Abrar Aljahani
Postdoctoral Scholar, Developmental Biology
All Publications
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CTCF depletion decouples enhancer-mediated gene activation from chromatin hub formation.
Nature structural & molecular biology
2025
Abstract
Enhancers and promoters interact in three-dimensional (3D) chromatin structures to regulate gene expression. Here we characterize the mechanisms that drive the formation and function of these structures in a lymphoid-to-myeloid transdifferentiation system. Based on analyses at base pair resolution, we demonstrate a close correlation between binding of regulatory proteins, formation of chromatin interactions and gene expression. Multi-way interaction analyses and computational modeling show that tissue-specific gene loci are organized into chromatin hubs, characterized by cooperative interactions between multiple enhancers, promoters and CTCF-binding sites. While depletion of CTCF strongly impairs the formation of these chromatin hubs, the effects of CTCF depletion on gene expression are modest and can be explained by rewired enhancer-promoter interactions. These findings demonstrate a role for enhancer-promoter interactions in gene regulation that is independent of cooperative interactions in chromatin hubs. Together, these results contribute to our understanding of the structure-function relationship of the genome during cellular differentiation.
View details for DOI 10.1038/s41594-025-01555-z
View details for PubMedID 40360814
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The relationship between nucleosome positioning and higher-order genome folding.
Current opinion in cell biology
2024; 89: 102398
Abstract
Eukaryotic genomes are organized into 3D structures, which range from small-scale nucleosome arrays to large-scale chromatin domains. These structures have an important role in the regulation of transcription and other nuclear processes. Despite advances in our understanding of the properties, functions, and underlying mechanisms of genome structures, there are many open questions about the interplay between these structures across scales. In particular, it is not well understood if and how 1D features of nucleosome arrays influence large-scale 3D genome folding patterns. In this review, we discuss recent studies that address these questions and summarize our current understanding of the relationship between nucleosome positioning and higher-order genome folding.
View details for DOI 10.1016/j.ceb.2024.102398
View details for PubMedID 38991477
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FACT maintains chromatin architecture and thereby stimulates RNA polymerase II pausing during transcription in vivo.
Molecular cell
2024; 84 (11): 2053-2069.e9
Abstract
Facilitates chromatin transcription (FACT) is a histone chaperone that supports transcription through chromatin in vitro, but its functional roles in vivo remain unclear. Here, we analyze the in vivo functions of FACT with the use of multi-omics analysis after rapid FACT depletion from human cells. We show that FACT depletion destabilizes chromatin and leads to transcriptional defects, including defective promoter-proximal pausing and elongation, and increased premature termination of RNA polymerase II. Unexpectedly, our analysis revealed that promoter-proximal pausing depends not only on the negative elongation factor (NELF) but also on the +1 nucleosome, which is maintained by FACT.
View details for DOI 10.1016/j.molcel.2024.05.003
View details for PubMedID 38810649
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The Mediator complex regulates enhancer-promoter interactions.
Nature structural & molecular biology
2023; 30 (7): 991-1000
Abstract
Enhancer-mediated gene activation generally requires physical proximity between enhancers and their target gene promoters. However, the molecular mechanisms by which interactions between enhancers and promoters are formed are not well understood. Here, we investigate the function of the Mediator complex in the regulation of enhancer-promoter interactions, by combining rapid protein depletion and high-resolution MNase-based chromosome conformation capture approaches. We show that depletion of Mediator leads to reduced enhancer-promoter interaction frequencies, which are associated with a strong decrease in gene expression. In addition, we find increased interactions between CTCF-binding sites upon Mediator depletion. These changes in chromatin architecture are associated with a redistribution of the Cohesin complex on chromatin and a reduction in Cohesin occupancy at enhancers. Together, our results indicate that the Mediator and Cohesin complexes contribute to enhancer-promoter interactions and provide insights into the molecular mechanisms by which communication between enhancers and promoters is regulated.
View details for DOI 10.1038/s41594-023-01027-2
View details for PubMedID 37430065
View details for PubMedCentralID PMC10352134
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Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF.
Nature communications
2022; 13 (1): 2139
Abstract
Enhancers and promoters predominantly interact within large-scale topologically associating domains (TADs), which are formed by loop extrusion mediated by cohesin and CTCF. However, it is unclear whether complex chromatin structures exist at sub-kilobase-scale and to what extent fine-scale regulatory interactions depend on loop extrusion. To address these questions, we present an MNase-based chromosome conformation capture (3C) approach, which has enabled us to generate the most detailed local interaction data to date (20 bp resolution) and precisely investigate the effects of cohesin and CTCF depletion on chromatin architecture. Our data reveal that cis-regulatory elements have distinct internal nano-scale structures, within which local insulation is dependent on CTCF, but which are independent of cohesin. In contrast, we find that depletion of cohesin causes a subtle reduction in longer-range enhancer-promoter interactions and that CTCF depletion can cause rewiring of regulatory contacts. Together, our data show that loop extrusion is not essential for enhancer-promoter interactions, but contributes to their robustness and specificity and to precise regulation of gene expression.
View details for DOI 10.1038/s41467-022-29696-5
View details for PubMedID 35440598
View details for PubMedCentralID PMC9019034