Extensive folding variability between homologous chromosomes in mammalian cells

Extensive folding variability between homologous chromosomes in mammalian cells

Abstract Genetic variation and 3D chromatin structure have major roles in gene regulation. Due to challenges in mapping chromatin conformation with haplotype-specific resolution, the effects of genetic sequence variation on 3D genome structure and gene expression imbalance remain understudied. Here,...

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Main Authors: Ibai Irastorza-Azcarate, Alexander Kukalev, Rieke Kempfer, Christoph J Thieme, Guido Mastrobuoni, Julia Markowski, Gesa Loof, Thomas M Sparks, Emily Brookes, Kedar Nath Natarajan, Stephan Sauer, Amanda G Fisher, Mario Nicodemi, Bing Ren, Roland F Schwarz, Stefan Kempa, Ana Pombo
Format: Article
Language:English
Published: Springer Nature 2025-05-01
Series:Molecular Systems Biology
Subjects:
Genome Structure
Gene Regulation
Allele-specific Expression
Polycomb
Histone Locus
Online Access:https://doi.org/10.1038/s44320-025-00107-3
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Summary:Abstract Genetic variation and 3D chromatin structure have major roles in gene regulation. Due to challenges in mapping chromatin conformation with haplotype-specific resolution, the effects of genetic sequence variation on 3D genome structure and gene expression imbalance remain understudied. Here, we applied Genome Architecture Mapping (GAM) to a hybrid mouse embryonic stem cell (mESC) line with high density of single-nucleotide polymorphisms (SNPs). GAM resolved haplotype-specific 3D genome structures with high sensitivity, revealing extensive allelic differences in chromatin compartments, topologically associating domains (TADs), long-range enhancer–promoter contacts, and CTCF loops. Architectural differences often coincide with allele-specific differences in gene expression, and with Polycomb occupancy. We show that histone genes are expressed with allelic imbalance in mESCs, and are involved in haplotype-specific chromatin contacts marked by H3K27me3. Conditional knockouts of Polycomb enzymatic subunits, Ezh2 or Ring1, show that one-third of ASE genes, including histone genes, is regulated through Polycomb repression. Our work reveals highly distinct 3D folding structures between homologous chromosomes, and highlights their intricate connections with allelic gene expression.
ISSN:1744-4292

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