Dynamic changes in Lamin B1 and heterochromatin coincide with chromatin condensation during human erythropoiesis - Genome Biology

Background Chromatin condensation, accompanied by pronounced nuclear shrinkage, is a pivotal step in terminal erythroid differentiation and is essential for enucleation. However, the precise timing and molecular mechanisms initiating this process remain poorly understood, particularly as global transcriptional repression occurs only at the orthochromatic erythroblast stage. Results Here we perform a comprehensive analysis of three-dimensional chromatin architecture dynamics during erythropoiesis using integrative epigenomic and imaging approaches. We demonstrate that chromatin condensation begins earlier than previously recognized, initiating at the late basophilic erythroblast stage. Mechanistically, these intergenic regions were tethered to the nuclear lamina (predominantly heterochromatic) and enriched in H3K9me3, which drive large-scale chromatin compaction. Furthermore, we find that the redistribution of H3K9me3 and dynamic remodeling of Lamin B1 are critical for this structural transition, directly impacting erythroid maturation. Conclusions These findings reveal a previously unrecognized regulatory axis linking H3K9me3 and chromatin-lamina interactions, providing novel insights into the spatial and temporal control of chromatin organization during erythroid development.

Nucleus confinement within concave microcavities modulates nuclear morphology, subnuclear dynamics and mechanotransduction in human osteosarcoma cells

Cells dynamically integrate biochemical and mechanical signals arising from their surrounding microenvironment to regulate morphology and behavior. Mechanical cues like matrix stiffness, surface topography, and other physical perturbations modify biophysical signals. Surface topography, particularly curvature regime acts as any important mediator of mechanotransduction by coordinating cytoskeletal organization, focal adhesion dynamics, and nuclear architecture. Curvature response has been demonstrated at broader length scales and influences nucleus shape change, chromatin organization, and gene regulation, positioning the nucleus as an active mechanosensitive hub. Bone tissue consists of a curvature-rich microenvironment defined by a trabecular architecture at tissue scale and by resorption cavities such as Howship lacunae at cellular scale. While these geometries are essential for homeostasis, their role in pathological context remains poorly understood. Osteosarcoma develops within this mechanically complex multiscale architecture, but how bone-inspired curvature regulates nuclear behavior and signaling in osteosarcoma cells remains unclear. Here, we engineered three-dimensional (3D) concave hemispherical substrates that recapitulate nucleus-scale bone micro-curvature and assessed their effects on human SaOS-2 osteosarcoma cells. In comparison with flat surfaces, concave confinement resulted in pronounced nuclear rounding and softening, accompanied by Lamin A/C reorganization and increased heterochromatin compaction marked by H3K9me3. Curvature-driven nuclear remodeling selectively modulated Hippo pathway main effectors YAP/TAZ without activating NF-kB mediated canonical inflammatory responses. Furthermore, cells maintained overall viability without elevated pathological DNA damage or apoptotic signaling, suggesting an adaptive, damage-tolerant nuclear response. Overall, these findings indicate nucleus-scale curvature as a critical regulator within the bone microenvironment that governs nuclear modelling and mechanosensitive signaling in osteosarcoma cells. Incorporating physiologically relevant geometry into in vitro models establishes new insight into cancer microenvironment crosstalk and highlights nuclear interior and outer architecture as a key regulator of tumor cell behavior. ### Competing Interest Statement The authors have declared no competing interest. Agence Nationale de la Recherche, https://ror.org/00rbzpz17, ANR-22-CE45-0010.

Correction: MMP-3 cleavage of Lamin A induces pro-migratory nuclear deformity, nucleophagy, and their autophagic secretion with extracellular vesicles in metastatic cancer - Cell Communication and Signaling

The zinc metalloprotease ZMPSTE24 binds a distinct topological isoform of the tail-anchored protein IFITM3

