Biology subjects

Yucel, A. D.

Publications and source records attributed to Yucel, A. D..

3 recordsLinked to original sources

bioRxiv2026

Architectural fragility of gene regulatory networks underlies hematopoietic stem cell aging

Hematopoietic stem and progenitor cell (HSPC) aging contributes to immune dysfunction and age-associated disease, but its regulatory mechanisms remain unclear. Here, we present the largest single-cell multiome atlas of human circulating HSPCs to date, with >380,000 paired RNA and ATAC profiles across 77 donors. Beyond recapitulating established hallmarks of HSPC aging, we reconstructed a high-resolution gene regulatory network and identified a global rewiring in which stress-response and myeloid transcription factor (TF) programs expand, while self-renewal and lymphoid lineage-defining circuitry collapses. We associate these phenotypes with increased cis-regulatory entropy, including elevated transcriptomic noise, weakened peak-to-gene coupling, and chromatin peak broadening. This rewiring is selective, where TFs with GC-rich, promoter-proximal architectures are preserved or amplified, and complex, distal enhancer-dependent identity networks are eroded. Thus, these findings suggest that progressive entropic destabilization of gene regulatory architecture simultaneously drives stress hyperactivation, myeloid bias, and identity loss in aging HSPCs.

genomics↗

bioRxiv2025

Conserved Master Regulators Orchestrate Cellular Reprogramming-Induced Rejuvenation

Partial somatic cell reprogramming has been proposed as a rejuvenation strategy, yet the regulatory architecture orchestrating age reversal remains unclear. Here, we performed gene regulatory network reconstruction across several independent systems to identify master regulators that coordinate reprogramming-induced rejuvenation (RIR). In mouse mesenchymal stem cells, mouse adipocytes, and human fibroblasts undergoing partial reprogramming, we identified genes showing opposite expression dynamics during aging and reprogramming. This approach revealed regulators governing rejuvenation rather than developmental programs. Despite divergent overall network architectures, nine transcription factors converged as master regulators across all three systems, including Ezh2, Parp1, and Brca1. These regulators undergo coordinated reorganization during reprogramming, characterized by broader target engagement and enhanced regulatory coherence. We further demonstrated that direct perturbation of Ezh2 bidirectionally modulates transcriptomic age. Notably, overexpression of a catalytically inactive Ezh2 mutant achieved rejuvenation, suggesting mechanisms distinct from canonical H3K27me3-mediated regulation are involved in RIR. Our findings reveal that cellular rejuvenation is orchestrated by conserved master regulators whose network coordination can be targeted independently of the reprogramming process.

systems biology↗

bioRxiv2020

Near-Physiological-Temperature Serial Femtosecond X-ray Crystallography Reveals Novel Conformations of SARS-CoV-2 Main Protease Active Site for Improved Drug Repurposing

The COVID19 pandemic has resulted in 25+ million reported infections and nearly 850.000 deaths. Research to identify effective therapies for COVID19 includes: i) designing a vaccine as future protection; ii) structure-based drug design; and iii) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determined two apo structures of Severe Acute Respiratory Syndrome CoronaVirus-2 main protease at ambienttemperature by Serial Femtosecond X-ray crystallography. We employed detailed molecular simulations of selected known main protease inhibitors with the structures and compared binding modes and energies. The combined structural biology and molecular modeling studies not only reveal the dynamics of small molecules targeting main protease but will also provide invaluable opportunities for drug repurposing and structure-based drug design studies against SARS-CoV-2. One Sentence SummaryRadiation-damage-free high-resolution SARS-CoV-2 main protease SFX structures obtained at near-physiological-temperature offer invaluable information for immediate drug-repurposing studies for the treatment of COVID19.

biophysics↗