Research Highlights of joint populations or of populations in haemoglobin are known to affect ­­­­­­­­­­ ­TECHNIQUE stratified by self-identified​ race or the results of glycated haemoglobin ethnicity, with African American (HbA1c) assays, which are used to populations having weaker diagnose and monitor type 2 diabetes Optoepigenetics for 3D effect sizes than Hispanic/Latino mellitus. The PAGE study identified an populations. These data emphasize association between a missense variant genome engineering that effect sizes and risk prediction in the HBB (which encodes the Paladin/Alamy Paul Credit: Loop engineering techniques that modulate long-range scores derived from one population haemoglobin β-chain)​ and HbA1c cannot be assumed to apply to levels in the Hispanic/Latino chromosomal interactions play a pivotal part in deciphering different populations. population, an association that had the relationship between 3D genome architecture and Next, the authors showed been previously reported for African function. Now, Kim, Rege et al. present the light-activated that data from genetically diverse Americans. Given the shared dynamic looping (LADL) system, which is based on a synthetic populations can help fine-map​ African ancestry of African Americans architectural that rapidly induces long-range associations, reducing the number and some Hispanic/Latinos, this result chromatin interactions in response to blue light. of candidate causative variants. suggests that ancestry-specific​ findings The LADL system comprises two plasmids, one encoding A meta-analysis​ that combined from one group may have relevance for a LADL ‘anchor’ and one encoding sequence-specific CRISPR PAGE with GIANT data (from other groups that share components of guide RNAs (gRNAs) designed to target two genomic regions to be joined through loop formation. The LADL anchor more than 250,000 individuals of that genetic ancestry. is formed of an enzymatically inactive Cas9 (dCas9) that is European ancestry) reduced the Taken together, the findings of this fused to a truncated version of the CIB1 protein (CIBN; average 95% credible set size from study powerfully illustrate the need for also known as factor bHLH63) from Arabidopsis 11.94 SNPs to 9.68 for 390 variants a more inclusive approach to GWAS thaliana. gRNAs guide the LADL anchor to the two desired associated with height in GIANT; if genetic discovery and precision genomic anchoring sites. The gRNA-encoding plasmid also by contrast, addition of data from medicine are to benefit everyone, includes CRY2, whose protein product acts as an inducible 50,000 randomly sampled white regardless of genetic ancestry. bridging factor that joins the two anchoring sites upon British participants from the UK Dorothy Clyde activation with blue light (470 nm wavelength) through Biobank (UKB50k) to GIANT had Original article Wojcik, G. L. et al. Genetic heterodimerization with CIBN. no significant effect. analyses of diverse populations improves discovery Using mouse embryonic stem (ES) cells, the authors Finally, the authors demonstrated for complex traits. Nature 570, 514–518 (2019) Further reading Gurdasani, D. et al. Genomics compared transfected cells exposed to 24 h of blue light or the importance of ancestry-specific​ of disease risk in globally diverse populations. dark and found no differences in dCas9 and CRY2 transcript findings for medically relevant Nat. Rev. Genet. https://doi.org/10.1038/s41576- 019-0144-0 (2019) levels nor in the expression of pluripotency markers between variants. For example, genetic variants the two conditions. This finding suggests that transfection and light induction had no impact on transgene expression or the course when they are part of relevant mass index (BMI)-associated variant ES cell state. To test the LADL system, the authors chose a regulatory elements. rs28818910, for which the effect on ~800-kb-sized region around the and Zfp462 , Beyond chromatin signatures of expression of C15orf39 is strongest reasoning that loop engineering would redirect the interaction cardiomyocyte enhancers, the late transiently in the middle of the between Klf4 and its long-range enhancer to Zfp462. dynamic eQTLs were enriched for genes developmental time course and was Recruitment of the LADL system to its target locations was related to . not identified through analyses of cell measured by chromatin immunoprecipitation followed by Moreover, the authors identified several lines or mature tissues. quantitative PCR (ChIP–qPCR), which confirmed the presence dynamic eQTLs that were not previously This study illustrates that capturing of dCas9–CIBN at both the Klf4 enhancer element and the known from analyses of cell lines or the time course of Zfp462 under dark conditions. tissues at single time points but which enables the discovery of dynamic Blue light activation led to a doubling in intensity of the have plausible links to cardiac biology. eQTLs that would otherwise be dCas9–CIBN ChIP signal at the Zfp462 promoter and a slight For example, single-nucleotide variants challenging­ to find. Furthermore, signal decrease at the Klf4 enhancer. A high-resolution map of rs7633988 and rs6599234 associated such approaches are likely to long-range chromatin interactions generated by with rhythm also showed pinpoint not only disease-relevant conformation capture carbon copy (5C) showed the formation association with dynamic expression genes but also the particular of a new contact between Zfp462 and the Klf4 enhancer upon of the sodium channel gene SCN5A, developmental stages at which their which is involved in heart contraction, disruption becomes pathogenic, blue light illumination. The loop between Klf4 and its enhancer and the cardiomyopathy-associated which may provide opportunities for remained largely unperturbed. Notably, the newly formed loop variant rs11124033 also associated clinical monitoring or therapeutic between Zfp462 and the enhancer was detectable 4 h after with dynamic regulation of the intervention. the start of the light stimulus, which is substantially faster heart-enriched gene FHL2. Finally, the analytical frameworks than current chemical loop engineering approaches. Using an alternative analysis strategy, are applicable to diverse systems Finally, single-molecule RNA fluorescence in situ hybridization the authors identified 693 dynamic beyond cardiomyocyte differentiation, showed a modest increase in Zfp462 expression. eQTLs for which the effect changes so could be a valuable approach to While the approach requires improvements to increase the in non-linear ways throughout the understand diverse traits and diseases. strength of LADL-induced contacts, the method should prove differentiation time course (that is, Darren J. Burgess useful for 3D optoepigenetic engineering of chromatin at not just a progressive increase or Original article Strober, B. J. et al. Dynamic short time scales. decrease in effect size). Several of these genetic regulation of gene expression during Linda Koch eQTLs are leads for further mechanistic . Science 364, 1287–1290 (2019) Original article Kim, J. H. & Rege, M. et al. LADL: light-activated dynamic looping characterization, such as the body for endogenous gene expression control. Nat. Methods 16, 633–639 (2019)

NAture RevIeWS | Genetics volume 20 | September 2019 | 501