From genetic variation to phenotype via chromatin

Stower, Hannah

doi:10.1038/nrg3622

Research Highlight
Published: 29 October 2013

Gene regulation

From genetic variation to phenotype via chromatin

Hannah Stower

Nature Reviews Genetics volume 14, page 824 (2013)Cite this article

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McVicker et al. and Kilpinen et al. took a similar approach, which was to carry out chromatin immunoprecipitation followed by sequencing (ChIP–seq) to survey histone modifications, transcription factor binding and actively transcribed sites as defined by the locations of RNA polymerase II. Kilpinen et al. analysed these features in lymphoblastoid cell lines (LCLs) from parent–offspring trios and from eight unrelated individuals in the 1,000 Genomes Project, whereas McVicker et al. surveyed LCLs from ten unrelated Yoruba individuals. Both studies found allelic specificity of histone modifications, which, importantly, was coordinated with transcription factor binding. This finding indicates that sequence-specific transcription factors may specify histone modifications, and that there is thus a sequence-specific component to the deposition of histone modifications. This allelic specificity leads, in turn, to changes in both enhancer choice and gene expression between different haplotypes, even in distal enhancers.

The approach of Kasowski et al. was to map histone modifications by ChIP–seq and gene expression by RNA sequencing in 19 individuals from the 1,000 Genomes Project. In addition, the locations of two general transcription factors were mapped. By dividing the genome into regions with different combinations of chromatin modifications, they found that there are extensive differences in enhancer states between individuals, as well as in transcription factor-binding sites that are associated with different chromatin states. However, they found that, to alter gene expression, multiple enhancers that are linked to a gene must have alterations in their histone modification states.

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References

Heinz, S. et al. Effect of natural genetic variation on enhancer selection and function. Nature http://dx.doi.org/10.1038/nature12615 (2013)
Kasowski, M. et al. Extensive variation in chromatin states across humans. Science http://dx.doi.org/10.1126/science.1242510 (2013)
Kilpinen, H. et al. Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription. Science http://dx.doi.org/10.1126/science.1242463 (2013)
McVicker, G. et al. Identification of genetic variants that affect histone modifications in human cells. Science http://dx.doi.org/10.1126/science.1242429 (2013)