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The REX element is associated with long-range enhancer–promoter interactions.

Human enhancers contain a high density of sequence features that are required for their normal in vivo function.

MPRAs and in vivo transgenic mouse assays are two potentially complementary ways to assay the impact of noncoding variants. Here, authors find a strong and specific correlation between the assays in neural cells. Mouse assays also reveal pleiotropic effects not observed in MPRA.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

Although enhancers are crucial and widespread gene-regulatory elements, we are far from a complete understanding of how they function or their importance in areas such as disease and evolution. Five prominent researchers discuss some of the key outstanding questions in enhancer biology.

Gene enhancer knockout phenotypes and analysis of enhancer activity patterns show that developmental genes are regulated by multiple redundant enhancers in mouse embryos.

Len Pennacchio, Axel Visel and colleagues use an epigenomic approach to identify a large number of candidate enhancers from human heart tissue. This work will facilitate further studies into the role of enhancers in human cardiac development and disease.

Len Pennacchio and colleagues used ChIP-Seq with the enhancer-associated protein p300 to identify 3,000 candidate cardiac transcriptional enhancers in embryonic mice at E11.5. Notably, most candidate heart enhancers at this time point are not deeply evolutionarily conserved.

The authors here show that chromatin interactions during mouse fetal development are spatiotemporally dynamic. Integrating interactomes with other datasets predicts target genes for candidate enhancers and helps interpret noncoding risk variants in the human genome.

Here, the authors present a multi-omic framework using single cell technology to identify non-coding genetic variants in cranial motor neuron disorders, offering insights into their genetic basis and methods for studying other Mendelian diseases.

Approximately a quarter of the human genome consists of gene deserts. Here, Abassah-Oppong et al. reveal the biological relevance, embryonic functions and underlying enhancer architecture of a genomic gene desert flanking the Shox2 transcription factor essential for limb, craniofacial and cardiac pacemaker development.

Supervised machine-learning models trained using Drosophila epigenetic and STARR-seq data can be transferred to predict mouse and human enhancers.

A study reports single-cell RNA-sequencing profiles for more than 1.6 million cell nuclei from 101 whole mouse embryos including 22 mutant and 4 wild-type genotypes, from one experiment.

This is an issue edsumm for ng1939. Identification of the Palaeocene/Eocene thermal maximum in a marine sedimentary sequence. It shows that sea surface temperatures near the North Pole increased from roughly 18 degrees Celsius to over 23 degrees Celsius — such warm values imply the absence of ice and thus exclude the influence of ice-albedo feedbacks on this Arctic warming.

Martin Zenker, Marco Tartaglia, Reza Ahmadian and colleagues report the identification of a restricted spectrum of NRAS mutations in individuals with Noonan syndrome. Functional testing revealed that the mutations confer enhanced stimulus-dependent MAPK activation.

Rajderkar et al. provide a genome-wide compendium of transcriptional enhancers active in human craniofacial development, along with single-cell resources for studies of mammalian craniofacial morphogenesis.

A catalog of enhancer–promoter (E–P) interactions across ten mouse embryonic tissues, supported by in vivo functional experiments, shows that E–P proximity increases upon enhancer activation during development.

Helen Hobbs and colleagues report an association between coding variation in PNPLA3 and susceptibility to nonalcoholic fatty liver disease. The associated alleles vary in frequency among Hispanics, African Americans and European Americans and contribute to differences in disease prevalence among these ancestry groups.

GATA2 regulatory mutations are associated with hereditary congenital facial paresis in humans. A genetically engineered mouse model recapitulates the human phenotype, showing altered neuron-specific Gata2 expression and a bias in formation of inner-ear efferent neurons over facial branchial motor neurons.

Mutagenesis of 23 ultraconserved enhancers and examination of their activities in transgenic mouse reporter assays show that overall their regulatory properties are robust to mutation. Manipulation of endogenous loci in mice corroborates reporter assay data.

Sequence conservation of noncoding DNA across species can indicate functional conservation. However, a new study demonstrates notable differences between human and mouse stem cell regulatory networks, suggesting caution in generalizing from sequence to functional conservation.

Globin loci harbor genes that are expressed embryonically and silenced postnatally. Here the authors show that zeta-globin silencing depends upon selective hypoacetylation of its TAD subdomain, which blocks its interaction with the alpha-globin super-enhancer, and zeta-globin can be reactivated by acetylation.

Analysis of chromatin state and accessibility in mouse tissues from twelve sites and eight developmental stages provides a comprehensive view of chromatin dynamics.

Analysis of 168 methylomes from 12 mouse tissues at 9 developmental stages sheds light on the epigenetic and regulatory landscape during mammalian fetal development.

RNA expression is quantified at a tissue level in seventeen mouse tissues across embryonic development, and at the single-cell level in the developing limb.

An intestine-critical region on human chromosome 16, and its regulation of PERCC1, a newly identified gene, is shown to underlie the genetic basis of a severe, inherited form of diarrhoea.

Identification of non-coding variants has outstripped our ability to annotate and interpret them. Dickel et al. present a compendium of over 80,000 putative human heart enhancers and demonstrate that two conserved enhancers are required for proper cardiac function in mice.

Determining the spatial and temporal activity patterns of enhancers remains a challenge in the functional annotation of the human genome. In this study, the genome-wide occupancy of the enhancer-associated protein p300 was determined in developing mouse tissues by using chromatin immunoprecipitation followed by massively parallel sequencing. Testing the p300-bound sequences in a transgenic mouse enhancer assay confirmed that p300 binding is a highly effective means to identify enhancers and to predict in which tissues they are active.

Putative enhancer elements of a genomic region of interest are cloned in front of a reporter gene, integrated in a single site in mouse embryonic stem cells, and screened for enhancer activity using flow cytometry and high-throughput sequencing.

Transcription factors (TFs) drive spatiotemporal patterns of gene expression that control organ development and disease responses. Here, He et al.show that chromatin occupancy of GATA4 varies between fetal, adult and hypertrophic heart to direct developmental stage- and disease-specific transcriptional programs.

As part of the mouse ENCODE project, genome-wide transcription factor (TF) occupancy repertoires and co-association patterns in mice and humans are studied; many aspects are conserved but the extent to which orthologous DNA segments are bound by TFs in mice and humans varies both among TFs and genomic ___location, and TF-occupied sequences whose occupancy is conserved tend to be pleiotropic and enriched for single nucleotide variants with known regulatory potential.

Strong genetic evidence points to a significant role for heterozygous mutations to general chromatin remodeling factors, such as CHD8, in autism. Gompers et al. combine genomic, neuroanatomical and behavioral approaches to present an initial integrative picture of transcriptional mechanisms and widespread impacts of Chd8 haploinsufficiency across brain development in mice.

Two groups describe approaches for synthesizing and assaying the function of thousands of variants of mammalian DNA regulatory elements. Melnikov et al. use their results to engineer short optimized regulatory elements in human cells, whereas Patwardhan et al. study enhancers hundreds of bases long in mice.

Douglas Higgs and colleagues functionally test the α-globin super-enhancer in mice by genetically deleting its constituent enhancers. They find that the individual regulatory elements seem to act independently and in an additive way with respect to hematological phenotype, gene expression, and chromatin structure and conformation.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.