bims-caglex 2026-02-22 papers

J Vis Exp. 2026 Jan 30.

Measuring Single-Cell Aging with an Imaging-based Biomarker of Chromatin and Epigenetic Aging.

Kenta Ninomiya, Krystal Ortaleza, Josue A Lopez, Alexey V Terskikh.

To advance personalized healthcare and assess potential rejuvenation strategies, biomarkers reflecting biological age are crucial. We have introduced imaging-based chromatin and epigenetic age (ImAge), an imaging-based biomarker derived from the spatial organization of chromatin and epigenetic marks within single nuclei, capturing intrinsic age-related changes. ImAge effectively captures and quantifies the effects of interventions modulating biological age, showing sensitivity through significant decreases following rejuvenation strategies (such as caloric restriction and partial reprogramming through transient Oct4, Sox2, Klf4, and Myc (OSKM) expression) and increases after treatments like chemotherapy. Furthermore, lower ImAge correlated with higher locomotor activity, suggesting it captures functional improvements alongside biological age reversal, offering a promising single-cell tool to evaluate longevity interventions. As ImAge is an integrative method requiring good-quality imaging and meticulous computational analysis, we aim to provide thorough guidance to extract and validate it. This comprehensive protocol will detail the workflow for both wet laboratory procedures (sample preparation and imaging) and the proper utilization of our open-sourced computational pipeline (environment setup and processing of the imaging data) to extract and validate ImAge.

DOI: https://doi.org/10.3791/69057

Stem Cell Reports. 2026 Feb 19. pii: S2213-6711(26)00032-9. [Epub ahead of print] 102821

Post-replicative chromatin accessibility predicts cell fate change.

Teresa E Knudsen, Nazaret Reverón-Gómez, Alva Biran, Nicolas Alcaraz, Sihem Cheloufi, Konrad Hochedlinger, Joshua M Brickman, Anja Groth, Kathleen R Stewart-Morgan.

It has long been hypothesized that DNA replication is important in reconfiguring the chromatin landscape during cell identity changes in development, disease, and reprogramming. There is now a large body of work showing that DNA replication indeed alters chromatin structure and composition, but a function for these changes has remained elusive. Using replication-coupled ATAC-seq in differentiating embryonic stem cells and reprogramming mouse embryonic fibroblasts, we profiled replicated and unreplicated chromatin and observed de novo chromatin opening specifically in the replicated fraction. These opening events created an accessibility landscape similar to that seen in later time points, and binding of lineage-specific transcription factors was enriched in these regions. Opening of these regions was impaired when replication was inhibited during early reprogramming. This work bridges the gap between replication-induced structural chromatin changes and functional consequences by demonstrating that replication facilitates a "window of opportunity" that advances the chromatin landscape during cell identity change.

Keywords: DNA replication; cell fate change; chromatin accessibility; differentiation; repli-ATAC-seq; reprogramming; transcription factor binding

DOI: https://doi.org/10.1016/j.stemcr.2026.102821

Stem Cells Transl Med. 2026 Jan 26. pii: szaf072. [Epub ahead of print]15(2):

The harmonies played by miR-302/367 cluster in pluripotency, reprogramming, and rejuvenation.

Melika Zamanian, Sharif Moradi, Hossein Baharvand.

The conserved, pluripotency-associated miR-302/367 cluster coordinates cell fate and aging via epigenetic, cell cycle, and signaling regulation. Highly expressed in pluripotent stem cells and silenced during differentiation, it promotes efficient somatic cell reprogramming by suppressing senescence mediators (eg, p16INK4a, p21) and replacing oncogenes such as c-Myc to minimize tumorigenic risks. Beyond pluripotency, the miR-302/367 cluster reduces oxidative stress, mitochondrial dysfunction, and fibrosis, indicating therapeutic potential in age-associated conditions such as neurodegenerative, ocular, and fibrotic diseases. This review summarizes the dual ability of miR-302/367 cluster in promoting cell state transitions and transiently resetting cellular aging to enable healthspan extension. We critically discuss the pivotal role of miR-302/367 cluster in pluripotency and reprogramming while countering aging hallmarks. Finally, we explore how combining single-miRNA therapeutics with clinically viable delivery systems (lipid nanoparticles and extracellular vesicles) can link cellular reprogramming with targeted rejuvenation therapies.

Keywords: ESC; cell fate conversion; iPSC; microRNA; regenerative medicine; senescence

DOI: https://doi.org/10.1093/stcltm/szaf072

Nat Struct Mol Biol. 2026 Feb 20.

Global reorganization of genome architecture at the transition to gametogenesis.

Tien-Chi Huang, Maria Rigau, Valeriya Malysheva, Chad Whilding, Stella Siciliani, Jingyu Li, Irina Balaguer Balsells, Pavel Artemov, Camille Dion, Mikhail Spivakov, Juan M Vaquerizas, Petra Hajkova.

Global epigenetic resetting in the gonadal primordial germ cells (PGCs) enables transition from early PGCs to gametogenesis and eventual restoring of totipotency after fertilization. This reprogramming process involves global DNA demethylation, changes in nuclear morphology and remodeling of repressive histone modifications. Here, using combined cytological and Hi-C-based methods, we reveal that, following the epigenetic reprogramming and concomitant with their commitment to gametogenesis, premeiotic gonadal germ cells display a distinct chromosome and genome architecture. This involves separation of individual chromosomes, anchoring of centromeres at the nuclear periphery, reduction in interchromosome interactions and disentangling of chromosome ends. Furthermore, genome-wide contact mapping documents remodeling of the three-dimensional (3D) genome architecture across all observable levels, including disruption of topologically associating domains (TADs), loss of detectable loops and reduced active-active compartment interactions. We further show that the diminished TADs correlate with the reduced levels of CCCTC-binding factor, thus providing an in vivo physiological model to understand genome folding principles. Lastly, we show that PGC-like cells, derived from embryonic stem cells, do not exhibit the same chromatin organization as embryonic germ cells. Collectively, our findings uncover the existence of a distinct chromatin architecture in premeiotic male and female gonadal germ cells and show that, alongside global DNA demethylation, the germline epigenetic reprogramming involves erasure of memory at the genome architectural level through profound reorganization of the 3D genome.

DOI: https://doi.org/10.1038/s41594-026-01747-1