Articles in 2017

This month's research articles span the range of scales of gene-regulatory mechanisms, from a deceptively simple gene therapy vector, via synthetic gene expression circuits, to extremely intricate epigenetic switches. We encourage investigation of synthetic circuits exploring the functions of the 3D genome.

DNA copy number represents an essential parameter in the dynamics of synthetic gene circuits but typically is not explicitly considered. A new study demonstrates how dynamic control of DNA copy number can serve as an effective strategy to program robust oscillations in gene expression circuits.

Severe allergic disease is common, and few monogenic causes of atopy have been described. A new study that convincingly links severe atopic dermatitis to heterozygous CARD11 mutations with dominant-interfering activity serves as a timely reminder that clinicians should consider the possibility of an underlying monogenic immune disorder when caring for patients suffering from severe allergic disease.

Ernesto Guccione and colleagues report that the transcription factor PRDM15 regulates naive pluripotency in mouse embryos and embryonic stem cells and in derivation of mouse and human iPSCs. They further show that PRDM15 promotes WNT signaling and inhibits MAPK–ERK signaling by directly regulating the expression of R-spondin1 and Sprouty1, respectively.

Isabelle Janoueix-Lerosey, Valentina Boeva and colleagues analyze the super-enhancer landscape of 25 neuroblastoma cell lines to define core regulatory circuits controlling gene expression programs. They find and functionally characterize two types of cell identity that contribute to the tumor heterogeneity of neuroblastoma.

Peter Balint-Kurti, Qin Yang and colleagues report that ZmCCoAOMT2, which encodes a caffeoyl-CoA O-methyltransferase, is a gene within the quantitative trait locus qMdr_9.02, which confers resistance to southern leaf blight and gray leaf spot. Their findings suggest that resistance might be caused by differences in levels of lignin and other metabolites in the phenylpropanoid pathway.

Sekar Kathiresan and colleagues perform a genome-wide association test for coronary artery disease (CAD) using data from the UK Biobank. They identify 15 new loci and perform phenome-wide association scanning, implicating insulin resistance pathways and transendothelial migration of leukocytes in CAD.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease.

Hugh Watkins and colleagues meta-analyze data from the UK Biobank along with recent genome-wide association studies for coronary artery disease. They identify 13 new loci that were genome-wide significant and 243 loci at a 5% false discovery rate.

Kumarasamy Thangaraj, David Reich and colleagues identify 81 South Asian groups descended from extreme founder events, including 14 with a census size of over 1 million people, thus providing an opportunity to test for and decrease the burden of recessive genetic diseases in these populations.

Jeff Hasty and colleagues use an endonuclease from S. cerevisiae along with quorum sensing from A. fischeri to produce sustained cycling of DNA plasmid concentration across a colony of E. coli cells. This copy number modulation system enables dynamic regulation of gene circuit elements without the need for specially engineered promoters.

Matthew Robinson, Peter Visscher and colleagues use phenotypic data on 172,000 sibling pairs and phenotypic and SNP data on 150,832 unrelated individuals to estimate the heritability of body mass index across a range of experimental designs. They conclude that substantially larger sample sizes across ages and lifestyle factors will be required to understand the full genetic architecture of this trait.

Terence Capellini, David Kingsley and colleagues use transgenic mice to show that a Gdf5 enhancer (termed GROW1) is required for normal bone length. They suggest that a common variant at the human GROW1 enhancer was under selection in human populations and also contributes to arthritis susceptibility.

Charles Mullighan, Stephen Hunger, Jinghui Zhang and colleagues report a genomic analysis of 264 pediatric and young adult T-lineage acute lymphoblastic leukemia (T-ALL) samples. They identify 106 candidate driver genes, 53 of which have not been described previously in pediatric T-ALL, as well as associations between mutations and disease stage or subtype.

Junko Takita, Seishi Ogawa and colleagues profile 121 cases of pediatric T cell acute lymphoblasic leukemia (T-ALL) and identify recurrent SPI1 (PU.1) gene fusions. They find that these SPI1 fusions correlated with poor survival, retained transcriptional activity and, in a mouse stem cell model, enhanced cell proliferation.

Schahram Akbarian and colleagues report that mutation of the gene encoding the SETDB1 (KMT1E) histone methyltransferase in mouse neurons leads to dissolution of chromosome conformations and a topologically associated domain at the clustered protocadherin locus. They show that SETDB1 prevents excess CTCF binding and is important for maintaining developmentally important higher-order chromatin organization.

A study in this issue demonstrates that epigenome-modifying drugs used in cancer chemotherapy induce transcription from thousands of previously unannotated transcription start sites, most of which are derived from ancient endogenous retroviruses (ERVs). This work, coupled with previous related findings, suggests that induction of ERVs, rather than direct effects on specific genes, may have a central role in the cellular responses to such agents and, in turn, their therapeutic efficacy.

Promoters and enhancers have long been regarded as distinct elements, a notion that has been challenged more recently. Two new studies now identify promoters that function as long-range enhancers in vivo to regulate the transcription of distal genes.

This journal and Scientific Data are calling for submissions containing linked open data models that embody and extend the FAIR principles: that data should be findable, accessible, interoperable and reusable by both humans and machines. These principles are achievable with existing resources, languages and vocabularies to enable computers to combine and reanalyze data sets automatically and lead humans to new discoveries.