Reviews & Analysis

Pathways linked to the modification of RNA with N⁶-methyladenosine (m⁶A) are known to be involved in initiating and maintaining cancer. But many of the key components of these pathways remain undiscovered. The RBFOX2 protein has now been identified as an m⁶A reader involved in locus-specific chromatin regulation, with therapeutic implications for myeloid leukaemia.

The interaction of non-immune and immune cells in the tumour microenvironment (TME) determines the quality of the immune attack on nascent tumour cells. A new study in melanoma cells shows that specific histone variants dampen the expression of cytokine genes in cancer-associated fibroblasts, leading to an immunosuppressive TME.

A fast protocol for chemical cellular reprogramming reveals a diapause-like state, endogenous retrovirus activation and barriers to cell-fate transitions on the way to pluripotency. The system offers insights into manipulation of cellular regeneration and rejuvenation, two processes with great therapeutic potential.

In many species, a mother’s environment can impact offspring’s metabolism, but the mechanisms that mediate such intergenerational effects are unclear. In this issue, a study finds that the provisioning of a sphingolipid from mothers to offspring drives changes in offspring metabolism that protect against neuronal damage.

Pioneer transcription factors bind closed chromatin regions, alter local accessibility and activate target genes. A study reveals that the SOX9 transcription factor drives cell fate switching by activating hair follicle cell enhancers, while simultaneously repressing epidermal enhancers via sequestration of epigenetic factors.

Reprogramming of somatic cells is an inherently inefficient process. A new study has now identified histone H3K36 methylation as a crucial reprogramming barrier that operates downstream of TGFβ signalling. Global inhibition of H3K36 methylation induced PRC2-dependent silencing of mesenchymal genes and dramatically increased reprogramming efficiency.

The compact state of chromatin induced by the methylation of lysine 9 on histone H3 has long been implicated in a heritable state of transcriptional repression. A study now shows that transient deposition of H3K9me3 helps to stabilize stalled DNA replication forks, while its reversal enables accurate fork restart.

The PHD–pVHL pathway is essential for oxygen-dependent prolyl hydroxylation of HIFA. A recent study identifies RIPK1 as a hydroxylation target in this pathway during hypoxia-induced cell death and presents a 2.8 Å resolution crystal structure of the pVHL–elongin B/C complex bound to hydroxylated RIPK1.

Mitochondria are dynamic organelles, changing their morphology and functional capacity in response to physiological and metabolic cues. A study uncovers a role for the typically nutrient-responsive mTORC2 during fasting in vivo to promote mitochondrial fission via the activation of a signalling pathway that involves NDRG1 and CDC42.

The nuclear envelope participates in the spatial regulation of DNA repair, but the mechanisms behind this are unclear. A study now reports that a nuclear envelope-localized nuclease, NUMEN/ENDOD1, guides the choice of DNA-repair pathway by inhibiting the resection of DNA ends and aberrant recombination, ensuring genome stability.

Disruptions in the autophagy–lysosome pathway in neurons have been implicated in Alzheimer’s disease. A study now reports that autophagy is also critical for disease-associated microglia surrounding amyloid plaques and is protective against microglial senescence and neuropathology in an Alzheimer’s disease mouse model.

Desmosomes and keratin are now found to regulate the distribution and dynamics of the endoplasmic reticulum (ER). This suggests that a range of ER functions may be coordinated by this intercellular adhesive and cytoskeletal network.

A new study shows that the enzymes involved in de novo pyrimidine synthesis and ferroptosis form a complex called the pyrimidinosome, which is controlled by AMPK. Cancer cells low in AMPK expression rely on the pyrimidinosome, suggesting that co-inhibition of AMPK and the pyrimidinosome represents a potential cancer treatment strategy.

Receptor-mediated endocytosis delivers low-density lipoproteins (LDLs) to late endosomes, from where cholesterol is trafficked to mitochondria. Zhou et al. report that LDL-containing endosomes fuse with mitochondria, supplying cholesterol for steroid biosynthesis and enabling mitochondrial degradation of the LDL receptor.

How mucosal-associated invariant T (MAIT) cells acquire memory-like features after infection and the factors that control this process have been unclear. A study now defines two subsets of antigen-adapted MAIT cells emerging after immunization that differ in functions, lung localization and metabolic requirements.

Accumulation of senescent cells and compositional changes in gut microbiota have been independently reported to occur as a function of age. A study now suggests that these two seemingly disparate processes are more intimately linked than previously appreciated via a B cell–IgA–microbiota axis.

In cancer, alternative polyadenylation has been shown to lead to altered 3′ UTRs with different regulatory potentials. A study now suggests a mechanism that leads to 3′ UTR lengthening and translational repression of a subset of metastasis-suppressing genes, revealing a new prospective therapeutic vulnerability.

The selenoprotein glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, a form of cell death earmarked by unrestrained lipid peroxidation. A new study shows that the metabolic enzyme creatinine kinase B (CKB) phosphorylates GPX4, which may influence the susceptibility of cancer cells to ferroptosis.

The cGAS–STING cytosolic double-stranded-DNA-sensing pathway provides protection against infection but also contributes to inflammatory pathology and thus must be tightly regulated. In this issue, Jie et al. find that endoplasmic-reticulum-associated degradation of the adaptor STING by SEL1L–HRD1 controls steady-state STING levels to limit STING-driven inflammation.

The Mediterranean diet correlates with increased human lifespan; it is rich in foods with high levels of cis-monounsaturated fatty acids (MUFAs), such as olive oil. A study now shows that MUFAs stimulate a lipid droplet–peroxisome organelle network to decrease lipid oxidation and protect cell membranes during ageing.