Biology subjects

Estrada, M. E.

Publications and source records attributed to Estrada, M. E..

3 recordsLinked to original sources

bioRxiv2026

Protein-driven colloid-osmotic pressure controls nuclear size, organization, and function

The size of the cell nucleus is tightly controlled and changes in nuclear size correlate with altered nuclear function during development, cell differentiation and senescence. How nuclear size is regulated and whether changes thereof are functionally relevant remains unclear. Here, we demonstrate that nuclear size is determined by the osmotic pressure exerted by proteins in yeast, human cells and frog egg extracts. The biophysical model we establish solves the long-standing question of how the nuclear-to-cytoplasmic ratio is regulated and maintained. Furthermore, altering protein-driven osmotic balance modulates the physical properties of the nucleus, with a direct effect on chromatin organization and gene expression: Nuclear enlargement causes the dissolution of heterochromatic structures and derepression of subtelomeres and transposons, while simultaneously down-regulating highly expressed housekeeping genes. Importantly, these global transcriptional patterns closely mimic the gene expression changes that occur as yeast, human, and drosophila cells enlarge. Importantly, artificially forcing nuclear compression is sufficient to reverse these size-associated expression changes. Together, our findings provide a quantitative, mechanistic explanation for the coupling between the size of the nucleus and the cell, and they establish nuclear size as a modulator of chromatin organization and gene expression.

cell biology↗

bioRxiv2026

Non-coding DNA dictates cell size and impairs fitness by sequestering RNA polymerase

Genome size varies greatly between organisms, largely because of varying amounts of non-coding DNA. In multicellular organisms, non-coding DNA can make up 99% of the genome, while unicellular organisms have little non-coding information. How non-coding DNA affects cell physiology remains a key question in understanding genome evolution. Here, we developed a system to conditionally accumulate large amounts of non-coding DNA in budding yeast cells. We show that cells adjust their size to DNA content, regardless of its coding capacity. The direct coupling of cell size to DNA content occurs independently of the known cell size control and DNA damage checkpoints and explains the long-observed correlation between cell size, genome size, and ploidy. Furthermore, we find that excess non-functional DNA compromises cell fitness and renders them hypersensitive to transcription inhibitors. Providing a potential explanation for this observation, we uncover that the transcription machinery binds non-coding DNA and is titrated away from coding genes, resulting in a reduced overall concentration of yeast transcripts. We propose that the inability of yeast to repress non-coding DNA increases the fitness cost associated with non-functional DNA and prevents its expansion in the yeast genome on evolutionary timescales.

cell biology↗

bioRxiv2022

Cell cycle progression defects and impaired DNA damage signaling drive enlarged cells into senescence

Cellular senescence plays an important role in development, ageing, and cancer biology. Senescence is associated with increased cell size, but how this contributes to permanent cell cycle exit is poorly understood. Using reversible G1 cell cycle arrests combined with growth rate modulation, we examined the effects of excess cell size on cell cycle progression in human cells. We show that enlarged cells paradoxically have high levels of G1/S regulators relative to cells that were maintained at physiological size but also induce p21, which restrains cell cycle entry and protects against cell division failure. Furthermore, we find that enlarged cells bear an increased propensity for DNA breakage and concomitant DNA damage repair defects that are established during G1. Based on these observations, we propose that impaired DNA damage repair pathways prime enlarged cells for persistent replication-acquired damage, ultimately leading to catastrophic cell cycle failure and permanent cell cycle exit.

cell biology↗