Emerging evidence suggest that gene expression is controlled though the modulation of transcriptional bursting across species. However, the underlying regulatory mechanisms remain largely uncertain. Recent live-imaging studies have reported that transcription factors (TFs) form a cluster at enhancers just prior to gene activation, thereby locally concentrating the active transcription machinery. This process is thought to […]
Generation and validation of a human iPSC-derived TDP-43 knockout model for ALS disease modeling.
Nuclear depletion and cytoplasmic aggregation of TDP-43 occur in ~97% of amyotrophic lateral sclerosis (ALS) cases and disrupt RNA processing through aberrant cryptic exon inclusion. Existing cellular models rely on partial knockdown, TARDBP mutations, or pharmacological stress, each with limitations. Here, we generated homozygous TARDBP-knockout human iPSC lines using CRISPR-Cas9 and differentiated them into spinal […]
Mitochondrial uracil DNA glycosylase contributes to nuclear base excision repair
The universally conserved enzyme uracil-DNA N-glycosylase (UNG) plays a central role in maintaining genome stability. It serves as the initiating factor in uracil base excision repair (UBER) by catalyzing the removal of uracil lesions in genomic DNA, a necessary first step in restoring genome integrity after hydrolytic deamination of cytosine to uracil or misincorporation of […]
The TET-dependent DNA demethylation pathway is the driving force of hematopoiesis
A complex network of signaling cascades regulates the differentiation of hematopoietic stem and progenitor cells (HSPCs) into mature blood cells during hematopoiesis. We demonstrated that DNA demethylation driven by Ten-Eleven Translocation (TET) enzymes controls the activity of multiple of these signaling cascades. This occurs because dozens of genes, essential for the specification (e.g., Gata1, Tcf7, […]
Targeting ZC3H12C improves T cell persistence and antitumor function in adoptive T cell therapy
Adoptive T cell therapy (ACT) has achieved remarkable clinical responses in hematologic malignancies but remains limited by progressive T cell dysfunction under chronic antigen stimulation. Here, we identify ZC3H12C as a conserved feature of dysfunctional T cells and show that its disruption enhances the durability and antitumor activity of engineered T cells. By integrating single-cell […]
In vivo CRISPR-based screen identifies ZC3H12C as a mediator of CAR-T cell dysfunction in solid tumors
CAR-T cell therapy has shown limited efficacy in solid tumors, largely due to T cell dysfunction driven by chronic antigen exposure. To uncover mediators of this dysfunction, we developed an in vivo screening platform using an ovarian xenograft tumor model in which CD28-based CAR-T cells undergo exhaustion leading to tumor escape. Transcriptomic profiling of tumor-infiltrating […]
Nuclear mTOR-Polycomb synergism at developmental gene promoters prone to activation
Pluripotent cells hold the capacity to differentiate into cells with diverse functions, enabling development and regeneration. The balance between local epigenetic repression and maintaining the potential for prompt transcriptional activation supports pluripotency while allowing imminent differentiation. How the activation of developmental pathways is correctly timed in sync with the environment remains poorly understood. Here we […]
In vivo CRISPR-based screen identifies ZC3H12C as a mediator of CAR-T cell dysfunction in solid tumors
CAR-T cell therapy has shown limited efficacy in solid tumors, largely due to T cell dysfunction driven by chronic antigen exposure. To uncover mediators of this dysfunction, we developed an in vivo screening platform using an ovarian xenograft tumor model in which CD28-based CAR-T cells undergo exhaustion leading to tumor escape. Transcriptomic profiling of tumor-infiltrating […]
Nuclear mTOR-Polycomb synergism at developmental gene promoters prone to activation
Pluripotent cells hold the capacity to differentiate into cells with diverse functions, enabling development and regeneration. The balance between local epigenetic repression and maintaining the potential for prompt transcriptional activation supports pluripotency while allowing imminent differentiation. How the activation of developmental pathways is correctly timed in sync with the environment remains poorly understood. Here we […]
Targeting ZC3H12C improves T cell persistence and antitumor function in adoptive T cell therapy
Adoptive T cell therapy (ACT) has achieved remarkable clinical responses in hematologic malignancies but remains limited by progressive T cell dysfunction under chronic antigen stimulation. Here, we identify ZC3H12C as a conserved feature of dysfunctional T cells and show that its disruption enhances the durability and antitumor activity of engineered T cells. By integrating single-cell […]
The Unified Human Virome Database: A toolkit for expanded human virome analysis
Current approaches for computationally analyzing viruses within human microbiomes often rely on databases largely composed of fragmented viral genomes from gastrointestinal samples, limiting identification of viruses exclusively found outside the gastrointestinal tract and analyses requiring high-quality genomes. To address these issues, we created the Unified Human Virome Database (UHVDB), comprising 575,497 high-quality, annotated viral genomes […]
A decrease in specific health-associated commensals is linked to progressive periodontal tissue destruction independent of dysbiotic community profiles
Periodontitis is a chronic inflammatory disease associated with dysbiotic microbial communities that leads to destruction of the tooth-supporting tissues. The transition from host-microbial periodontal homeostasis to disease remains poorly understood. The murine ligature-induced periodontitis model was employed to characterize the temporal dynamics of the subgingival microbiome and host tissue features. Ligatures were placed in C57BL/6N […]