bims-ginsta Biomed News
on Genome instability
Issue of 2023–10–15
23 papers selected by
Jinrong Hu, National University of Singapore
  1. The structural mechanism of dimeric DONSON in replicative helicase activation.
  2. DNA damage induces nuclear envelope rupture through ATR-mediated phosphorylation of lamin A/C.
  3. Epithelial apoptotic pattern emerges from global and local regulation by cell apical area.
  4. Reduced female fertility due to sequestration of RNA Pol II by pervasive transcription in exosome RNase-depleted oocytes.
  5. Cytoplasmic division cycles without the nucleus and mitotic CDK/cyclin complexes.
  6. Essential role of Mg2+ in mouse preimplantation embryo development revealed by TRPM7 chanzyme-deficient gametes.
  7. Establishment of dsDNA-dsDNA interactions by the condensin complex.
  8. MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer.
  9. Adhesion-based capture stabilizes nascent microvilli at epithelial cell junctions.
  10. Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.
  11. Chromatin and gene expression changes during female Drosophila germline stem cell development illuminate the biology of highly potent stem cells.
  12. Complex haploinsufficiency in pluripotent cells yields somatic cells with DNA methylation abnormalities and pluripotency induction defects.
  13. Notch-mediated cellular interactions between vascular cells.
  14. Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction.
  15. Bone-derived PDGF-BB drives brain vascular calcification in male mice.
  16. Clearing the slate: RNA turnover to enable cell-state switching?
  17. Chromatin organization drives the search mechanism of nuclear factors.
  18. Chromosome-level genome editing uncovers aneuploidy addiction in cancer.
  19. A comparative atlas of single-cell chromatin accessibility in the human brain.
  20. SETD2 maintains nuclear lamina stability to safeguard the genome.
  21. SUN1/2 controls macrophage polarization via modulating nuclear size and stiffness.
  22. A family portrait of human brain cells.
  23. Comprehensive cell atlas of the first-trimester developing human brain.
  1. Mol Cell. 2023 Oct 10. pii: S1097-2765(23)00761-X. [Epub ahead of print]
    The structural mechanism of dimeric DONSON in replicative helicase activation.
    Milos A Cvetkovic, Paolo Passaretti, Agata Butryn, Alicja Reynolds-Winczura, Georgia Kingsley, Aggeliki Skagia, Cyntia Fernandez-Cuesta, Divyasree Poovathumkadavil, Roger George, Anoop S Chauhan, Satpal S Jhujh, Grant S Stewart, Agnieszka Gambus, Alessandro Costa.
      The MCM motor of the replicative helicase is loaded onto origin DNA as an inactive double hexamer before replication initiation. Recruitment of activators GINS and Cdc45 upon S-phase transition promotes the assembly of two active CMG helicases. Although work with yeast established the mechanism for origin activation, how CMG is formed in higher eukaryotes is poorly understood. Metazoan Downstream neighbor of Son (DONSON) has recently been shown to deliver GINS to MCM during CMG assembly. What impact this has on the MCM double hexamer is unknown. Here, we used cryoelectron microscopy (cryo-EM) on proteins isolated from replicating Xenopus egg extracts to identify a double CMG complex bridged by a DONSON dimer. We find that tethering elements mediating complex formation are essential for replication. DONSON reconfigures the MCM motors in the double CMG, and primordial dwarfism patients' mutations disrupting DONSON dimerization affect GINS and MCM engagement in human cells and DNA synthesis in Xenopus egg extracts.
    Keywords:  DNA replication initiation; DONSON; Xenopus egg extract; cryo-EM; primordial dwarfism; replicative helicase
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.029
  2. Mol Cell. 2023 Oct 06. pii: S1097-2765(23)00750-5. [Epub ahead of print]
    DNA damage induces nuclear envelope rupture through ATR-mediated phosphorylation of lamin A/C.
    Marton Tibor Kovacs, Marie Vallette, Pauline Wiertsema, Florent Dingli, Damarys Loew, Guilherme Pedreira de Freitas Nader, Matthieu Piel, Raphael Ceccaldi.
      The integrity of the nuclear envelope (NE) is essential for maintaining the structural stability of the nucleus. Rupture of the NE has been frequently observed in cancer cells, especially in the context of mechanical challenges, such as physical confinement and migration. However, spontaneous NE rupture events, without any obvious physical challenges to the cell, have also been described. The molecular mechanism(s) of these spontaneous NE rupture events remain to be explored. Here, we show that DNA damage and subsequent ATR activation leads to NE rupture. Upon DNA damage, lamin A/C is phosphorylated in an ATR-dependent manner, leading to changes in lamina assembly and, ultimately, NE rupture. In addition, we show that cancer cells with intrinsic DNA repair defects undergo frequent events of DNA-damage-induced NE rupture, which renders them extremely sensitive to further NE perturbations. Exploiting this NE vulnerability could provide a new angle to complement traditional, DNA-damage-based chemotherapy.
