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Abstract HMGA1 is an abundant non-histone chromatin protein that has been implicated in embryonic development, cancer, and cellular senescence, but its specific role remains elusive. Here, we combine functional genomics approaches with graph theory to investigate how HMGA1 genomic deposition controls high-order chromatin networks in an oncogene-induced senescence model. While the direct role of HMGA1 in gene activation has been described previously, we find little evidence to support this. Instead, we show that the heterogeneous linear distribution of HMGA1 drives a specific 3D chromatin organization. HMGA1-dense loci form highly interactive networks, similar to, but independent of, constitutive heterochromatic loci. This, coupled with the exclusion of HMGA1-poor chromatin regions, leads to coordinated gene regulation through the repositioning of genes. In the absence of HMGA1, the whole process is largely reversed, but many regulatory interactions also emerge, amplifying the inflammatory senescence-associated secretory phenotype. Such HMGA1-mediated fine-tuning of gene expression contributes to the heterogeneous nature of senescence at the single-cell level. A similar ‘buffer’ effect of HMGA1 on inflammatory signalling is also detected in lung cancer cells. Our study reveals a mechanism through which HMGA1 modulates chromatin compartmentalization and gene regulation in senescence and beyond.

Multicellular cancer spheroids (MCSs) have emerged as a promising in vitro model that recaptures many features of solid tumours in vivo. To generate cancer spheroids, cells are encapsulated in microgels with high throughput. While the biophysical properties of the cancer spheroid and biomaterial influence the function and behavior of the cells, characterization of these properties remains largely unexplored. In addition, many existing techniques lack control over cell positioning, resulting in the formation of spheroids with large variability. Herein, a versatile, microfluidic platform for generating biocompatible core–shell microgels with uniform cancer spheroids is reported. In addition, an in situ micromechanics measuring device to determine the stiffness of individual artificial cancer niches is used. The power of the microfluidics‐based method by making MCS‐laden microgels to model the interactions of stromal cancer cells is demonstrated. Together with in vivo data, it is shown that tumor cell proliferation is promoted by cocultured fibroblasts.

Senescence is a state of stable proliferative arrest. Here, the authors perform Hi-C analysis on oncogenic RAS-induced senescence in human fibroblasts and characterize the changes in the 3D genome folding associated with the senescence-specific gene expression profile, which are mediated in part through cohesin redistribution on chromatin.

The architectural protein CTCF is a mediator of chromatin conformation, but how CTCF binding to DNA is regulated remains poorly understood. Here the authors find that there is a shared subset of CTCF-bound sites resistant to protein depletion in different cell lines, which are enriched at domain boundaries and chromatin loops constitutive to all cell types.

Notch can drive senescence in a cell contact dependent manner. Here the authors show that NOTCH signalling can modulate chromatin structure autonomously and non-autonomously via the JAG1-NOTCH-HMGA1 interplay during senescence.

Developmental programming links growth in early life with health status in adulthood. Although environmental factors such as maternal diet can influence the growth and adult health status of offspring, the genetic influences on this process are poorly understood. Using the mouse as a model, we identify the imprinted gene Grb10 as a mediator of nutrient supply and demand in the postnatal period. The combined actions of Grb10 expressed in the mother, controlling supply, and Grb10 expressed in the offspring, controlling demand, jointly regulate offspring growth. Furthermore, Grb10 determines the proportions of lean and fat tissue during development, thereby influencing energy homeostasis in the adult. Most strikingly, we show that the development of normal lean/fat proportions depends on the combined effects of Grb10 expressed in the mother, which has the greater effect on offspring adiposity, and Grb10 expressed in the offspring, which influences lean mass. These distinct functions of Grb10 in mother and pup act complementarily, which is consistent with a coadaptation model of imprinting evolution, a model predicted but for which there is limited experimental evidence. In addition, our findings identify Grb10 as a key genetic component of developmental programming, and highlight the need for a better understanding of mother-offspring interactions at the genetic level in predicting adult disease risk.