Dijkwel, Y. | Search bioRxiv

bioRxiv2026

HP1α depletion and TGFβ activation exert antagonistic effects on 3D genome organization

The three-dimensional (3D) organization of the human genome plays a critical role in regulating gene expression and is frequently disrupted in cancer. However, how key factors like Heterochromatin Protein 1 alpha (HP1) and Transforming Growth Factor beta (TGF{beta}) remodel this architecture to drive tumorigenesis remains poorly understood. We investigated the effects of HP1 knockdown and TGF{beta} treatment on higher-order chromatin structure and gene expression in human mammary epithelial cells. Our findings reveal that HP1 depletion and TGF{beta} stimulation exert distinct and opposing effects on genome compartmentalization and sub compartmentalization. HP1 knockdown drives a genome-wide shift of chromatin from transcriptionally inactive B compartments to active A compartments. This is accompanied by a stepwise redistribution of A subcompartments toward the most transcriptionally active state (A3), and the upregulation of oncogenic genes involved in EMT and proliferation. In contrast, TGF{beta} treatment promotes chromatin compaction, increases the proportion of B compartments, and drives a stepwise reduction in active A subcompartments. Our results highlight the differential roles of HP1 and TGF{beta} in shaping the 3D genome and underscore how precise, stepwise architectural changes contribute to malignant transformation. This study provides critical insight into how chromatin architecture acts as a regulatory layer in breast cancer development. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/705282v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@11c7475org.highwire.dtl.DTLVardef@121b305org.highwire.dtl.DTLVardef@1704b64org.highwire.dtl.DTLVardef@1659c34_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

genomics↗

bioRxiv2023

Multi-level 3D genome organization deteriorates during breast cancer progression

Breast cancer entails intricate alterations in genome organization and expression. However, how three-dimensional (3D) chromatin structure changes in the progression from a normal to a breast cancer malignant state remains unknown. To address this, we conducted an analysis combining Hi-C data with lamina-associated domains (LADs), epigenomic marks, and gene expression in an in vitro model of breast cancer progression. Our results reveal that while the fundamental properties of topologically associating domains (TADs) are overall maintained, significant changes occur in the organization of compartments and subcompartments. These changes are closely correlated with alterations in the expression of oncogenic genes. We also observe a restructuring of TAD-TAD interactions, coinciding with a loss of spatial compartmentalization and radial positioning of the 3D genome. Notably, we identify a previously unrecognized interchromosomal insertion event, wherein a locus on chromosome 8 housing the MYC oncogene is inserted into a highly active subcompartment on chromosome 10. This insertion is accompanied by the formation of de novo enhancer contacts and activation of MYC, illustrating how structural genomic variants can alter the 3D genome to drive oncogenic states. In summary, our findings provide evidence for the loss of genome organization at multiple scales during breast cancer progression revealing novel relationships between genome 3D structure and oncogenic processes.

genomics↗