    Keywords:  ATR; DNA damage; NE vulnerability; homologous recombination deficiency; lamin A/C phosphorylation; lamina; nuclear envelope rupture; replication stress; synthetic lethality
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.023
  3. Curr Biol. 2023 Oct 04. pii: S0960-9822(23)01298-8. [Epub ahead of print]
    Epithelial apoptotic pattern emerges from global and local regulation by cell apical area.
    Victoire M L Cachoux, Maria Balakireva, Mélanie Gracia, Floris Bosveld, Jesús M López-Gay, Aude Maugarny, Isabelle Gaugué, Florencia di Pietro, Stéphane U Rigaud, Lorette Noiret, Boris Guirao, Yohanns Bellaïche.
      Geometry is a fundamental attribute of biological systems, and it underlies cell and tissue dynamics. Cell geometry controls cell-cycle progression and mitosis and thus modulates tissue development and homeostasis. In sharp contrast and despite the extensive characterization of the genetic mechanisms of caspase activation, we know little about whether and how cell geometry controls apoptosis commitment in developing tissues. Here, we combined multiscale time-lapse microscopy of developing Drosophila epithelium, quantitative characterization of cell behaviors, and genetic and mechanical perturbations to determine how apoptosis is controlled during epithelial tissue development. We found that early in cell lives and well before extrusion, apoptosis commitment is linked to two distinct geometric features: a small apical area compared with other cells within the tissue and a small relative apical area with respect to the immediate neighboring cells. We showed that these global and local geometric characteristics are sufficient to recapitulate the tissue-scale apoptotic pattern. Furthermore, we established that the coupling between these two geometric features and apoptotic cells is dependent on the Hippo/YAP and Notch pathways. Overall, by exploring the links between cell geometry and apoptosis commitment, our work provides important insights into the spatial regulation of cell death in tissues and improves our understanding of the mechanisms that control cell number and tissue size.
    Keywords:  Drosophila; Hippo/YAP; Notch; apoptosis; cell size; compression; crowding; division; epithelium; geometry
    DOI:  https://doi.org/10.1016/j.cub.2023.09.049
  4. Cell Rep. 2023 Oct 12. pii: S2211-1247(23)01259-7. [Epub ahead of print]42(10): 113247
    Reduced female fertility due to sequestration of RNA Pol II by pervasive transcription in exosome RNase-depleted oocytes.
    Di Wu, Jurrien Dean.
      Perturbing the transcriptome of mammalian oocytes results in meiotic failure. We previously reported that RNA-exosome-associated RNase, EXOSC10, degrades unwanted protein-coding RNA and processes ribosomal RNA to ensure proper oocyte maturation. Here, we establish oocyte-specific knockout mice of another RNA-exosome-associated RNase, DIS3. Mutant females (Dis3cKO) exhibit significantly reduced fertility because oocytes arrest after the growth phase. Single-oocyte RNA sequencing (RNA-seq) and CUT&Tag analyses show that DIS3 degrades intergenic RNA and mediates transcription silencing that is essential for chromatin condensation and resumption of meiosis. Dis3cKO oocytes exhibit elevated H3K27me3 in a pre-defined manner due to insufficient demethylation. During oocyte growth, EXOSC10 functions with DIS3 to degrade intergenic RNA. Double-knockout oocytes have earlier growth defects and more accumulated transcripts. We conclude that RNA exosomes synergistically degrade unwanted RNA and mediate transcription termination to ensure transcriptome integrity during oocyte development.
    Keywords:  CP: Molecular biology; RNA degradation; histone modification; mouse oocyte development; pervasive transcription
    DOI:  https://doi.org/10.1016/j.celrep.2023.113247
  5. Cell. 2023 Oct 12. pii: S0092-8674(23)01031-0. [Epub ahead of print]186(21): 4694-4709.e16
    Cytoplasmic division cycles without the nucleus and mitotic CDK/cyclin complexes.
    Anand Bakshi, Fabio Echegaray Iturra, Andrew Alamban, Miquel Rosas-Salvans, Sophie Dumont, Mustafa G Aydogan.
