A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes

Toyonori Sakata; Shoin Tei; Kosuke Izumi; Ian D Krantz; Masashige Bando; Katsuhiko Shirahige

doi:10.1016/j.cub.2025.01.044

A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes

Curr Biol. 2025 Mar 24;35(6):1353-1363.e5. doi: 10.1016/j.cub.2025.01.044. Epub 2025 Feb 20.

Authors

Toyonori Sakata¹, Shoin Tei², Kosuke Izumi³, Ian D Krantz⁴, Masashige Bando², Katsuhiko Shirahige⁵

Affiliations

¹ Karolinska Institutet, Department of Cell and Molecular Biology, Biomedicum, Tomtebodavägen 16, Stockholm 171 77, Sweden; Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-Ku, Tokyo 113-0032, Japan. Electronic address: toyonori.sakata@ki.se.
² Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-Ku, Tokyo 113-0032, Japan.
³ Division of Genetics and Metabolism, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA; Laboratory of Rare Disease Research Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-Ku, Tokyo 113-0032, Japan.
⁴ Division of Pediatric Genetics and Genomics, Cohen Children's Medical Center, Northwell Health, 225 Community Drive, Suite 110, Great Neck, NY 11021, USA; Department of Pediatrics, Zucker School of Medicine, Hofstra University, 500 Hempstead, New York, NY 11549, USA.
⁵ Karolinska Institutet, Department of Cell and Molecular Biology, Biomedicum, Tomtebodavägen 16, Stockholm 171 77, Sweden; Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-Ku, Tokyo 113-0032, Japan. Electronic address: katsuhiko.shirahige@ki.se.

PMID: 39983729
DOI: 10.1016/j.cub.2025.01.044

Abstract

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.

Keywords: 3D genome structure; AFF4; BRD4; CHOPS syndrome; CdLS; H3K27ac; NIPBL; SEC; cohesin; enhancer.

MeSH terms

Cell Cycle Proteins* / genetics
Cell Cycle Proteins* / metabolism
Chromosomal Proteins, Non-Histone* / genetics
Chromosomal Proteins, Non-Histone* / metabolism
Cohesins
De Lange Syndrome* / genetics
De Lange Syndrome* / metabolism
Histones / metabolism
Humans
Mutation
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
NIPBL protein, human
Cohesins
Transcription Factors
Histones