Volume 552 Number 7684

Editorials

How to avoid glib interdisciplinarity p.148

To make progress on the grand challenges, authors, reviewers and editors must take the time to respect each others’ expertise and blind spots.

doi: 10.1038/d41586-017-08465-1

News

News Features

News & Views

Early embryos kept in check p.178

As pluripotent stem cells become primed to give rise to all bodily cell types, they begin to form the amniotic cavity in which the mammalian fetus will grow. A checkpoint that gates this transition has now been identified.

doi: 10.1038/d41586-017-07436-w

Stellar cannibalism in fits and starts p.179

Dense stellar remnants called white dwarfs are often found in binary star systems. Satellite observations suggest a previously unknown way in which a white dwarf can draw material from its companion star.

doi: 10.1038/d41586-017-08286-2

A dark side to omega-3 fatty acids p.180

The molecule 19,20-dihydroxydocosapentaenoic acid, formed by the metabolism of a fatty acid involved in normal brain function, promotes the development of a diabetes-associated form of blindness in a mouse model.

doi: 10.1038/d41586-017-07678-8

Longer life through an odd Pol enzyme p.182

The evolutionarily conserved enzyme RNA polymerase III is a driver of protein synthesis and cell growth. It emerges that partial suppression of this essential enzyme extends lifespan in yeast, roundworms and flies.

doi: 10.1038/d41586-017-07435-x

Antarctic ice dynamics in warm climates p.183

A geological record reveals that the Aurora sector of the Antarctic Ice Sheet showed contrasting responses to past periods of atmospheric warmth. The findings might help to predict the ice sheet’s response to modern warming.

doi: 10.1038/d41586-017-08285-3

Viruses hijack a long non-coding RNA p.184

Manipulation of host-cell metabolism is an essential aspect of viral replication cycles. Viral co-option of a cellular long non-protein-coding RNA has now been found to be a key step in this process.

doi: 10.1038/d41586-017-07692-w

Articles

Letters

Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy p.248

A product of the soluble epoxide hydrolase enzyme, 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP), is implicated in the pathogenesis of diabetic retinopathy; levels of 19,20-DHDP increase in the retinas of mice and humans with diabetes, and inhibition of its production can rescue vascular abnormalities in a mouse model of the disease.

doi: 10.1038/nature25013

Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours p.253

Tissue-resident memory CD8+ T (TRM) cells are found at common sites of pathogen exposure, where they elicit rapid and robust protective immune responses. However, the molecular signals that control TRM cell differentiation and homeostasis are not fully understood. Here we show that mouse TRM precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory cell populations at the levels of gene expression and chromatin accessibility. Using computational and pooled in vivo RNA interference screens, we identify the transcription factor Runx3 as a key regulator of TRM cell differentiation and homeostasis. Runx3 was required to establish TRM cell populations in diverse tissue environments, and supported the expression of crucial tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Furthermore, we show that human and mouse tumour-infiltrating lymphocytes share a core tissue-residency gene-expression signature with TRM cells that is associated with Runx3 activity. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ tumour-infiltrating lymphocytes failed to accumulate in tumours, resulting in greater rates of tumour growth and mortality. Conversely, overexpression of Runx3 enhanced tumour-specific CD8+ T cell abundance, delayed tumour growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of TRM cell differentiation, these results provide insight into the signals that promote T cell residency in non-lymphoid sites, which could be used to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.

doi: 10.1038/nature24993

KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase p.273

Histone modifications, such as the frequently occurring lysine succinylation, are central to the regulation of chromatin-based processes. However, the mechanism and functional consequences of histone succinylation are unknown. Here we show that the α-ketoglutarate dehydrogenase (α-KGDH) complex is localized in the nucleus in human cell lines and binds to lysine acetyltransferase 2A (KAT2A, also known as GCN5) in the promoter regions of genes. We show that succinyl-coenzyme A (succinyl-CoA) binds to KAT2A. The crystal structure of the catalytic domain of KAT2A in complex with succinyl-CoA at 2.3 Å resolution shows that succinyl-CoA binds to a deep cleft of KAT2A with the succinyl moiety pointing towards the end of a flexible loop 3, which adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Site-directed mutagenesis indicates that tyrosine 645 in this loop has an important role in the selective binding of succinyl-CoA over acetyl-CoA. KAT2A acts as a succinyltransferase and succinylates histone H3 on lysine 79, with a maximum frequency around the transcription start sites of genes. Preventing the α-KGDH complex from entering the nucleus, or expression of KAT2A(Tyr645Ala), reduces gene expression and inhibits tumour cell proliferation and tumour growth. These findings reveal an important mechanism of histone modification and demonstrate that local generation of succinyl-CoA by the nuclear α-KGDH complex coupled with the succinyltransferase activity of KAT2A is instrumental in histone succinylation, tumour cell proliferation, and tumour development.

doi: 10.1038/nature25003