      Cytoplasmic divisions are thought to rely on nuclear divisions and mitotic signals. We demonstrate in Drosophila embryos that cytoplasm can divide repeatedly without nuclei and mitotic CDK/cyclin complexes. Cdk1 normally slows an otherwise faster cytoplasmic division cycle, coupling it with nuclear divisions, and when uncoupled, cytoplasm starts dividing before mitosis. In developing embryos where CDK/cyclin activity can license mitotic microtubule (MT) organizers like the spindle, cytoplasmic divisions can occur without the centrosome, a principal organizer of interphase MTs. However, centrosomes become essential in the absence of CDK/cyclin activity, implying that the cytoplasm can employ either the centrosome-based interphase or CDK/cyclin-dependent mitotic MTs to facilitate its divisions. Finally, we present evidence that autonomous cytoplasmic divisions occur during unperturbed fly embryogenesis and that they may help extrude mitotically stalled nuclei during blastoderm formation. We postulate that cytoplasmic divisions occur in cycles governed by a yet-to-be-uncovered clock mechanism autonomous from CDK/cyclin complexes.
    Keywords:  Cdk; Drosophila embryo; autonomous clocks; cell cycle; centrosome; cyclin; cytokinesis; epithelial homeostasis; microtubules; mitosis
    DOI:  https://doi.org/10.1016/j.cell.2023.09.010
  6. Cell Rep. 2023 Oct 10. pii: S2211-1247(23)01244-5. [Epub ahead of print]42(10): 113232
    Essential role of Mg2+ in mouse preimplantation embryo development revealed by TRPM7 chanzyme-deficient gametes.
    Neha Gupta, Cristina Soriano-Úbeda, Paula Stein, Virginia Savy, Brian N Papas, Goli Ardestani, Ingrid Carvacho, Dominique Alfandari, Carmen J Williams, Rafael A Fissore.
      TRPM7 (transient receptor potential cation channel subfamily M member 7) is a chanzyme with channel and kinase domains essential for embryo development. Using gamete-specific Trpm7-null lines, we report that TRPM7-mediated Mg2+ influx is indispensable for reaching the blastocyst stage. TRPM7 is expressed dynamically from gametes to blastocysts; displays stage-specific localization on the plasma membrane, cytoplasm, and nucleus; and undergoes cleavage that produces C-terminal kinase fragments. TRPM7 underpins Mg2+ homeostasis, and excess Mg2+ but not Zn2+ or Ca2+ overcomes the arrest of Trpm7-null embryos; expressing Trpm7 mRNA restores development, but mutant versions fail or are partially rescued. Transcriptomic analyses of Trpm7-null embryos reveal an abundance of oxidative stress-pathway genes, confirmed by mitochondrial dysfunction, and a reduction in transcription factor networks essential for proliferation; Mg2+ supplementation corrects these defects. Hence, TRPM7 underpins Mg2+ homeostasis in preimplantation embryos, prevents oxidative stress, and promotes gene expression patterns necessary for developmental progression and cell-lineage specification.
    Keywords:  ART; CP: Cell biology; CP: Developmental biology; Ca(2+) oscillations; Zn(2+); eggs; fertilization; mammals; nuclear localization; oocytes; oxidative stress; sperm
    DOI:  https://doi.org/10.1016/j.celrep.2023.113232
  7. Mol Cell. 2023 Sep 27. pii: S1097-2765(23)00746-3. [Epub ahead of print]
    Establishment of dsDNA-dsDNA interactions by the condensin complex.
    Minzhe Tang, Georgii Pobegalov, Hideki Tanizawa, Zhuo A Chen, Juri Rappsilber, Maxim Molodtsov, Ken-Ichi Noma, Frank Uhlmann.
      Condensin is a structural maintenance of chromosomes (SMC) complex family member thought to build mitotic chromosomes by DNA loop extrusion. However, condensin variants unable to extrude loops, yet proficient in chromosome formation, were recently described. Here, we explore how condensin might alternatively build chromosomes. Using bulk biochemical and single-molecule experiments with purified fission yeast condensin, we observe that individual condensins sequentially and topologically entrap two double-stranded DNAs (dsDNAs). Condensin loading transitions through a state requiring DNA bending, as proposed for the related cohesin complex. While cohesin then favors the capture of a second single-stranded DNA (ssDNA), second dsDNA capture emerges as a defining feature of condensin. We provide complementary in vivo evidence for DNA-DNA capture in the form of condensin-dependent chromatin contacts within, as well as between, chromosomes. Our results support a "diffusion capture" model in which condensin acts in mitotic chromosome formation by sequential dsDNA-dsDNA capture.
