HerQuLes: Chromatin Dynamics During Cellular Quiescence

Objective

Stem cell pools in our body regulate tissue differentiation in development and remain available during our lifetime for tissue regeneration. These cells exsit in a cell cycle arrested but metabolically active state known as quiescence. Understanding how these cells maintain quiescence and survive over years is fundamental, as its dysregulation impairs regenerative capacity and is linked to ageing, cancer, and degenerative diseases. The HerQuLes project aims to uncover the mechanisms by which key transcription factors establish and maintain cellular quiescence by studying a novel aspect: the chromatin organization during this state. Preliminary data strongly suggest that two transcription factors involved in the stress response play a pivotal role in modulating chromatin compaction during quiescence. However, the mechanisms by which the cell cycle is blocked remains an open question. To address this, I will use the nematode Caenorhabditis elegans, an excellent model for studying quiescence. Upon starvation, larvae enter in L1 arrest state that resembles mammalian stem cell quiescence. As in mammals, chromatin reorganization and stress-related transcriptional responses occur in arrested L1 larvae. Using cutting-edge in vivo tools, I will quantify the degree of chromatin compaction, determine which chromatin regions are bound by the transcription factors and study its physical interaction, all under L1 arrest. Quiescent cells accumulate damage over time, delaying re-entry into the cell cycle and contributing to age-related regenerative decline. European healthcare systems are challenged as the population over 65 is expected to double within the next 35 years, and so do the illnesses associated to ageing. HerQuLes provides mechanistic insights into how quiescence is preserved and opens new targeting avenues to maintain tissue regeneration capacity in older adults, ultimately accelerating healing and reducing the societal and economic burden of ageing-related diseases.