Review Article | Published:

Spatial genome organization and cognition

Nature Reviews Neuroscience volume 17, pages 681691 (2016) | Download Citation

Abstract

Nonrandom chromosomal conformations, including promoter–enhancer loopings that bypass kilobases or megabases of linear genome, provide a crucial layer of transcriptional regulation and move vast amounts of non-coding sequence into the physical proximity of genes that are important for neurodevelopment, cognition and behaviour. Activity-regulated changes in the neuronal '3D genome' could govern transcriptional mechanisms associated with learning and plasticity, and loop-bound intergenic and intronic non-coding sequences have been implicated in psychiatric and adult-onset neurodegenerative disease. Recent studies have begun to clarify the roles of spatial genome organization in normal and abnormal cognition.

Key points

  • The spatial organization of the chromosomal material inside the nuclei of neurons, glia and their progenitor cells is highly regulated in the developing and mature brain.

  • Chromosomal loopings that mediate promoter–enhancer interactions provide a crucial layer of transcriptional regulation in the context of neuronal plasticity. Four specific models of promoter–enhancer interactions have been described: protein cargo model, enhancer RNA decoy model, loop competition model and strand-break mobilization model.

  • Mutations and structural variants in genes encoding chromosomal scaffolding proteins, including several subunits of the cohesin complex and CCCTC-binding factor (CTCF), are associated with monogenic neurodevelopmental disease.

  • A subset of common polymorphisms contributing to the genetic risk architecture of neurodevelopmental or neurodegenerative disease locate to enhancer and other cis-regulatory sequences. For some candidate genes, such as calcium voltage-gated channel subunit alpha 1C (CACNA1C) and GRIN2B (which encodes GluN2B), risk-associated non-coding DNA has been shown to interact with gene transcription start sites via loop-bound chromosomal conformations.

  • Recent advances in epigenomic editing techniques make it possible to load loop-bound regulatory sequences with transcriptional activators or repressors by harnessing RNA-guided CRISPR–Cas systems. Therefore, experimental or therapeutic interference with gene expression is possible by targeting regulatory sequences that are separated from the promoter even by hundreds of kilobases.

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Acknowledgements

This work was supported by the US National Institute of Mental Health (NIMH), grants P50MH096890 and R01MH106056.

Author information

Affiliations

  1. Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, 10029 New York, USA.

    • Prashanth Rajarajan
    • , Kristen J. Brennand
    •  & Schahram Akbarian
  2. Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.

    • Sergio Espeso Gil
  3. Universitat Pompeu Fabra (UPF), Plaça de la Mercè 10, Barcelona 08002, Spain.

    • Sergio Espeso Gil

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Schahram Akbarian.

Glossary

Chromosomal scaffolding

A 3D chromatin structure, the integrity of which is maintained by non-histone scaffolding proteins (for example, cohesin and CTCF).

Transcriptional units

Stretches of DNA that are transcribed into RNA molecules.

Eukaryotic

A life form with a well-delineated nucleus that is separated from the cytoplasm by a nuclear membrane.

Nucleosomal arrays

Chromatin packaging in the form of repeating units of DNA-bound core histone octamers connected by linker DNA and linker histone proteins.

Nucleolar membranes

Membranes of the nucleolus, a specialized nuclear organelle that is necessary for the production of ribosome subunits.

Cis-regulatory sequences

Non-coding portions of the genome that regulate transcription of nearby or distal genes (for example, promoters and enhancers).

Preinitiation complex

A large collection of proteins that are essential to begin DNA transcription, acting by recruiting RNA polymerase II, denaturing DNA and properly positioning the DNA in the active site of polymerase.

Immediate early gene (IEG) transcription factors

Activator proteins, such as FOS, JUN and early growth response 1 (EGR1), expressed in response to stimulus-based triggering of cyclic AMP and other intracellular signalling cascades, rapidly accumulate within 15 min of a stimulus in sensitive neurons.

Microdeletions

Loss of fragments of a chromosome.

Copy number variations

Genomic sequences, typically in a kilobase or megabase range, that are either duplicated or deleted.

Intergenic

The genome sequence between two annotated genes.

Common sequence variants

DNA polymorphisms with minor allele frequencies exceeding 0.05 in the general population.

Methylome

The genome-wide distribution of DNA cytosine methylation in specific cells or tissues.

CRISPR–Cas

Clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein, an RNA-guided DNA endonuclease enzyme in bacteria that is increasingly used as a tool for targeted genomic and epigenomic editing in multicellular organisms.

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https://doi.org/10.1038/nrn.2016.124

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