Genome Structure and Regulation

The genome is the complete set of DNA within a cell, encompassing protein-coding genes, non-coding elements and vast tracts of intergenic sequence. In eukaryotes, this information is packaged into chromatin, a dynamic complex of DNA and histone proteins, which folds hierarchically from nucleosomes (10-nm fibres) to higher-order domains. Epigenetic marks—such as histone acetylation, methylation and DNA methylation—govern chromatin accessibility, creating permissive (euchromatin) or repressive (heterochromatin) states. Within the nucleus, chromatin segregates into self-interacting topologically associating domains (TADs) that insulate groups of genes and their regulatory elements, while long-range loops between enhancers and promoters enable precise control of transcription. Larger compartments distinguish active regions associated with nuclear speckles from repressed regions tethered to the nuclear lamina. In prokaryotes, the nucleoid is organised by supercoiling and nucleoid-associated proteins into dynamic loops that balance compaction with the need for rapid gene regulation. Together, the interplay of DNA sequence, chromatin architecture, three-dimensional folding and epigenetic modification underpins the global control of gene expression, DNA replication and repair, ensuring cellular identity, developmental progression and genome stability.

Research from Nature Portfolio

High-resolution structures of the bacterial RuvAB–Holliday junction complex have revealed the chemo-mechanical cycle by which two AAA+ ATPase motors coordinate strand migration. Time-resolved cryo-EM captured seven conformational states during branch migration, showing how ATP binding, hydrolysis and release drive lever-like motions that pull DNA through a rotating hexameric ring, providing a blueprint for small-molecule inhibitors of recombination motors.

Chromatin remodelling by RNA polymerase II (Pol II) has been shown to prime RNA polymerase III (Pol III) transcription at tRNA genes. In fission yeast, Pol II recruits a SAGA histone acetyltransferase complex and a CTD-phospho-S2-Mst2 pathway to maintain nucleosome depletion at Pol III loci. This Pol II-dependent depletion ensures rapid Pol III re-initiation upon exit from quiescence, linking mRNA-synthesis machinery to non-coding RNA production.

A deep-learning framework has been developed to predict cell-type-specific three-dimensional chromatin organisation from DNA sequence, CTCF binding profiles and chromatin accessibility data. By in silico screening of genetic variants, the model identifies elements whose perturbation alters loop formation or TAD boundaries and uncovers candidate trans-acting regulators that shape domain architecture, enabling high-throughput interrogation of non-coding variants in normal and disease states.

Research from all publishers

A synthesis of recent advances in bacterial chromosome folding highlights how macromolecular crowding, supercoiling and nucleoid-associated proteins cooperate to form dynamic loops and domains within the nucleoid. High-resolution genomics and imaging studies reveal how transcription and DNA replication remodel domain boundaries, and how phase separation may contribute to the spatial segregation of active and inactive regions in prokaryotic cells.

Genome-wide mapping of replication-fork stalling sites in human cells demonstrates that highly transcribed genes coincide with hotspots of fork pausing. Slowing transcription elongation directly modulates replication dynamics, and fragile chromosomal regions align with collision sites. These findings underscore the interplay between transcription and replication in maintaining genome integrity and reveal how disruption of this balance leads to DNA damage and genomic instability.

Genome Structure and Regulation publication trend

The graph below shows the total number of articles in genome structure and regulation across all publications each year (not limited to Nature Index journals).

Technical terms

Chromatin: The complex of DNA and histone proteins that packages the genome and regulates its accessibility.

Epigenetic mark: A chemical modification of DNA or histones that influences chromatin structure and gene activity without altering the DNA sequence.

Topologically associating domain (TAD): A self-interacting chromatin region within which enhancers and promoters preferentially contact each other.

Enhancer: A distal cis-regulatory element that binds transcription factors to increase transcription of target genes.

Replication fork: The Y-shaped region where DNA is unwound and replicated, susceptible to stalling when encountering transcription machinery.

AAA+ ATPase: A family of motor proteins that hydrolyse ATP to drive mechanical processes such as DNA translocation.

References

1. Mechanism of AAA+ ATPase-mediated RuvAB–Holliday junction branch migration. Nature (2022).
2. Chromatin remodeling by Pol II primes efficient Pol III transcription. Nature Communications (2023).
3. Cell-type-specific prediction of 3D chromatin organization enables high-throughput in silico genetic screening. Nature Biotechnology (2023).
4. Insights in bacterial genome folding. Current Opinion in Structural Biology (2023).
5. Genome-wide identification of replication fork stalling/pausing sites and the interplay between RNA Pol II transcription and DNA replication progression. Genome Biology (2024).