Gene Regulation Knows Its Boundaries

doi:10.1016/j.tig.2019.09.002

Trends in Genetics

Volume 35, Issue 12, December 2019, Pages 883-885

https://doi.org/10.1016/j.tig.2019.09.002 Get rights and content

The genome is folded nonrandomly inside the cell nucleus. How this contributes to gene regulation is an important subject of investigation. A new study by Despang et al. shows how the spatial segregation of genes and regulatory regions can influence developmental expression in subtle, but critical ways.

References (10)

M. Vietri Rudan
Comparative Hi-C reveals that CTCF underlies evolution of chromosomal domain architecture
Cell Rep
(2015)
W. Akhtar
Chromatin position effects assayed by thousands of reporters integrated in parallel
Cell
(2013)
J.R. Dixon
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Nature
(2012)
E.P. Nora
Spatial partitioning of the regulatory landscape of the X-inactivation centre
Nature
(2012)
E.P. Nora
Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization
Cell
(2017)

There are more references available in the full text version of this article.

Cited by (2)

Emerging Methods and Resources for Biological Interrogation of Neuropsychiatric Polygenic Signal
2021, Biological Psychiatry
Citation Excerpt :
Contact points between chromatin regions that can be kilobases and megabases apart from each other may still structurally and functionally interact (48). Changes in chromatin organization can influence gene expression in subtle ways (49,50). The 4D Nucleome program aims to map the spatial and temporal genome organization in humans and mice (51) (Table 1).
Most neuropsychiatric disorders are highly polygenic, implicating hundreds to thousands of causal genetic variants that span much of the genome. This widespread polygenicity complicates biological understanding because no single variant can explain disease etiology. A strategy to advance biological insight is to seek convergent functions among the large set of variants and map them to a smaller set of disease-relevant genes and pathways. Accordingly, functional genomic resources that provide data on intermediate molecular phenotypes, such as gene-expression and methylation status, can be leveraged to functionally annotate variants and map them to genes. Such molecular quantitative trait locus mappings can be integrated with genome-wide association studies to make sense of the polygenic signal that underlies complex disease. Other resources that provide data on the 3-dimensional structure of chromatin and functional importance of specific genomic regions can be integrated similarly. In addition, mapped genes can then be tested for convergence in biological function, tissue, cell type, or developmental stage. In this review, we provide an overview of functional genomic resources and methods that can be used to interpret results from genome-wide association studies, and we discuss current challenges for biological understanding and future requirements to overcome them.
The Consequences of Abnormal Gene Dosage: Lessons from Chromosome 18
2020, Trends in Genetics
Citation Excerpt :
In addition to sequence-determined and expression-determined hypotheses, another is based on the spatial context in which the gene lies within the nucleus. The nuclear localization hypothesis suggests that haploinsufficiency is a combination of a potentially dosage-sensitive gene located within a region of hemizygosity that then alters the 3D structure and position of the chromatin within the interphase nucleus [24]. Changes in these topologically associated domains (TADs) can change the expression of the genes within those domains, by changing the proximity of a gene to cis regulatory element such as promotors or enhancers by changing the epigenetic modifications that then impact gene expression [24].
Accurate interpretation of genomic copy number variation (CNV) remains a challenge and has important consequences for both congenital and late-onset disease. Hemizygosity dosage characterization of the genes on chromosome 18 reveals a spectrum of outcomes ranging from no clinical effect, to risk factors for disease, to both low- and high-penetrance disease. These data are important for accurate and predictive clinical management. Additionally, the potential mechanisms of reduced penetrance due to dosage compensation are discussed as a key to understanding avenues for potential treatment. This review describes the chromosome 18 findings, and discusses the molecular mechanisms that allow haploinsufficiency, reduced penetrance, and dosage compensation.

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Trends in Genetics

SpotlightGene Regulation Knows Its Boundaries

Cell Rep

Cell

Topological domains in mammalian genomes identified by analysis of chromatin interactions

Nature

Spatial partitioning of the regulatory landscape of the X-inactivation centre

Nature

Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization

Cell

Spotlight
Gene Regulation Knows Its Boundaries