Biology subjects

Eliazer, S.

Publications and source records attributed to Eliazer, S..

3 recordsLinked to original sources

bioRxiv2026

Mechanical Signaling Regulates DNA Methylation to Maintain Muscle Stem Cell Quiescence

Skeletal muscle stem cells (MuSCs) reside within a mechanically dynamic niche where they integrate biophysical and biochemical cues to maintain quiescence. Here, we show that substrate stiffness and RhoA-dependent signaling regulate MuSC fate. MuSCs cultured on soft matrices or depleted of RhoA exhibit altered morphology, diminished actomyosin organization, and undergo premature activation. Loss of RhoA reshapes the DNA methylation landscape, leading to widespread changes in gene expression and alternative splicing. Dnmt3a was among the genes transcriptionally downregulated following loss of RhoA signaling. Mechanistically, RhoA maintains Dnmt3a expression by promoting SP1 occupancy at its promoter. Importantly, loss of Dnmt3a in quiescent MuSCs is sufficient to drive activation, identifying Dnmt3a as a key epigenetic effector downstream of mechanical signaling. Together, these findings define a mechanotransduction-epigenetic axis in which RhoA maintains stem cell quiescence by preserving DNA methylation programs through Dnmt3A.

cell biology↗

bioRxiv2025

The Integrated Stress Response Pathway Improves Aged Murine Muscle Stem Cell Activation and in vivo Regeneration.

For efficient regeneration, muscle stem cells (MuSCs) transition out of quiescence through a series of progressively more activated states. During MuSC aging, transition through the earliest steps is the slowest and delayed, with the molecular regulators that govern this transition not well characterized. By analyzing the dynamic changes of MuSCs at the molecular (scRNA-Seq and Cell Painting) and phenotypic (heteromotility) level at single cell resolution we found that the Integrated Stress Response (ISR) Pathway is a critical regulator of MuSC transition states. Aged MuSCs have increased baseline ISR activity in quiescence that does not increase during activation to levels observed in adult MuSCs. Rapid and transient pharmacological ISR activation in vitro was sufficient to increase aged MuSC activation rate and migratory behavior as well as alter the transcriptional states toward a younger phenotype. ISR activation also improved aged MuSC potency and aged mouse muscle regeneration in vivo. Therefore, pharmacological activation of the ISR has therapeutic potential to improve MuSC function and skeletal muscle repair during aging.

cell biology↗

bioRxiv2020

Spatial Heterogeneity of Delta-Like 4 Within a Multinucleated Niche Cell Maintains Muscle Stem Cell Diversity

The quiescent muscle stem cell (QSC) pool is heterogeneous and generally characterized by the presence and levels of intrinsic myogenic transcription factors. Whether extrinsic factors maintain the diversity of states across the QSC pool remains unknown. The muscle fiber is a multinucleated syncytium that serves as a niche to QSCs, raising the possibility that the muscle fiber regulates the diversity of states across the QSC pool. Here we show that the muscle fiber maintains a continuum of quiescent states, through a gradient of Notch ligand, Dll4, produced by the fiber and captured by QSCs. The abundance of Dll4 captured by the QSC correlates with levels of the SC identity gene, Pax7. Niche-specific loss of Dll4 decreases QSC diversity and shifts the continuum, towards more proliferative and committed states. We reveal that fiber-derived Mindbomb1 (Mib1), an E3 ubiquitin ligase activates Dll4 and controls the spatial localization of Dll4. In response to injury, with a Dll4-replenished niche, the normal continuum and diversity of SC pool is restored, demonstrating bi-directionality within the SC continuum. Our data shows that a post-translational mechanism controls spatial heterogeneity of Notch ligands in a multinucleated niche cell to maintain a continuum of diverse states within the SC pool during tissue homeostasis.

cell biology↗