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Background B-type lamins are critical nuclear envelope proteins that interact with the three-dimensional genomic architecture. However, identifying the direct roles of B-lamins on dynamic genome organization has been challenging as their joint depletion severely impacts cell viability. To overcome this, we engineered mammalian cells to rapidly and completely degrade endogenous B-type lamins using Auxin-inducible degron technology. Results Using live-cell Dual Partial Wave Spectroscopic (Dual-PWS) microscopy, Stochastic Optical Reconstruction Microscopy (STORM), in situ Hi-C, CRISPR-Sirius, and fluorescence in situ hybridization (FISH), we demonstrate that lamin B1 and lamin B2 are critical structural components of the nuclear periphery that create a repressive compartment for peripheral-associated genes. Lamin B1 and lamin B2 depletion minimally alters higher-order chromatin folding but disrupts cell morphology, significantly increases chromatin mobility, redistributes both constitutive and facultative heterochromatin, and induces differential gene expression both within and near lamin-associated domain (LAD) boundaries. Critically, we demonstrate that chromatin territories expand as upregulated genes within LADs radially shift inwards. Our results indicate that the mechanism of action of B-type lamins comes from their role in constraining chromatin motion and spatial positioning of gene-specific loci, heterochromatin, and chromatin domains. Conclusions Our findings suggest that, while B-type lamin degradation does not significantly change genome topology, it has major implications for three-dimensional chromatin conformation at the single-cell level both at the lamina-associated periphery and the non-LAD-associated nuclear interior with concomitant genome-wide transcriptional changes. This raises intriguing questions about the individual and overlapping roles of lamin B1 and lamin B2 in cellular function and disease.

Reconstructing the source regions of past atmospheric dust preserved in ice remains a challenge in Antarctic glaciology. Until now, different dust properties were obtained by separate techniques and could not be directly correlated at single particle level limiting the dust characterization. Here we apply a novel technique (single particle Inductively Coupled Plasma-Time of Flight Mass Spectrometry) to characterize millions of individual particles in low-volume (< 2 mL) ice samples. We analyzed more than 2,000,000 individual particles smaller than 2.5 µm in 28 discrete samples from Taylor Glacier, coastal East Antarctica, spanning 44—9 kyr BP. We show a glacial-interglacial shift in particle number and mass concentrations, as well as in the elemental and mineralogical compositions. Our observations suggest a common potential dust source area for central and coastal East Antarctica during the Last Glacial Period, followed by a transition to different dominant sources in coastal sites during the Holocene. These changes likely reflect large-scale variations in dust sources, and environmental conditions in the Southern Hemisphere. We have also identified and measured the elemental composition of thousands of volcanic particles < 2.5 µm, indicating occasional tephra deposition from one of the Victoria Land volcanoes around 14.8 kyr BP.

Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N -methyladenosine (m A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m A mRNA marks promote the translation of a network of genes required for human erythropoiesis.

Single‐cell RNA sequencing has emerged as a powerful tool for resolving cellular states associated with normal and maligned developmental processes. Here, we used scRNA‐seq to examine the cell cycle states of expanding human neural stem cells (hNSCs). From these data, we constructed a cell cycle classifier that identifies traditional cell cycle phases and a putative quiescent‐like state in neuroepithelial‐derived cell types during mammalian neurogenesis and in gliomas. The Neural G0 markers are enriched with quiescent NSC genes and other neurodevelopmental markers found in non‐dividing neural progenitors. Putative glioblastoma stem‐like cells were significantly enriched in the Neural G0 cell population. Neural G0 cell populations and gene expression are significantly associated with less aggressive tumors and extended patient survival for gliomas. Genetic screens to identify modulators of Neural G0 revealed that knockout of genes associated with the Hippo/Yap and p53 pathways diminished Neural G0 in vitro, resulting in faster G1 transit, down‐regulation of quiescence‐associated markers, and loss of Neural G0 gene expression. Thus, Neural G0 represents a dynamic quiescent‐like state found in neuroepithelial‐derived cells and gliomas. SYNOPSIS scRNA‐seq and functional genomics are applied to human neural stem cells to characterize cell cycle phases and factors increasing proliferative rate. A new cell cycle state “Neural G0” is discovered, offering insights into glioma patient tumors and patient survival. Unsupervised cell clustering reveals eight distinct cell cycle phases in human neural stem cells. A novel Neural G0 cell cycle phase is characterized by up‐regulation of genes with key roles in neural development. Increased expression of a GBM‐specific Neural G0 gene signature is associated with better prognosis for glioma patients, independent of tumor grade and IDH1/2 mutation. A functional‐genomics screen identifies genes that alter the time spent in G0/G1‐like states thereby increasing the proliferative rate of neural stem cells. Graphical Abstract scRNA‐seq and functional genomics are applied to human neural stem cells to characterize cell cycle phases and factors increasing proliferative rate. A new cell cycle state “Neural G0” is discovered, offering insights into glioma patient tumors and patient survival.

