The genome in space and time comes of age.

DNA sequencing is not enough to grasp the complexity of genome organization and function. The four-dimensional (three in space, one in time) configuration of the eukaryotic nucleus varies with cell types, during development and in diseased tissues, and has to be taken into account to decipher genome function. To study, discuss, and advance in such direction, the International Nucleome Consortium COST Action, funded by the European Union, held its concluding symposium 'The Genome in Space and Time' at the Ionian University in Corfu, Greece, on September 10-13, 2023.

Senescence-associated transcriptional derepression in subtelomeres is determined in a chromosome-end-specific manner.

Aging is a continuous process leading to physiological deterioration with age. One of the factors contributing to aging is telomere shortening, causing alterations in the protein protective complex named shelterin and replicative senescence. Here, we address the question of the link between this telomere shortening and the transcriptional changes occurring in senescent cells. We found that in replicative senescent cells, the genes whose expression escaped repression are enriched in subtelomeres. The shelterin protein TRF2 and the nuclear lamina factor Lamin B1, both downregulated in senescent cells, are involved in the regulation of some but not all of these subtelomeric genes, suggesting complex mechanisms of transcriptional regulation. Indeed, the subtelomeres containing these derepressed genes are enriched in factors of polycomb repression (EZH2 and H3K27me3), insulation (CTCF and MAZ), and cohesion (RAD21 and SMC3) while being associated with the open A-type chromatin compartment. These findings unveil that the subtelomere transcriptome associated with senescence is determined in a chromosome-end-specific manner according to the type of higher-order chromatin structure.

A Pivotal Genetic Program Controlled by Thyroid Hormone during the Maturation of GABAergic Neurons.

Mammalian brain development critically depends on proper thyroid hormone signaling, via the TRα1 nuclear receptor. The downstream mechanisms by which TRα1 impacts brain development are currently unknown. In order to investigate these mechanisms, we used mouse genetics to induce the expression of a dominant-negative mutation of TRα1 specifically in GABAergic neurons, the main inhibitory neurons in the brain. This triggered post-natal epileptic seizures and a profound impairment of GABAergic neuron maturation in several brain regions. Analysis of the transcriptome and TRα1 cistrome in the striatum allowed us to identify a small set of genes, the transcription of which is upregulated by TRα1 in GABAergic neurons and which probably plays an important role during post-natal maturation of the brain. Thus, our results point to GABAergic neurons as direct targets of thyroid hormone during brain development and suggest that many defects seen in hypothyroid brains may be secondary to GABAergic neuron malfunction.

Cancer cells induce immune escape via glycocalyx changes controlled by the telomeric protein TRF2.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with strong immunosuppressive activity that promote tumor growth. In this study, we describe a mechanism by which cancer cells control MDSCs in human cancers by upregulating TRF2, a protein required for telomere stability. Specifically, we showed that the TRF2 upregulation in cancer cells has extratelomeric roles in activating the expression of a network of genes involved in the biosynthesis of heparan sulfate proteoglycan, leading to profound changes in glycocalyx length and stiffness, as revealed by atomic force microscopy. This TRF2-dependent regulation facilitated the recruitment of MDSCs, their activation via the TLR2/MyD88/IL-6/STAT3 pathway leading to the inhibition of natural killer recruitment and cytotoxicity, and ultimately tumor progression and metastasis. The clinical relevance of these findings is supported by our analysis of cancer cohorts, which showed a correlation between high TRF2 expression and MDSC infiltration, which was inversely correlated with overall patient survival.