Biology subjects

Galun, E.

Publications and source records attributed to Galun, E..

3 recordsLinked to original sources

bioRxiv2026

Bidirectional modulation of aging-associated cellular phenotypes by mitochondrial genome replacement

Mitochondrial dysfunction is a hallmark of cellular aging, but whether age-associated cellular decline can be functionally reversed remains unclear. Here, we applied mitochondrial genome replacement to replicative senescent fibroblasts and aged T cells derived from mice and humans. In senescent fibroblasts, replacement with mitochondria from young cells extended proliferative lifespan, whereas replacement with aged mitochondria accelerated proliferative decline, indicating bidirectional modulation of aging-associated phenotypes. In aged mouse T cells, mitochondrial genome replacement restored proliferative capacity and significantly enhanced antitumor activity following adoptive transfer into tumor-bearing mice. Similarly, mitochondrial genome replacement in aged human T cells enhanced cytokine production and shifted the transcriptomic programs toward a more youthful state. Collectively, these findings identify mitochondrial genetic integrity as a functional regulator of aging-associated cellular states and support the emerging view that mitochondria actively influence cellular aging trajectories.

Cell Biology↗

bioRxiv2020

Peripheral sgp130-mediated trans-signaling blockade induces obesity and insulin resistance in mice via PPARα suppression

IL-6 signaling via its receptor (IL-6R) and co-receptor (gp130) performs multiple roles in regulating metabolic homeostasis. However, gp130 is also expressed systemically in a soluble form (sgp130), which limits soluble IL-6 receptor (sIL-6R)-mediated signaling - also called trans-signaling. Here we find that transgenic peripheral sgp130-mediated trans-signaling blockade induces mature-onset obesity, while differentially affecting age-dependent behavioral determinants of energy expenditure. In youth, trans-signaling blockade increases feeding associated with reduced leptin sensitivity but increases energy expenditure to maintain metabolic balance. In aging, reduced physical activity predisposes mice to adiposity, adipose tissue macrophage recruitment, hepatosteatosis, hyperglycemia, and insulin resistance. Mechanistically, trans-signaling blockade reduces hepatic Stat3 phosphorylation and suppresses PPAR, associated with miR-21 upregulation, while pharmacological activation of PPAR prevents obesity and hepatosteatosis, and rescues insulin sensitivity. Together these experiments reveal a role for peripheral IL-6 trans-signaling in metabolic homeostasis and provide clinical significance to elevated sgp130 levels found in some obese and diabetic patients.

physiology↗

bioRxiv2019

ChIP-seq of plasma cell-free nucleosomes identifies cell-of-origin gene expression programs

AbstractGenomic DNA is packed by histone proteins that carry a multitude of post-translational modifications that reflect cellular transcriptional state. Cell-free DNA (cfDNA) is derived from fragmented chromatin in dying cells, and as such it retains the histones markings present in the cells of origin. Here, we pioneer chromatin immunoprecipitation followed by sequencing of cell-free nucleosomes (cfChIP-seq) carrying active chromatin marks. Our results show that cfChIP-seq provides multidimensional epigenetic information that recapitulates the epigenetic and transcriptional landscape in the cells of origin. We applied cfChIP-seq to 268 samples including samples from patients with heart and liver pathologies, and 135 samples from 56 metastatic CRC patients. We show that cfChIP-seq can detect pathology-related transcriptional changes at the site of the disease, beyond the information on tissue of origin. In CRC patients we detect clinically-relevant, and patient-specific information, including transcriptionally active HER2 amplifications. cfChIP-seq provides genome-wide information and requires low sequencing depth. Altogether, we establish cell-free chromatin immunoprecipitation as an exciting modality with potential for diagnosis and interrogation of physiological and pathological processes using a simple blood test. One Sentence SummaryChIP-seq of plasma-circulating nucleosomes (cfChIP-seq) from a simple blood test provides detailed information about gene expression programs in human organs, and cancer.

molecular biology↗