Volume 542 Number 7642

Editorials

News

News Features

News & Views

Diversity in sight p.418

A systematic analysis of bipolar cells, which act as a central signalling conduit in the retina, reveals that the neurons' diverse responses to light are generated largely by feedback from neighbouring amacrine cells. See Article p.439

doi: 10.1038/nature21498

Predictable ice ages on a chaotic planet p.419

Statistical analysis has revealed a simple rule for the occurrence of warm periods during the Quaternary, whereas on much longer timescales geological data have confirmed that the Solar System is chaotic. See Article p.427 & Letter p.468

doi: 10.1038/542419a

RNA editing packs a one-two punch p.420

Optimal protein synthesis requires bases in transfer RNAs to be modified. A key modification has been shown to involve an unusual two-step mechanism that entails the sequential activities of two enzymes. See Letter p.494

doi: 10.1038/542420a

Earth's seven sisters p.421

Seven small planets whose surfaces could harbour liquid water have been spotted around a nearby dwarf star. If such a configuration is common in planetary systems, our Galaxy could be teeming with Earth-like planets. See Letter p.456

doi: 10.1038/542421a

Organic analogues of graphene p.423

Chemists have long aspired to synthesize two-dimensional polymers that are fully conjugated — an attribute that imparts potentially useful properties. Just such a material has been prepared using a solid-state polymerization reaction.

doi: 10.1038/nature21503

A targeted treatment with off-target risks p.424

It emerges that blood-cancer-targeting drugs that block a tumour-survival pathway also activate a mutation-causing enzyme in mice and in human cells. This might have implications for the clinical use of these drugs. See Letter p.489

doi: 10.1038/nature21504

Articles

Letters

m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition p.475

The maternal-to-zygotic transition (MZT) is one of the most profound and tightly orchestrated processes during the early life of embryos, yet factors that shape the temporal pattern of vertebrate MZT are largely unknown. Here we show that over one-third of zebrafish maternal messenger RNAs (mRNAs) can be N6-methyladenosine (m6A) modified, and the clearance of these maternal mRNAs is facilitated by an m6A-binding protein, Ythdf2. Removal of Ythdf2 in zebrafish embryos decelerates the decay of m6A-modified maternal mRNAs and impedes zygotic genome activation. These embryos fail to initiate timely MZT, undergo cell-cycle pause, and remain developmentally delayed throughout larval life. Our study reveals m6A-dependent RNA decay as a previously unidentified maternally driven mechanism that regulates maternal mRNA clearance during zebrafish MZT, highlighting the critical role of m6A mRNA methylation in transcriptome switching and animal development.

doi: 10.1038/nature21355

Metabolic gatekeeper function of B-lymphoid transcription factors p.479

The B-lymphoid transcription factors PAX5 and IKZF1 restrict the supply of glucose and energy to B cells to levels that are not enough to fuel a driver-oncogene, thereby acting as tumour suppressors and sensitizing acute lymphoblastic leukaemia B cells to glucocorticoid therapy.

doi: 10.1038/nature21076

Phosphatidylinositol 3-kinase δ blockade increases genomic instability in B cells p.489

Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation. The phosphatidylinositol 3-kinase δ (PI3Kδ) pathway regulates AID by suppressing its expression in B cells. Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3Kδ activity directly or indirectly, potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both of these effects were completely abrogated in AID-deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumours in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IGH and AID off-target sites in human chronic lymphocytic leukaemia and mantle cell lymphoma cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased somatic hypermutation in AID off-targets. In summary, we show that PI3Kδ or Bruton’s tyrosine kinase inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. This effect should be carefully considered, as such inhibitors can be administered to patients for years.

doi: 10.1038/nature21406