Abstract
The human genome is tightly packed into the 3D environment of the cell nucleus. Rapidly evolving and sophisticated methods of mapping 3D genome architecture have shed light on fundamental principles of genome organization and gene regulation. The genome is physically organized on different scales, from individual genes to entire chromosomes. Nuclear landmarks such as the nuclear envelope and nucleoli have important roles in compartmentalizing the genome within the nucleus. Genome activity (for example, gene transcription) is also functionally partitioned within this 3D organization. Rather than being static, the 3D organization of the genome is tightly regulated over various time scales. These dynamic changes in genome structure over time represent the fourth dimension of the genome. Innovative methods have been used to map the dynamic regulation of genome structure during important cellular processes including organism development, responses to stimuli, cell division and senescence. Furthermore, disruptions to the 4D genome have been linked to various diseases, including of the kidney. As tools and approaches to studying the 4D genome become more readily available, future studies that apply these methods to study kidney biology will provide insights into kidney function in health and disease.
Key points
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Technological innovations in sequencing-based and imaging-based approaches to mapping 3D genome architecture have led to numerous insights into the 3D organization of the genome and chromatin interactions with nuclear features.
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Time course and live cell imaging experiments have been used to study changes in 3D genome structure over time, which represents the fourth dimension of the genome.
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Within the nucleus, the genome is highly ordered on different scales from nucleosomes to chromatin loops and topologically associated domains, A and B compartments and chromosome territories; this 3D organization and its dynamic regulation have an impact on genome function and gene expression.
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Induced changes in chromatin looping bring enhancers into proximity with promoters to activate gene transcription; single-cell methods have shown remarkable variation in genome topology and gene expression, but how this translates into stable organ-level phenotypes remains unclear.
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Kidney cells have distinct 3D genome architectures that impact kidney-specific cellular responses to disease; kidney genome-wide association studies and expression quantitative trait loci analyses utilize 3D genome maps to link sequence variants to putative target genes and identify disease-causing mechanisms.
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Intensive efforts are being made to extend 3D genome mapping technologies into single cells and intact tissues and to study genome architecture over time; application of these technologies to studies of kidney biology will lead to remarkable advances in understanding the role of the 4D genome in kidney health and disease.
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Acknowledgements
The author’s work was supported in part by a Damon Runyon Dale F. Frey Breakthrough Award (to B.J.B. 32-19), the National Institutes of Health (under grants 1R35GM137916 to B.J.B, 1UM1HG011586 to Jay Shendure and B.J.B., 1R01DK130386 to S.A.), the Andy Hill Cancer Research Endowment (under a COVID-19 Response Grant Award to B.J.B. and S.A), and the Diabetic Complications Consortium (under grant 19AU3987 to S.A. and B.J.B.).
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Glossary
- Acrocentric chromosomes
-
Chromosomes with centromeres located near to one end, resulting in a short and a long arm. The human acrocentric chromosomes (chromosomes 13, 14, 15, 21 and 22) harbour DNA elements that help to organize the nucleolus.
- Background noise
-
Non-specific or random interactions in Hi-C data; the larger the genomic distance being examined, the more of these non-specific interactions are likely to be detected. Deep sequencing may be needed to achieve sufficient signal for specific interactions to be discernible above the background noise.
- Chromogens
-
Substances that lack intrinsic colour, but can be enzymatically converted into a pigment that stays localized at the site of conversion.
- Cis-coaccessibility networks
-
Weighted matrices of predicted enhancer–promoter interactions deduced from mapping the simultaneous open chromatin states (accessibility) of enhancer and promoter regions. If the promoter and enhancer are both accessible in some cell types, but not others, and this co-accessibility correlates with the expression of the target gene of the promoter, the cis-coaccessibility network connection implies regulation of the promoter and its associated gene by the co-accessible enhancer.
- Constitutive genes
-
Also known as housekeeping genes, constitutive genes are expressed in most cells. They often encode proteins that are required for basic cellular structure and function.
- Constitutive heterochromatin
-
Condensed chromatin that has a role in genome organization rather than gene expression. Pericentromeric regions and telomeres are examples of constitutive heterochromatin.
- Facultative heterochromatin
-
Condensed chromatin that may be made accessible and become transcriptionally active in certain contexts, such as cell lineage specification.
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Beliveau, B.J., Akilesh, S. A guide to studying 3D genome structure and dynamics in the kidney. Nat Rev Nephrol 21, 97–114 (2025). https://doi.org/10.1038/s41581-024-00894-2
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DOI: https://doi.org/10.1038/s41581-024-00894-2
