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Maternal genome-wide analyses identify variants associated with gestational duration and preterm delivery. Maternal alleles positively associated with gestational duration exhibit negative fetal effects on birth weight, likely reflecting antagonistic pleiotropy.

Allele-preferential transcription factor binding can influence pancreatic ductal adenocarcinoma risk loci function. Here, the authors show allele-specific JunB and JunD binding at chr1p36.33 and propose a role for KLHL17 in protein homeostasis by mitigating inflammation.

During meiotic prophase chromosomes organise into a series of chromatin loops, but the mechanisms of assembly remain unclear. Here the authors use Saccharomyces cerevisiae to elucidate how this elaborate three-dimensional chromosome organisation is linked to genomic sequence, and demonstrate an essential role for cohesin during this process.

Aberrant changes in DNA methylation have been implicated in various neurodevelopmental disorders but remain under studied in developmental and epileptic encephalopathies. Here, the authors demonstrate the diagnostic utility of genome-wide DNA methylation analyses toward identifying molecular etiologies in developmental and epileptic encephalopathies.

Genetic variants associated with susceptibility to pancreatic cancer have been identified using genome wide association studies (GWAS). Here, the authors combine data from over 9000 patients and perform a meta-analysis to identify five novel loci linked to pancreatic cancer.

Ependymoma is a type of neural tumour that arises throughout the central nervous system. Using comparative transcriptomics in mouse and human tumours, these authors home in on mutations that are specific to individual tumour subgroups. In doing so, they generate the first mouse model of ependymoma and demonstrate the power of interspecific genomic comparisons to interrogate cancer subgroups.

The progress in pre-clinical drug discovery for Wilms tumor (WT) is limited by a lack of disease models. Here, the authors develop 45 heterotopic WT patient-derived xenografts including several anaplastic models that recapitulate the biological heterogeneity of WT, and propose this as a resource for evaluating future therapeutics for WT.

Germline mutations in the Elongator complex gene ELP1 predispose individuals to the development of childhood medulloblastoma.

Blanco et al. show that PTEN loss results in accumulation of type-17 innate-like T cells via altered metabolic reprogramming and mTOR, Foxo1 and IL-23–Stat3 signalling.

The mechanisms underlying perinatal mortality due to intrahepatic cholestasis of pregnancy are not fully understood. Here, the authors show that absence of the nuclear receptor and bile acid regulator Nrli2 and the biliary transporter Abcb11 strongly reduces maternal serum bile acid levels, improving neonatal survival.

Genes related to lysosomal and autophagic systems are transcriptionally regulated by the Mit/TFE family of transcription factors. Here the authors show that MYC, in association with HDACs, suppresses the expression of lysosomal and autophagy genes by competing with the Mit/TFE transcription factors for occupancy of their target gene promoters.

Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.

The adaptor ASC functions in inflammasome assembly. Kanneganti and colleagues show that ASC has an inflammasome-independent role in regulating the stability of Dock2 mRNA and thereby governs the chemotaxis and phagocytosis of cells of the immune response.

Gastroesophageal reflux disease (GERD) is a major risk factor for Barret’s esophagus (BE) and esophageal adenocarcinoma (EA). Here, An et al. report 25 genetic loci for GERD, many of which associate with BE and EA or with other traits such as BMI.

IL-7R activation drives early B cell development, but the signalling is unclear. Here the authors show PLCγ is involved in IL-7R-induced mTOR activation via a DAG/PKC-dependent pathway, and that double deficiency of the two PLCγ isoforms arrests B cell development at the pre-pro-B stage in mice.

The authors previously showed that mTOR controls the function of regulatory T cells. Here they show how this mTOR signaling orchestrates homeostasis of T_reg-cell subsets and prevents fatal autoimmunity.

T_reg cells control effector cells such as T_H1 and T_FH cells. Chi and colleagues demonstrate that PTEN is cell-intrinsically required for T_reg cell lineage stability and regulation of effector T cell responses.

Regulatory T (T_reg) cells have a distinct cellular metabolism compared to effector T cells. Chi and colleagues show that autophagy is required to maintain the functional integrity and metabolic homeostasis of T_reg cells in the face of inflammatory environmental cues.

The mechanisms that control activation of the AIM2 inflammasome by cytosolic bacteria are unclear. Kanneganti and colleagues demonstrate that a pathway involving the transcription factor IRF1 is required for the activation of AIM2.

Richard Gilbertson and colleagues report an in vivo screen of 84 candidate oncogenes and 39 candidate tumor-suppressor genes in ependymoma mouse models. The validated targets are involved in vesicle trafficking, DNA modification and cholesterol biosynthesis.

Linda Holmfeldt, Lei Wei et al. report whole-genome and exome sequencing of 40 childhood hypodiploid acute lymphoblastic leukemias.

Immune quiescence is sustained through a tightly regulated but poorly understood process. Chi and colleagues show that the tumor suppressor Tsc1 is essential in maintaining T cell quiescence.

Phenotypically, transcriptionally and metabolically diverse subsets of T_H17 cells develop in a chronic autoimmune disease: one subset has inferred stemness features and low anabolic metabolism, while a reciprocal subset has higher metabolic activity that supports transdifferentiation into T_H1 cells.

A data-driven analysis helps to identify specific roles of the Hippo signalling kinases Mst1 and Mst2 in integrating metabolic activity and cytokine signalling in dendritic cells, and thereby orchestrating immune cell function.

Jun Yang and colleagues show that common variants in GATA3 are associated with risk of Ph-like acute lymphoblastic leukemia (ALL). They further show that these variants are associated with variation in GATA3 expression levels and with risk of ALL relapse.

The tumour suppressor liver kinase B1 (LKB1) regulates the metabolic and functional fitness of regulatory T cells in the control of immune tolerance and homeostasis.

Mary Relling and colleagues report results of a genome-wide association study of childhood acute lymphoblastic leukemia (ALL) and its subtypes, identifying a specific association between common variants in ARID5B and B-hyperdiploid ALL.

Here, mTORC1-dependent lipogenic programming is shown to be important for regulatory T-cell function, in part through the upregulation of the effector molecules CTLA4 and ICOS.

A mouse model of pleomorphic rhabdomyosarcoma, an aggressive and treatment-resistant form of pediatric sarcoma, provides an ideal tool for future diagnostic and therapeutic studies.