Biology subjects

Guirola, M.

Publications and source records attributed to Guirola, M..

4 recordsLinked to original sources

bioRxiv2024

Nuclear metabolism oscillation during the cell cycle reveals a link between the phosphatidylinositol pathway and histone methylation.

The progression of the cell cycle is regulated by the expression of specific genes and fluctuations in cellular metabolic states. Previous research has employed cell cycle-based transcriptomics, proteomics, and metabolomics analyses to identify cell cycle-dependent changes at the gene expression, protein, and metabolic levels. However, the role of protein compartmentalization in regulating protein function, coupled with evidence that metabolic enzymes can localize to the nucleus and influence chromatin states, suggests that fluctuations in nuclear metabolism may play a role in regulating cell cycle progression. In this study, we developed an approach to resolve chromatin and nuclear changes during the cell cycle in an unbiased and systematic manner. This was achieved by integrating cell cycle fluorescent reporters with chromatin mass spectrometry and cellular imaging. Our investigation focused on metabolic enzymes and revealed that phosphatidylinositol metabolism localizes to the nucleus in a cell cycle-dependent manner. Moreover, disruption of phosphatidylinositol metabolism affects the nuclear distribution of phosphatidylinositol 4,5-bisphosphate, alters the number and morphology of nucleoli, and influences the maintenance of distinct heterochromatin states throughout the cell cycle. Finally, given the established link between phosphatidylinositol metabolism and methionine synthesis, as well as the differential impact observed on distinct histone marks when phosphatidylinositol metabolism is perturbed, we proposed that distinct pools of methionine may be involved in the maintenance of histone marks that decorate heterochromatin in a cell cycle-dependent manner.

cell biology↗

bioRxiv2023

Comprehensive chromatome profiling identifies metabolic enzymes on chromatin in healthy and cancer cells

Metabolic and epigenetic rewiring are widely considered hallmarks of cancer, with emerging evidence of crosstalk between them. Anecdotal evidence of metabolic enzymes moonlighting in the chromatin environment has suggested how this crosstalk might be facilitated, but the extent of nuclear relocalization of metabolic enzymes remains elusive. Here, we provide a comprehensive chromatin proteomics resource across cancer lineages as well as healthy samples and demonstrate that metabolic enzyme moonlighting on chromatin is widespread across tissues and pathways. We show that the abundance of metabolic enzymes on chromatin is tissue-specific, with oxidative phosphorylation proteins depleted in lung cancer samples, perhaps suggesting an interplay between cell identity and nuclear metabolism. Finally, we explore metabolic functions in the chromatin environment and show that one-carbon folate enzymes are associated with DNA damage and repair processes, providing an approach to explore non-canonical functions of metabolic enzymes.

cancer biology↗

bioRxiv2022

The BRD4S-LOXL2-MED1 interaction at the forefront of cell cycle transcriptional control in triple-negative breast cancer

Triple-negative breast cancer often develops resistance to single-agent treatments, which can be circumvented with targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 cooperate to reduce triple-negative breast cancer proliferation in vitro and in vivo. Mechanistically, we reveal that LOXL2 interacts in the nucleus with the short isoform of BRD4 and MED1 to control cell cycle progression at the gene expression level via sustaining the formation of BRD4-MED1 nuclear transcriptional foci. Indeed, the pharmacological or transcriptional repression of LOXL2 provokes downregulation of cell cycle gene expression, G1-S cell cycle arrest, and loss of BRD4-MED1 foci. Our results indicate that the BRD4S-LOXL2-MED1 interaction is fundamental for the proliferation of triple-negative breast cancer. Therefore, targeting such interaction holds potential for the development of novel triple-negative breast cancer therapies.

cancer biology↗

bioRxiv2019

PRDM14 controls X-chromosomal and global epigenetic reprogramming of H3K27me3 in migrating mouse primordial germ cells

In order to prepare the genome for gametogenesis, primordial germ cells (PGCs) undergo extensive epigenetic reprogramming during migration towards the gonads in mammalian embryos. This includes changes on a genome-wide scale and additionally in females the remodeling of the inactive X-chromosome to enable X-chromosome reactivation (XCR). However, if global and X-chromosomal remodeling are related and which factors are important is unknown. Here we identify the germ cell determinant PR-domain containing protein 14 (PRDM14) as the first known factor that is instrumental for both global and X-chromosomal reprogramming in migrating mouse PGCs. We find that global upregulation of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark is PRDM14 dosage-dependent in PGCs of both sexes. When focusing on XCR, we observed that PRDM14 is required for removal of H3K27me3 from the inactive X-chromosome. Furthermore we show that global and X-chromosomal H3K27me3 reprogramming are functionally separable, despite their common regulation by PRDM14. Thereby we provide mechanistic insight and spatiotemporal resolution to the remodeling of the epigenome during mouse PGC migration and link epigenetic reprogramming to its developmental context in vivo.

developmental biology↗