A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes

The cohesin protein complex is essential for the formation of topologically associating domains (TADs) and chromatin loops on interphase chromosomes.¹^,²^,³^,⁴^,⁵ For the loading onto chromosomes, cohesin requires the cohesin loader complex formed by NIPBL⁶^,⁷^,⁸ and MAU2.⁹ Cohesin localizes at enhancers and gene promoters with NIPBL in mammalian cells¹⁰^,¹¹^,¹²^,¹³^,¹⁴ and forms enhancer-promoter loops.¹⁵^,¹⁶ Cornelia de Lange syndrome (CdLS) is a rare, genetically heterogeneous disorder affecting multiple organs and systems during development,¹⁷^,¹⁸ caused by mutations in the cohesin loader NIPBL gene (>60% of patients),¹⁹^,²⁰^,²¹^,²²^,²³ as well as in genes encoding cohesin, a chromatin regulator, BRD4, and cohesin-related factors.²⁴^,²⁵^,²⁶^,²⁷ We also reported CHOPS syndrome that phenotypically overlaps with CdLS²⁸^,²⁹ and is caused by gene mutations of a super elongation complex (SEC) core component, AFF4. Although these syndromes are associated with transcriptional dysregulation,²⁴^,²⁸^,³⁰^,³¹^,³² the underlying mechanism remains unclear. In this study, we provide the first comprehensive analysis of chromosome architectural changes caused by these mutations using cell lines derived from CdLS and CHOPS syndrome patients. In both patient cells, we found a decrease in cohesin, NIPBL, BRD4, and acetylation of lysine 27 on histone H3 (H3K27ac)³³^,³⁴^,³⁵ in most enhancers with enhancer-promoter loop attenuation. By contrast, TADs were maintained in both patient cells. These findings reveal a shared molecular mechanism in these syndromes and highlight unexpected roles for cohesin, cohesin loaders, and the SEC in maintaining the enhancer complexes. These complexes are crucial for recruiting transcriptional regulators, sustaining active histone modifications, and facilitating enhancer-promoter looping.