FBR: Sara Sdelci, Ph.D.

Chromatin Beyond Epigenetics: A Metabolic Sponge at the Heart of the Cell

Abstract:

I am an internationally recognised researcher working at the interface of chromatin biology, genome regulation, epigenetics and cellular metabolism. Over the past seven years, I have pioneered the field of nuclear metabolism, demonstrating that metabolic enzymes are not merely cytoplasmic components but active and regulated elements of chromatin biology that directly influence transcription, genome stability, DNA repair, cell identity and therapeutic response in cancer.
My scientific trajectory combines expertise in cell-cycle biology, acquired during my PhD at IRB Barcelona; chromatin-targeted perturbation and chemical biology, developed during my postdoctoral training at CeMM in Vienna; and nuclear metabolism in cancer, which has been the focus of my independent laboratory at the Centre for Genomic Regulation (CRG) since 2019.
During my postdoctoral work at CeMM, I demonstrated that the folate enzyme MTHFD1 localises to chromatin and directly regulates transcription, providing one of the first mechanistic demonstrations that metabolic enzymes can perform local functions directly on chromatin. This work provided the conceptual foundation for my independent research programme at CRG.
Since then, my group has developed an integrative framework combining chromatin proteomics, metabolomics, quantitative imaging, CRISPR screening and computational biology to systematically dissect nuclear metabolic functions. We generated the first chromatome-scale analyses across human tissues and cancer models, identifying approximately 250 chromatin-associated metabolic enzymes and revealing that their association with chromatin is highly dynamic and context dependent. These studies established metabolic enzyme localisation as a widespread and regulated feature of nuclear biology and uncovered functions in transcriptional regulation, chromosome segregation, nuclear energy homeostasis, DNA repair and cancer vulnerability.
More recently, my laboratory has expanded this concept by asking whether chromatin itself can act as a metabolic entity. Chromatin is the largest macromolecular structure in the nucleus and represents an enormous reservoir of metabolite-derived chemical groups. Our work shows that chromatin not only regulates gene expression but can also control metabolite availability by capturing, storing and releasing metabolites in response to specific cellular conditions, including DNA damage and nutrient starvation. This introduces a fundamentally different perspective on chromatin: not only as a platform controlling genome function, but also as an active metabolic player capable of shaping the biochemical environment of the nucleus.
In my seminar, I will discuss this evolution in our understanding of nuclear metabolism, from the discovery of metabolic enzymes acting directly on chromatin to the emerging concept that chromatin itself can function as a dynamic metabolic reservoir.