The biogenesis of integral membrane proteins is complex, as revealed by an ever-growing number of cellular components shown to be dedicated to the insertion, folding, surveillance, rectification, or quality control of specific client membrane proteins. The zinc metalloprotease ZMPSTE24 and its yeast homolog Ste24 have well-established roles in the proteolytic maturation of the nuclear scaffold protein lamin A and yeast a-factor, respectively. Additionally, Ste24 has been implicated through yeast genetic screens in a variety of membrane processes, including ER- associated degradation (ERAD), Sec61 translocon “unclogging,” the unfolded protein response (UPR), and potentially as a membrane protein topology determinant. Recently, an interaction was demonstrated between ZMPSTE24 and the antiviral interferon induced transmembrane protein IFITM3, although the functional significance of this interaction is not well-understood. IFITM3 is a tail-anchored protein with a cytoplasmic N-terminus, a single transmembrane span, and a lumenal/exocellular C-terminus. Here, we show that a catalytic-dead version of ZMPSTE24, ZMPSTE24E336A, exhibits enhanced binding to IFITM3, and this bound species of IFITM3 is hypo-palmitoylated. Using a split fluorescence topology reporter, we demonstrate that ZMPSTE24E336A “traps” and stabilizes a subpopulation of IFITM3 molecules with an atypical membrane topology, whose C-terminus is cytosolic instead of lumenal. Such inverted forms of IFITM3 are also detected in the presence of ERAD inhibitors when ZMPSTE24E336A is absent. We hypothesize the ZMPSTE24E336A trap mutant reveals a normally transient isoform of IFITM3 whose transmembrane span is inverted and that ZMPSTE24 is involved in the quality control of IFITM3 topology, either inverting, correcting or assisting in removal of aberrant IFITM3 molecules. ### Competing Interest Statement The authors have declared no competing interest. NIH Common Fund, https://ror.org/001d55x84, R35GM127073

Inter–lamin interactions control meshwork topology in a polymer–gel model of nuclear lamina

The nuclear lamina, composed of supramolecular structures of lamin proteins, is a two–dimensional protein meshwork that preserves the structural integrity, elasticity, and morphology of the nucleus. Lamins—A/C–type and B–type—assemble into dynamic, individual but interacting networks with distinct structural properties. Lamina meshwork assembly can be disrupted by lamin mutations in diseases known as laminopathies. Despite extensive experimental insights, the biophysical mechanisms that alter the lamina meshwork topology in health and disease remain relatively poorly understood. In this study, we develop a coarse-grained molecular dynamics (MD) model of lamina self–assembly, where lamin dimers are modeled as semiflexible polymers confined within an elastic nuclear shell. By systematically interrogating inter–lamin and lamin–shell association affinities, our simulations reproduce a plethora of experimentally observed lamina architectures, from lattice–like to fibrous meshwork topologies. This elucidates how the interplay between inter–lamin and lamin–nuclear envelope interactions can shape the nuclear lamina. Importantly, inter–lamin interactions can cause a heterogeneous distribution of lamins on the surface and result in large, lamin–free surface domains at sufficiently low lamin-shell affinities. Furthermore, paracrystalline lamin sheets form with increasing propensity for parallel lamin alignment, in addition to the canonical, sticky terminal groups. Overall, our integrative MD and network analysis provide the first explicit polymer physics model of the lamina and demonstrate how lamin interactions may affect the mesoscale architecture of the lamina in disease. ### Competing Interest Statement The authors have declared no competing interest. Scientific and Technological Research Council of Turkey, https://ror.org/04w9kkr77, 124N935

Inter–lamin interactions control meshwork topology in a polymer–gel model of nuclear lamina

The nuclear lamina, composed of supramolecular structures of lamin proteins, is a two–dimensional protein meshwork that preserves the structural integrity, elasticity, and morphology of the nucleus. Lamins—A/C–type and B–type—assemble into dynamic, individual but interacting networks with distinct structural properties. Lamina meshwork assembly can be disrupted by lamin mutations in diseases known as laminopathies. Despite extensive experimental insights, the biophysical mechanisms that alter the lamina meshwork topology in health and disease remain relatively poorly understood. In this study, we develop a coarse-grained molecular dynamics (MD) model of lamina self–assembly, where lamin dimers are modeled as semiflexible polymers confined within an elastic nuclear shell. By systematically interrogating inter–lamin and lamin–shell association affinities, our simulations reproduce a plethora of experimentally observed lamina architectures, from lattice–like to fibrous meshwork topologies. This elucidates how the interplay between inter–lamin and lamin–nuclear envelope interactions can shape the nuclear lamina. Importantly, inter–lamin interactions can cause a heterogeneous distribution of lamins on the surface and result in large, lamin–free surface domains at sufficiently low lamin-shell affinities. Furthermore, paracrystalline lamin sheets form with increasing propensity for parallel lamin alignment, in addition to the canonical, sticky terminal groups. Overall, our integrative MD and network analysis provide the first explicit polymer physics model of the lamina and demonstrate how lamin interactions may affect the mesoscale architecture of the lamina in disease. ### Competing Interest Statement The authors have declared no competing interest. Scientific and Technological Research Council of Turkey, https://ror.org/04w9kkr77, 124N935