Citations 2
Epigenetic Regulation of Higher-Order Chromatin Structure (HOCS) and Its Implication in Human Diseases
Ladel, Luisa, Sailo, Bethsebie, Das, Paromita, Tan, Wan Ying , Chhoda, Ankit , Tang, Haoyu, Ang-Olson, Olivia, He, Linda, John, Nithyla, Kratz, Jeremy D. , Sharma, Anup , Ahuja, Nita, Ang-Olson, Olivia , Kratz, Jeremy D , Lin, Ethan Samuel , Tang, Haoyu , Ahuja, Nita
Cancers | February 2, 2026 | Volume: 18 | Issue: 3 | Pages: 483
Higher-order chromatin structures (HOCS) are fundamental to genome organization, gene regulation, and cellular homeostasis. This review examines the epigenetic mechanisms shaping HOCS, including DNA methylation, histone modifications, chromatin remodeling, and RNA-based regulatory processes. We also discuss the role of architectural proteins in maintaining chromatin topology while allowing dynamic changes to chromatin structure, thereby influencing gene expression. Growing evidence indicates that disruptions in HOCS contribute to a diverse array of human diseases, including cancer, aging-related disorders, and congenital abnormalities, primarily through aberrant gene regulation. We further discuss the concept of distinct genomic areas, in which specific chromatin regions orchestrate three-dimensional (3D) genome dynamics, positioning them as potential biomarkers and therapeutic targets. By emphasizing chromatin architecture on a global scale rather than at the level of individual genes, this review underscores its emerging relevance to precision medicine. Finally, we synthesize current technical advances, outline future directions for leveraging chromatin topology in disease diagnosis and treatment, and highlight key biological insights to reshape our understanding of genome function.
SPINK1-COL18A1 Crosstalk Shapes Epigenome and Drives Cancer Stemness in Pancreatic Ductal Adenocarcinoma
García-Milian, Rolando , Tang, Haoyu , Iacobuzio-Donahue, Christine A , Sailo, Bethsebie, Shang, Xingbo, Hossan, Md Shahadat , Kratz, Jeremy D. , Das, Paromita , Chhoda, Ankit , Aldo, Paulomi, Liu, He , Robert, Marie E. , Doucette, Saryn , Paris, Timothy J., Kunstman, John W. , Pappou, Emmanouil, Wood, Laura D. , Iacobuzio–Donahue, Christine A. , Wolfgang, Christopher L. , Mazzetto, Mariateresa , He, Linda, Pfaff, Marie, Hoggard, Timothy , Sharma, Anup, Levchenko, Andre , Ahuja, Nita
No container title available | March 7, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with an increasing incidence and extremely dismal prognosis. Discovery and mechanistic understanding of the genetic and epigenetic drivers of PDAC is therefore of critical importance. Here, we uncover serine protease inhibitor Kazal type 1 (SPINK1) as a putative determinant of clinical progression and demonstrate that it can have a non-canonical function as a regulator of epigenomic states of PDAC cells and associated extensive changes in gene expression. We show that SPINK1 expression, which varies in PDAC, is associated with key aggressive phenotypic cancer states and is correlated with the expression of stemness markers both in vitro and in patient samples. Mechanistically, our results strongly suggest that SPINK1 acts through a new signaling axis, by interacting with COL18A1 in the Golgi apparatus, promoting endostatin release and eventually inducing extensive histone H3 modifications. These results reveal a new function of SPINK1 in PDAC and suggest a potential therapeutic route to combat PDAC aggressiveness by targeting the SPINK1-COL18A1-endostatin signaling.