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