Nature Cell Biology

Cai, Chen; Yu, Jiancheng; Zhang, Xudong; Zhou, Tong; Chen, Qi

doi: 10.1038/s41556-025-01736-4pmid: 40836039

We hypothesize that stress-induced RNA structural changes, stabilized by RNA-binding proteins in biomolecular condensates, propagate via conformational catalysis in a prion-like manner across generations. Our model suggests that RNA structure encodes heritable memory, and its roles should be explored in epigenetic inheritance, evolutionary adaptation and disease.

Dean, Ann

doi: 10.1038/s41556-025-01743-5pmid: 40921735

During development as cells exit a pluripotent state, chromatin looping interactions are strengthened, but the mechanism for this is unknown. A study now shows that CTCF–RBP interactions increase upon differentiation of embryonic stem cells to neural stem cells, and that the non-coding RNA Pantr1 collaborates with CTCF and RBPs to contract the genome.

Wang, Yi-Hao; Dergun, Stanislav; Ho, Ping-Chih

doi: 10.1038/s41556-025-01756-0pmid: 40925953

A study now indicates that CD160⁺CD8⁺ T cells in patients with colorectal cancer modulate anti-tumour immune responses and may influence disease progression. Their combination with immune checkpoint blockade therapy has emerged as a promising strategy to enhance therapeutic efficacy and patient outcomes in colorectal cancer.

Suzuki, Daisuke; Takashima, Yasuhiro

doi: 10.1038/s41556-025-01733-7pmid: 40813452

To better understand trophoblast development, scientists have long sought stem cells that model the trophectoderm at the early blastocyst stage. Gao, Li et al. now derive trophectoderm stem cells from morula-stage embryos, representing an earlier pre-implantation stage than previously reported trophoblast stem cells.

doi: 10.1038/s41556-025-01731-9pmid: 40836038

How multiple chaperones are organized to co-ordinate their activities has been unclear. We observed that the chaperone PDIA6 forms phase-separated condensates in the endoplasmic reticulum to which several additional chaperones are recruited. These multi-chaperone condensates constitute a dedicated endoplasmic reticulum sub-compartment that facilitates protein biogenesis and prevents protein misfolding and aggregation.

doi: 10.1038/s41556-025-01746-2pmid: 40913149

Gene fusions are potent drivers of cancer, and nuclear condensates are known to have a role in transcription. By creating synthetic fusion oncogenes, we show that nuclear condensate formation might be a general feature of fusion oncoprotein-directed transcription, including in brain tumour development.

Andersson, Rebecca; Mejia-Ramirez, Eva; Florian, Maria Carolina

doi: 10.1038/s41556-025-01739-1pmid: 40855363

Ageing of the haematopoietic system is characterized by phenotypic and functional impairments that are driven by alterations of haematopoietic stem cells and of the bone marrow niche. Haematopoietic stem cells are responsible for the production of all the different cell types that constitute the blood, and their maintenance and differentiation must be tightly regulated during the whole life of an organism. Exciting new data emphasize that central aspects of blood ageing, ranging from inflammageing and immunosenescence to clonal haematopoiesis, are mechanistically linked to dysfunction and ageing of other tissues, supporting a central role for the haematopoietic system in this context. Here we review some of the recent findings with a focus on ageing of the haematopoietic system and provide an overview of its role in driving healthspan and lifespan of the whole organism.

Xu, Nan; Cho, Hyein S.; Hackland, James O. S.; Benito-Kwiecinski, Silvia; Saurat, Nathalie; Harschnitz, Oliver; Russo, Marco Vincenzo; Garippa, Ralph; Ciceri, Gabriele; Studer, Lorenz

doi: 10.1038/s41556-025-01751-5pmid: 40897805

Embryonic development follows a conserved sequence of events across species, yet the pace of development is highly variable and particularly slow in humans. Species-specific developmental timing is largely recapitulated in stem cell models, suggesting a cell-intrinsic clock. Here we use directed differentiation of human embryonic stem cells into neuroectoderm to perform a whole-genome CRISPR-Cas9 knockout screen and show that the epigenetic factors Menin and SUZ12 modulate the speed of PAX6 expression during neural differentiation. Genetic and pharmacological loss-of-function of Menin or SUZ12 accelerate cell fate acquisition by shifting the balance of H3K4me3 and H3K27me3 at bivalent promoters, thereby priming key developmental genes for faster activation upon differentiation. We further reveal a synergistic interaction of Menin and SUZ12 in modulating differentiation speed. The acceleration effects were observed in definitive endoderm, cardiomyocyte and neuronal differentiation paradigms, pointing to chromatin bivalency as a general driver of timing across germ layers and developmental stages.

Leder, Anna; Mas, Guillaume; Szentgyörgyi, Viktória; Jakob, Roman P.; Maier, Timm; Spang, Anne; Hiller, Sebastian

doi: 10.1038/s41556-025-01730-wpmid: 40789936

Protein folding in the endoplasmic reticulum (ER) relies on a network of molecular chaperones that facilitates the folding and maturation of client proteins. How the ER chaperones organize in a supramolecular manner to exert their cooperativity has, however, remained unclear. Here we report the discovery of a multichaperone condensate in the ER lumen, which is formed around the chaperone PDIA6 during protein folding homeostasis. The condensates form in a Ca2+-dependent manner and we resolve the underlying mechanism at the atomic and cellular levels. The PDIA6 condensates recruit further chaperones—Hsp70 BiP, J-domain protein ERdj3, disulfide isomerase PDIA1 and Hsp90 Grp94—which constitute some of the essential components of the early folding machinery. The chaperone condensates enhance folding of proteins, such as proinsulin, and prevent protein misfolding in the ER lumen. The PDIA6-scaffolded chaperone condensates hence provide the functional basis for spatial and temporal coordination of the dynamic ER chaperone network.

Rudinskiy, Mikhail; Galli, Carmela; Raimondi, Andrea; Molinari, Maurizio

doi: 10.1038/s41556-025-01728-4pmid: 40760246

Organellophagy receptors control the generation and delivery of portions of their homing organelle to acidic degradative compartments to recycle nutrients, remove toxic or aged macromolecules and remodel the organelle upon physiologic or pathologic cues. How they operate is not understood. Here we show that organellophagy receptors are composed of a membrane-tethering module that controls organellar and suborganellar distribution and by a cytoplasmic intrinsically disordered region (IDR) with net cumulative negative charge that controls organelle fragmentation and displays an LC3-interacting region (LIR). The LIR is required for lysosomal delivery but is dispensable for organelle fragmentation. Endoplasmic reticulum (ER)-phagy receptors’ IDRs trigger DRP1-assisted mitochondrial fragmentation and mitophagy when transplanted at the outer mitochondrial membrane. Mitophagy receptors’ IDRs trigger ER fragmentation and ER-phagy when transplanted at the ER membrane. This offers an interesting example of function conservation on sequence divergency. Our results imply the possibility to control the integrity and activity of intracellular organelles by surface expression of organelle-targeted chimeras composed of an organelle-targeting module and an IDR module with net cumulative negative charge that, if it contains a LIR, eventually tags the organelle portions for lysosomal clearance.