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Making the case for chromatin profiling: a new tool to investigate the immune-regulatory landscape

Nature Reviews Immunology volume 15, pages 585–594 (2015)Cite this article

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Abstract

Recent technological advances have enabled researchers to accurately and efficiently assay the chromatin dynamics of scarce cell populations. In this Opinion article, we advocate the application of these technologies to central questions in immunology. Unlike changes to other molecular structures in the cell, chromatin features can reveal the past (developmental history), present (current activity) and future (potential response to challenges) of a given immune cell type; chromatin profiling is therefore an important new tool for studying the immune-regulatory networks of health and disease.

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Figure 1: Representative chromatin profiling: from immune cells to the regulatory landscape.
Figure 2: Multiple layers of chromatin regulation in immune cells.
Figure 3: Association of human chromatin data and susceptibility to immune disease.

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Acknowledgements

The authors thank G. Brodsky for drafting the artwork. Research in the laboratory of I.A. is supported by the European Research Council (309788) and the Israeli Science Foundation (712163), The Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine and the Center for Excellence in Genome Science from the National Human Genome Research Institute (NHGRI; 1P50HG006193). Research in the laboratory of S.J. is supported by the Israeli Science Foundation (887/11), the European Research Council (340345) and the Deutsche Forschungsgemeinschaft (FOR1336). D.R.W. is grateful to the Azrieli Foundation for the Azrieli Fellowship award and for support from the European Molecular Biology Organization (EMBO; ALT766-2014) and the European Commission FP7 (Marie Curie Actions, EMBOCOFUND2012, GA-2012-600394).

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Author notes

  1. Deborah R. Winter and Ido Amit: D.R.W. and I.A. contributed equally to this work.

Authors and Affiliations

  1. Steffen Jung and Ido Amit are at the Department of Immunology, Deborah R. Winter, Weizmann Institute of Science, Rehovot 76100, Israel.,

    Deborah R. Winter, Steffen Jung & Ido Amit

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  1. Deborah R. Winter
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Correspondence to Deborah R. Winter or Ido Amit.

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Glossary

Assay for transposase-accessible chromatin

(ATAC). A method for identifying regions of open chromatin by using Tn5 transposase to insert paired sequencing adaptors into accessible chromatin.

Chromatin

The 3D complex of DNA and proteins within the nucleus. Features of chromatin (including localization, structure, interacting proteins, accessibility and modifications) regulate cell-type-specific gene expression.

Chromatin immunoprecipitation

(ChIP). A method for identifying genomic regions that associate with a particular protein, including specifically modified histones, through immunoprecipitation of the crosslinked DNA fragments.

Chromatin interaction analysis using paired-end tag sequencing

(ChIA-PET). A method for identifying pairs of regions associated with a particular protein by combining chromatin immunoprecipitation with the isolation of interacting DNA fragments.

Cis-acting elements

Functional regulatory elements (such as enhancers) within the genome that regulate the transcription of genes.

DNA methylation

The addition of a methyl group to a nucleic acid in the genome, typically to cytosine within a CpG pair.

DNase hypersensitivity assay

A method that relies on the preference of the enzyme DNaseI to digest unbound DNA to identify regions of open chromatin.

Enhancers

Distal regulatory elements that may function in combination with promoters or other enhancers to influence the transcription of one or more genes through the binding of transcription factors.

Epigenome

Modifications to the genome that do not change the DNA sequence, including DNA methylation, histone modifications and rearrangements of chromatin structure.

Expression quantitative trait loci

(eQTLs). Genomic loci that correlate with changes in gene expression analogously with the relationship between quantitative trait loci and phenotype.

Formaldehyde-assisted isolation of regulatory elements

(FAIRE). A method for identifying regions of open chromatin by isolating DNA fragments that are not bound to DNA after crosslinking.

Genome-wide association study

(GWAS). A statistical analysis comparing the occurrence of multiple common genetic variants (usually single-nucleotide polymorphisms) with a certain outcome (a phenotype or disease) to identify causal variants.

Hi-C and 5C

High-throughput adaptations of the chromosome conformation capture (3C) method that isolates DNA fragments interacting with each other. 5C searches for interactions between many loci, whereas Hi-C searches for all possible interactions in the genome.

Pioneer transcription factors

Sequence-specific DNA-binding proteins that target closed chromatin sites and recruit chromatin remodellers to transform these sites into an open chromatin state enabling the binding of additional transcription factors.

Promoter

A proximal regulatory element that is typically located upstream of the particular gene it regulates and includes the binding sites of general transcription factors such as RNA polymerase II.

Single-nucleotide polymorphisms

(SNPs). Mutations (substitutions, insertions or deletions) of an individual nucleotide in the genome sequence that are common in the population.

Trans-acting binding factors

Non-DNA molecules (typically referring to transcription factors or chromatin factors) that regulate the transcription of genes.

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Winter, D., Jung, S. & Amit, I. Making the case for chromatin profiling: a new tool to investigate the immune-regulatory landscape. Nat Rev Immunol 15, 585–594 (2015). https://doi.org/10.1038/nri3884

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