Volume 25 Issue 9, September 2023

In June 2023, the International Society for Stem Cell Research (ISSCR) released a report detailing standards for human stem cell research. We spoke to the co-chairs of the Steering Committee, Tenneille Ludwig, Senior Scientist and Director of the WiCell Stem Cell Bank, and Peter W. Andrews, Emeritus Professor at the University of Sheffield, and discussed the purpose and some of the basic aspects of these standards.

Embryonic diapause in development and paused pluripotency in embryonic stem cells result in a state of hypotranscription through mechanisms that remain unclear. A new study dissects the role of METTL3-deposited global m⁶A RNA methylation in mediating this transcriptional dormancy.

RNA modifications have emerged as key gene regulators. A new study shows that increased levels of reactive oxygen species in cancer induce widespread, sequence-specific modifications of guanines in the seed regions of microRNAs, altering the targets of those miRNAs and influencing tumorigenesis.

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.

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.

Cells use various metabolic pathways to synthesize the building blocks for growth and proliferation. To ensure balanced growth, these biosynthetic processes must be tightly coordinated. We describe a molecular machinery that senses the cellular capacity to make lipids to regulate other biosynthetic processes — such as protein synthesis — accordingly.

Genetic clearance of p16^high senescent cells or the use of senolytics improved the efficacy of stem cell reprogramming in vitro and in vivo, and helped establish induced pluripotent stem cells with features of experimental totipotency. When ablation of p16^high senescent cells was combined with partial four-factor reprogramming in vivo, we observed noticeable histopathological liver rejuvenation in aged mice.

The mechanisms controlling lysosome abundance in cells and how changes in lysosome pool size impact physiological and pathophysiological processes are discussed.

Grigorash et al. report that depletion of p16^High cells promotes a totipotent-like state to improve somatic cell reprogramming efficiency through an S-adenosyl-l-methionine-dependent mechanism.

Collignon et al. report that Mettl3-mediated m⁶A RNA methylation promotes developmental pausing in embryonic stem cells and blastocysts by establishing transcriptional dormancy.

Romanauska and Köhler manipulate the levels of endogenously produced saturated acyl chains in yeast and show that nuclear envelope and nuclear pore complex function are uniquely sensitive to lipid acyl chain unsaturation.

Nicastro, Brohée et al. find that the fatty acid synthesis intermediate malonyl-CoA inhibits mTORC1, showing mTORC1 senses the capacity of a cell to synthesise fatty acids and linking fatty acid generation with the overall biosynthetic output through mTORC1.

Meng et al. show that the RNA polymerase II elongation factor ELL3 suppresses the 5′ untranslated region activities of a subset of young LINE-1 elements, which activate genes such as Akt3, and regulate ERK signalling and naïve pluripotency in mouse embryonic stem cells.

Filipescu et al. report that macroH2A deficiency in cancer-associated fibroblasts leads to altered chromatin looping and elevated inflammatory gene expression, thereby affecting immune cell function and limiting the anti-tumour response in melanoma.

Duplaquet, Li et al. identify and characterize KDM6A as an epigenetic regulator that impacts chromatin accessibility to modulate ASCL1-to-NEUROD1 subtype switching in small cell lung cancer.

Dou, Xiao, Shen, Wang et al. show that RBFOX2 recognizes m⁶A on chromatin-associated RNAs and recruits RBM15, YTHDC1 and PRC2 to facilitate transcription suppression. Inhibition of the axis exerts anti-leukaemic effects.

Eom, Peak, Park, Ahn and colleagues reveal and provide a comprehensive resource of 8-oxoguanine modifications in tumour microRNAs and show how they differentially influence malignancy progression in gliomas and hepatocellular carcinoma.