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Long-range gene regulation in hormone-dependent cancer

Nature Reviews Cancer volume 23, pages 657–672 (2023)Cite this article

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Abstract

The human genome is organized into multiple structural layers, ranging from chromosome territories to progressively smaller substructures, such as topologically associating domains (TADs) and chromatin loops. These substructures, collectively referred to as long-range chromatin interactions (LRIs), have a significant role in regulating gene expression. TADs are regions of the genome that harbour groups of genes and regulatory elements that frequently interact with each other and are insulated from other regions, thereby preventing widespread uncontrolled DNA contacts. Chromatin loops formed within TADs through enhancer and promoter interactions are elastic, allowing transcriptional heterogeneity and stochasticity. Over the past decade, it has become evident that the 3D genome structure, also referred to as the chromatin architecture, is central to many transcriptional cellular decisions. In this Review, we delve into the intricate relationship between steroid receptors and LRIs, discussing how steroid receptors interact with and modulate these chromatin interactions. Genetic alterations in the many processes involved in organizing the nuclear architecture are often associated with the development of hormone-dependent cancers. A better understanding of the interplay between architectural proteins and hormone regulatory networks can ultimately be exploited to develop improved approaches for cancer treatment.

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Fig. 1: Genome organization in cells.
Fig. 2: Modulation of long-range interactions by steroid receptors.
Fig. 3: Enhancer functions in ER- and AR-related cancers.
Fig. 4: Mechanisms by which steroid receptors induce long-range interactions in cancer.

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Acknowledgements

This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The authors thank C. A. Meehan, NIH, and members of the NIH fellows editorial board for critical reading of the manuscript.

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Authors and Affiliations

  1. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD, USA

    Theophilus T. Tettey, Lorenzo Rinaldi & Gordon L. Hager

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  1. Theophilus T. Tettey
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  2. Lorenzo Rinaldi
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  3. Gordon L. Hager
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T.T.T. conducted extensive data research for the article, authored the manuscript and played a pivotal part in reviewing and editing the manuscript. T.T.T. also assumes responsibility for all aspects of the article. L.R. made significant contributions to the initial draft of the manuscript. G.L.H. contributed to the manuscript by editing it, incorporating additional content and providing valuable mentoring and supervision throughout the process.

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Correspondence to Gordon L. Hager.

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Glossary

1,6-hexanediol

A chemical compound commonly used as a protein denaturant and solvent that disrupts interactions between biomolecules and influences their conformation and function.

Chromatin compartments

Subdivisions of chromosome territories based on their transcriptional activity, histone modification and gene density. Compartment A is mostly transcriptionally active while compartment B is often repressed.

Chromatin landscape

The overall pattern of chromatin modifications, including histone modifications and DNA methylation.

Chromatin loops

Long-range interactions formed when segments of the DNA, such as enhancer or promoter, on the same chromosome are in close physical proximity to each other. Chromatin loops are held in place by architectural proteins such as CCCTC binding factor (CTCF) and the cohesin complex.

CLOuD9

A CRISPR-based system that uses nuclease-deficient Cas9 (dCas9) to achieve reversible, precise control of gene expression through targeted forced juxtaposition of any two genomic loci.

Condensates

Liquid-like droplets or membrane-less organelles formed through the process of liquid–liquid phase separation by the concentration of intrinsically disordered region-bearing transcription factors and nucleic acids.

Confinement state

A condition in which biomolecules are restricted within a defined space, which often results in altered molecular interactions and functional outcomes.

Crowding agent

A substance or condition that mimics the densely packed environment found in cells, influencing the behaviour and properties of biomolecules and cellular processes.

dCas9–Zip

A modified version of the CRISPR-associated protein dCas9 fused with a peptide that allows for targeted recruitment of specific proteins or molecules to a desired genomic location.

Enhancer hijacking

Misplacement of enhancers caused by genomic rearrangements, such as translocations or inversions, leading to the disruption of topologically associating domain structures and resulting in aberrant expression of oncogenes or downregulation of tumour suppressor genes.

Enhancer RNAs

(eRNAs). A class of long non-coding RNAs (lncRNAs) transcribed from the DNA sequence of enhancer regions.

Genomic output

A process by which changes in the 3D genome structure, including alterations in the positioning of chromatin domains and changes in chromatin interactions, can result in changes to gene expression and cellular function.

Global run-on sequencing

(GRO-seq). An assay to map and quantify nascent transcription by sequencing RNA that is actively being synthesized.

Hi-C

A genome-wide sequencing approach that allows detection of chromatin interactions in the nucleus by cross-linking and sequencing proximity ligation products.

Hormone-control regions

(HCRs). A cluster of specific DNA sequences, often enhancers and promoters, that are recognized and bound by hormone receptors to regulate hormone-responsive genes.

Hormone deprivation therapy

Use of surgery or drug administration to lower the levels of a hormone in hormone-dependent cancers.

Intrinsically disordered regions

(IDRs). Protein regions characterized by their lack of stable secondary or tertiary structure, often involved in protein–protein interactions, signalling and regulation.

Long-range chromatin interactions

(LRIs). Physical interactions between proximal and distal genomic elements, either on the same chromosome or between distinct chromosomes, that interact with higher frequency than expected and are important in transcriptional regulation of genes.

Loop extrusions

The process by which DNA loops are formed and regulated by molecular machinery, enabling spatial organization and gene regulation within the chromatin.

Mediator complex

A multisubunit protein complex that regulates RNA polymerase II transcription by assembling at the pre-initiation complex and transducing signals from activators bound to enhancer regions to the transcription machinery.

Micro-C

An enhanced version of Hi-C that addresses the limitations of traditional Hi-C by incorporating a micrococcal nuclease digestion step to investigate the proximity of nucleosome pairs, resulting in improved resolution and signal-to-noise ratio.

Nuclear lamina

A mesh-like network of proteins that lines the inner nuclear membrane, providing structural support to the nucleus and participating in gene regulation and chromatin organization.

Phase separation

A process by which biomolecules form distinct liquid-like droplets through either electrostatic, hydrophobic or bivalent interactions.

Response elements

Specific DNA sequences to which transcription factors bind to either activate or repress transcription of cognate genes.

Super-enhancer loops

Chromatin loops formed when super-enhancers are in close physical proximity to their target gene promoters.

Super-enhancers

Regions of the genome that contain clusters of enhancers that drive high levels of gene expression, typically associated with crucial cellular processes and disease states.

Steroid receptors

Intracellular receptors that bind to steroid hormones such as cortisol, oestrogen, progesterone and testosterone. Upon binding to hormone, the receptor undergoes a conformational change that enables it to translocate to the nucleus where it binds to a response DNA element to regulate gene expression.

Topologically associating domains

(TADs). Discrete regions of the genome often spanning tens or hundreds of kilobases with high frequency of self-associating contact, enclosed by CCCTC binding factor (CTCF) and cohesin-containing boundaries. TADs are insulated from neighbouring discrete genomic regions to prevent widespread uncontrolled DNA contacts.

Transcription activator-like effector nucleases

Enzymes engineered from bacterial proteins that can be used for precise gene editing, targeting specific DNA sequences for modification.

Zinc finger (ZF) gene editing tools

Synthetic proteins or nucleases engineered to bind and modify DNA at specific sequences using ZF motifs, allowing precise genome editing.

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Tettey, T.T., Rinaldi, L. & Hager, G.L. Long-range gene regulation in hormone-dependent cancer. Nat Rev Cancer 23, 657–672 (2023). https://doi.org/10.1038/s41568-023-00603-4

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