CTCF-RNA interactions orchestrate cell-specific chromatin loop organization

Abstract

CCCTC-binding factor (CTCF) is essential for chromatin organization. CTCF interacts with endogenous RNAs, and deletion of its ZF1 RNA binding region (ΔZF1) disrupts chromatin loops in mouse embryonic stem cells (ESCs). However, the functional significance of CTCF-ZF1 RNA interactions during cell differentiation is unknown. Using an ESC–to–neural progenitor cell (NPC) differentiation model, we show that CTCF-ZF1 is crucial for maintaining cell type–specific chromatin loops. Expression of CTCF-ΔZF1 leads to disrupted loops and dysregulation of genes within these loops, particularly those involved in neuronal development and function. We identified NPC-specific, CTCF-ZF1 interacting RNAs. Truncation of two such coding RNAs, Podxl and Grb10, disrupted chromatin loops in cis, similar to the disruption seen in CTCF-ΔZF1– expressing NPCs. These findings underscore the inherent importance of CTCF-ZF1 RNA interactions in preserving cell-specific genome structure and cellular identity.