Gene Regulation: from Genetic Variation to Phenotype Via Chromatin

RESEARCH HIGHLIGHTS

Nature Reviews Genetics | AOP, published online 29 October 2013; doi:10.1038/nrg3622

transcription factor binding and Heinz et al. also used natural genetic actively transcribed sites as defined variation as their ‘in vivo mutagenesis by the locations of RNA polymerase II. screen’ — they looked at differences Kilpinen et al. analysed these features in transcription factor binding and in P. Morgan/NPG P. in lymphoblastoid cell lines (LCLs) histone modifications between the from parent–offspring trios and from C57BL/6J and BALB/cJ strains of eight unrelated individuals in the 1,000 mice. They investigated the binding Genomes Project, whereas McVicker of the proposed lineage-defining et al. surveyed LCLs from ten unrelated transcription factors (LDTFs) PU.1 and Yoruba individuals. Both studies CCAAT/enhancer-binding protein-α, found allelic specificity of histone as well as the signalling-responsive modifications, which, importantly, was transcription factor NF-κB. They found GENE REGULATION coordinated with transcription factor that the binding of the proposed LDTFs binding. This finding indicates that is dependent on genetic variation, From genetic variation to sequence-specific transcription factors as are histone modifications, which may specify histone modifications, and suggests that these LDTFs determine phenotype via chromatin that there is thus a sequence-specific histone modification patterns. component to the deposition of histone Furthermore, the LDTFs seem to There is known to be some correlation modifications. This allelic specificity recruit each other, and they also seem among genetic variation, chromatin leads, in turn, to changes in both to determine the binding of NF-κB in modifications, transcription factor enhancer choice and gene expression response to signals. binding, gene expression and between different haplotypes, even in The overarching theme of these phenotypes. However, the jury is still distal enhancers. papers is that genetic variation may out on the strength of the links between The approach of Kasowski et al. was determine sites of transcription these different organismal features and to map histone modifications by factor binding, which, in turn, specify whether alterations in one directly cause ChIP–seq and gene expression histone modifications and enhancer alterations in the other. Four studies by RNA sequencing in 19 individuals choice; however, some combinational have now taken advantage of recently from the 1,000 Genomes Project. In alterations are required for gene developed genome-wide approaches addition, the locations of two general expression changes. and resources in both humans and transcription factors were mapped. By Hannah Stower mice to establish that genetic variation dividing the genome into regions with strongly determines sites of transcription different combinations of chromatin ORIGINAL RESEARCH PAPERS Heinz, S. et al. Effect of natural genetic variation on enhancer factor binding. This binding, in turn, modifications, they found that there selection and function. Nature http://dx.doi. results in altered histone modifications are extensive differences in enhancer org/10.1038/nature12615 (2013) | Kasowski, M. and enhancer choice, which lead to states between individuals, as well as et al. Extensive variation in chromatin states across humans. Science http://dx.doi. changes in both gene expression and the in transcription factor-binding sites org/10.1126/science.1242510 (2013) | Kilpinen, H. resultant phenotypes. that are associated with different et al. Coordinated effects of sequence variation McVicker et al. and Kilpinen et al. took chromatin states. However, they found on DNA binding, chromatin structure, and transcription. Science http://dx.doi.org/10.1126/ a similar approach, which was to carry that, to alter gene expression, multiple science.1242463 (2013) | McVicker, G. et al. out chromatin immunoprecipitation enhancers that are linked to a gene Identification of genetic variants that affect followed by sequencing (ChIP–seq) must have alterations in their histone histone modifications in human cells. Science http://dx.doi.org/10.1126/science.1242429 (2013) to survey histone modifications, modification states.

NATURE REVIEWS | GENETICS VOLUME 14 | DECEMBER 2013