining RNA pull-down sequencing with promoter-binding analysis, we demonstrate that CHASERR operates as a dual-function hub. It scaffolds a specific network of non-coding RNAs, including the catalytic RMRP, the responsive lncRNA CRNDE, and multiple microRNA host genes, supporting a role in post-transcriptional regulatory circuits. Simultaneously, CHASERR binds directly to gene promoters, and this binding is functionally linked to transcriptional changes upon its depletion. This integrated mechanism, coordinating direct DNA engagement with RNA-based regulatory networks, establishes CHASERR as a central node that bridges transcriptional and post-transcriptional control. Our work provides the missing physical and mechanistic foundation for its essential role in epigenetic regulation and human disease.