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Extensive folding variability between homologous chromosomes in mammalian cells

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Item Type:Article
Title:Extensive folding variability between homologous chromosomes in mammalian cells
Creators Name:Irastorza-Azcarate, I., Kukalev, A., Kempfer, R., Thieme, C.J., Mastrobuoni, G., Markowski, J., Loof, G., Sparks, T.M., Brookes, E., Natarajan, K.N., Sauer, S., Fisher, A.G., Nicodemi, M., Ren, B., Schwarz, R.F., Kempa, S. and Pombo, A.
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.
Keywords:Genome Structure, Gene Regulation, Allele-Specific Expression, Polycomb, Histone Locus
Source:Molecular Systems Biology
ISSN:1744-4292
Publisher:EMBO Press / Springer Nature
Page Range:1-41
Date:6 May 2025
Official Publication:https://doi.org/10.1038/s44320-025-00107-3
PubMed:View item in PubMed

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