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Copy number variation (CNV) refers to the number of copies of a specific sequence in a genome and is a type of chromatin structural variation. The development of the Hi‐C technique has empowered research on the spatial structure of chromatins by capturing interactions between DNA fragments. We utilized machine‐learning methods including the linear transformation model and graph convolutional network (GCN) to detect CNV events from Hi‐C data and reveal how CNV is related to three‐dimensional interactions between genomic fragments in terms of the one‐dimensional read count signal and features of the chromatin structure. The experimental results demonstrated a specific linear relation between the Hi‐C read count and CNV for each chromosome that can be well qualified by the linear transformation model. In addition, the GCN‐based model could accurately extract features of the spatial structure from Hi‐C data and infer the corresponding CNV across different chromosomes in a cancer cell line. We performed a series of experiments including dimension reduction, transfer learning, and Hi‐C data perturbation to comprehensively evaluate the utility and robustness of the GCN‐based model. This work can provide a benchmark for using machine learning to infer CNV from Hi‐C data and serves as a necessary foundation for deeper understanding of the relationship between Hi‐C data and CNV. [ABSTRACT FROM AUTHOR]

[CD8.sup.+] exhausted T cells ([T.sub.ex]) are heterogeneous. PD-1 inhibitors reinvigorate progenitor [T.sub.ex], which subsequently differentiate into irresponsive terminal [T.sub.ex]. The ability to maintain a capacity for durable proliferation of progenitor [T.sub.ex] is important, but the mechanism remains unclear. Here, we showed [CD8.sup.+] progenitor [T.sub.ex] pretreated with decitabine, a low-dose DNA demethylating agent, had enhanced proliferation and effector function against tumors after anti-PD-1 treatment in vitro. Treatment with decitabine plus anti-PD-1 promoted the activation and expansion of tumor-infiltrated [CD8.sup.+] progenitor T and efficiently suppressed tumor growth in multiple tumor models. Transcriptional and epigenetic profiling of tumor-infiltrated T cells demonstrated that the combination of decitabine plus anti-PD-1 markedly elevated the clonal expansion and cytolytic activity of progenitor [T.sub.ex] compared with anti-PD-1 monotherapy and restrained [CD8.sup.+] T cell terminal differentiation. Strikingly, decitabine plus anti-PD-1 sustained the expression and activity of the AP-1 transcription factor JunD, which was reduced following PD-1 blockade therapy. Downregulation of JunD repressed T cell proliferation, and activation of JNK/AP-1 signaling in [CD8.sup.+] T cells enhanced the antitumor capacity of PD-1 inhibitors. Together, epigenetic agents remodel [CD8.sup.+] progenitor [T.sub.ex] populations and improve responsiveness to anti-PD-1 therapy., Introduction Persistent antigen stimulation causes [CD8.sup.+] T cells to become functionally exhausted, with upregulation of programmed death-1 (PD-1) and other inhibitory receptors, perturbed proliferation and cytokine secretion, impaired immune memory, [...]

Advances in chromatin mapping have exposed the complex chromatin hierarchical organization in mammals, including topologically associating domains (TADs) and their substructures, yet the functional implications of this hierarchy in gene regulation and disease progression are not fully elucidated. Our study delves into the phenomenon of shared TAD boundaries, which are pivotal in maintaining the hierarchical chromatin structure and regulating gene activity. By integrating high-resolution Hi-C data, chromatin accessibility, and DNA double-strand breaks (DSBs) data from various cell lines, we systematically explore the complex regulatory landscape at high-level TAD boundaries. Our findings indicate that these boundaries are not only key architectural elements but also vibrant hubs, enriched with functionally crucial genes and complex transcription factor binding site–clustered regions. Moreover, they exhibit a pronounced enrichment of DSBs, suggesting a nuanced interplay between transcriptional regulation and genomic stability. Our research provides novel insights into the intricate relationship between the 3D genome structure, gene regulation, and DNA repair mechanisms, highlighting the role of shared TAD boundaries in maintaining genomic integrity and resilience against perturbations. The implications of our findings extend to understanding the complexities of genomic diseases and open new avenues for therapeutic interventions targeting the structural and functional integrity of TAD boundaries. [ABSTRACT FROM AUTHOR]