Topographical cues on cells can, through contact guidance, alter cellular plasticity and accelerate the regeneration of cultured tissue. Here we show how changes in the nuclear and cellular morphologies of human mesenchymal stromal cells induced by micropillar patterns via contact guidance influence the conformation of the cells’ chromatin and their osteogenic differentiation in vitro and in vivo. The micropillars impacted nuclear architecture, lamin A/C multimerization and 3D chromatin conformation, and the ensuing transcriptional reprogramming enhanced the cells’ responsiveness to osteogenic differentiation factors and decreased their plasticity and off-target differentiation. In mice with critical-size cranial defects, implants with micropillar patterns inducing nuclear constriction altered the cells’ chromatin conformation and enhanced bone regeneration without the need for exogenous signalling molecules. Our findings suggest that medical device topographies could be designed to facilitate bone regeneration via chromatin reprogramming. Micropillar patterns causing changes in the nuclear and cellular morphologies of human mesenchymal stromal cells influence the conformation of the cells’ chromatin and their osteogenic differentiation in vitro and in mice.

Quiescence cancer stem-like cells may play key roles in promoting tumor cell heterogeneity and recurrence for many tumors, including glioblastoma (GBM). Here we show that the protein acetyltransferase KAT5 is a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states in GBM. KAT5 activity suppresses the emergence of quiescent subpopulations with neurodevelopmental progenitor characteristics, while promoting GBM stem-like cell (GSC) self-renewal through coordinately regulating E2F- and MYC- transcriptional networks with protein translation. KAT5 inactivation significantly decreases tumor progression and invasive behavior while increasing survival after standard of care. Further, increasing MYC expression in human neural stem cells stimulates KAT5 activity and protein translation, as well as confers sensitivity to homoharringtonine, to similar levels to those found in GSCs and high-grade gliomas. These results suggest that the dynamic behavior of KAT5 plays key roles in G0 ingress/egress, adoption of quasi-neurodevelopmental states, and aggressive tumor growth in gliomas. Quiescent populations are a likely key source of treatment resistance in glioblastoma. Here, the authors characterize KAT5 as a critical mediator of quiescence and adoption of progenitor-like states.

Human tissues require a mechanism to generate durable, yet modifiable, transcriptional memories to sustain cell function across a lifetime. Previously, it was demonstrated that nanoscale packing domains couple heterochromatin (cores) and euchromatin (outer zone) into unified reaction volumes that can generate transcriptional memory. In prior work, this framework demonstrates that RNA synthesis occurred within the ideal zone (intermediate density) portions of the domain. Naturally, this creates a question of where genes are positioned in relation to the packing domain architecture and which genetic material fills the domain core to sustain transcription. Here, it is proposed that this can be solved by the encoded positioning of introns, intergenic segments, and exons as a projection of the functional packing layers of domains. This suggests that introns and intergenic segments are coupled to adjacent exons to generate coherent packing domain volumes. How this organization will reconcile contradictions in epigenetic patterns, non‐randomness in oncogenic mutations, and produce durable transcriptional memory is illustrated. The study concludes by showing that this genome geometry may have coincided with the rapid evolution of body‐plan complexity, suggesting that chromatin geometry could be fundamental to metazoan evolution. This study introduces a new hypothesis: exons, introns, and intergenic segments are non‐random projections of the functional layers of 3D structure of chromatin packing domains. Evidence is presented that this “geometric code” may encode volumetric structure, reconciling epigenetic patterns, correlates with oncogenic mutations, acting as a potential mechanism to generate transcriptional memory, and coincides with the evolution of complex body plans.

Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N 6 -methyladenosine (m 6 A) mRNA methyltransferase (MTase) complex, including, METTL14 , METTL3 , and WTAP . We demonstrate that m 6 A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m 6 A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m 6 A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m 6 A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m 6 A mRNA marks promote the translation of a network of genes required for human erythropoiesis. Erythropoiesis can be regulated by transcriptional, epigenetic, and post-transcriptional mechanisms. Here the authors report that N 6 -methyladenosine mRNA methyltransferase complex stimulates erythropoiesis by promoting translation of specific mRNAs.

Genome Geometry as the Physical Language of Cell Memory This cover highlights the transformation of genome information from chemical states into dynamic physical geometry. Genetic and epigenetic states pass through a geometric prism, proposing that exons and non‐exons couple as shell (gold) to volume (purple) ratios of ChromSTEM‐resolved packing domains. The Research Article by Igal Szleifer, Vadim Backman, and co‐workers (DOI: 10.1002/advs.202509964) advances a model in which cell memory resides not only in sequence composition, but in a heritably encoded 3D geometric language.

Human tissues require a mechanism to generate durable, yet modifiable, transcriptional memories to sustain cell function across a lifetime. Previously, we demonstrated that nanoscale packing domains couple heterochromatin (cores) and euchromatin (outer zone) into unified reaction volumes that can generate transcriptional memory. In prior work, this framework demonstrated that RNA synthesis occurred within the ideal zone (intermediate density) portions of the domain. Naturally, this creates a question of where genes are positioned in relation to the packing domain architecture and which genetic material fills the domain core to sustain transcription. Here we propose that this could be solved by the encoded positioning of introns, intergenic segments, and exons as a projection of the functional packing layers of domains. This suggests that introns and intergenic segments are coupled to adjacent exons to generate coherent packing domain volumes. We illustrate how this organization would reconcile contradictions in epigenetic patterns, non-randomness in oncogenic mutations, and produce durable transcriptional memory. We conclude by showing that this genome geometry might have coincided with the rapid evolution of body-plan complexity, suggesting that chromatin geometry could be fundamental to metazoan evolution.