    Keywords:  ChIA-PET; S. pombe; SMC complexes; biochemical reconstitution; chromosome formation; cohesin; condensin; mitosis; single-molecule microscopy
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.019
  8. Cell Rep. 2023 Oct 09. pii: S2211-1247(23)01233-0. [Epub ahead of print]42(10): 113221
    MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer.
    Preston D Crowell, Jenna M Giafaglione, Anthony E Jones, Nicholas M Nunley, Takao Hashimoto, Amelie M L Delcourt, Anton Petcherski, Raag Agrawal, Matthew J Bernard, Johnny A Diaz, Kylie Y Heering, Rong Rong Huang, Jin-Yih Low, Nedas Matulionis, Nora M Navone, Huihui Ye, Amina Zoubeidi, Heather R Christofk, Matthew B Rettig, Robert E Reiter, Michael C Haffner, Paul C Boutros, Orian S Shirihai, Ajit S Divakaruni, Andrew S Goldstein.
      Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.
    Keywords:  CP: Cancer; CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.113221
  9. Dev Cell. 2023 Oct 05. pii: S1534-5807(23)00467-7. [Epub ahead of print]
    Adhesion-based capture stabilizes nascent microvilli at epithelial cell junctions.
    Caroline S Cencer, Jennifer B Silverman, Leslie M Meenderink, Evan S Krystofiak, Bryan A Millis, Matthew J Tyska.
      To maximize solute transport, epithelial cells build an apical "brush border," where thousands of microvilli are linked to their neighbors by protocadherin-containing intermicrovillar adhesion complexes (IMACs). Previous studies established that the IMAC is needed to build a mature brush border, but how this complex contributes to the accumulation of new microvilli during differentiation remains unclear. We found that early in differentiation, mouse, human, and porcine epithelial cells exhibit a marginal accumulation of microvilli, which span junctions and interact with protrusions on neighboring cells using IMAC protocadherins. These transjunctional IMACs are highly stable and reinforced by tension across junctions. Finally, long-term live imaging showed that the accumulation of microvilli at cell margins consistently leads to accumulation in medial regions. Thus, nascent microvilli are stabilized by a marginal capture mechanism that depends on the formation of transjunctional IMACs. These results may offer insights into how apical specializations are assembled in diverse epithelial systems.
    Keywords:  actin; brush border; cadherins; differentiation; intermicrovillar adhesion; transporting epithelia
    DOI:  https://doi.org/10.1016/j.devcel.2023.09.001
  10. Cancer Cell. 2023 Oct 09. pii: S1535-6108(23)00319-7. [Epub ahead of print]41(10): 1788-1802.e10
    Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.
    Hongyi Zhang, Xuexin Yu, Jianfeng Ye, Huiyu Li, Jing Hu, Yuhao Tan, Yan Fang, Esra Akbay, Fulong Yu, Chen Weng, Vijay G Sankaran, Robert M Bachoo, Elizabeth Maher, John Minna, Anli Zhang, Bo Li.
      Mitochondria (MT) participate in most metabolic activities of mammalian cells. A near-unidirectional mitochondrial transfer from T cells to cancer cells was recently observed to "metabolically empower" cancer cells while "depleting immune cells," providing new insights into tumor-T cell interaction and immune evasion. Here, we leverage single-cell RNA-seq technology and introduce MERCI, a statistical deconvolution method for tracing and quantifying mitochondrial trafficking between cancer and T cells. Through rigorous benchmarking and validation, MERCI accurately predicts the recipient cells and their relative mitochondrial compositions. Application of MERCI to human cancer samples identifies a reproducible MT transfer phenotype, with its signature genes involved in cytoskeleton remodeling, energy production, and TNF-α signaling pathways. Moreover, MT transfer is associated with increased cell cycle activity and poor clinical outcome across different cancer types. In summary, MERCI enables systematic investigation of an understudied aspect of tumor-T cell interactions that may lead to the development of therapeutic opportunities.
    Keywords:  Mitochondrial Transfer; Statistical Deconvolution; T cell dysfunction; Tumor-Immune Interaction; mtDNA sequencing.; single cell genomics
    DOI:  https://doi.org/10.1016/j.ccell.2023.09.003
  11. Elife. 2023 Oct 13. pii: RP90509. [Epub ahead of print]12
    Chromatin and gene expression changes during female Drosophila germline stem cell development illuminate the biology of highly potent stem cells.
    Liang-Yu Pang, Steven DeLuca, Haolong Zhu, John M Urban, Allan C Spradling.
      Highly potent animal stem cells either self renew or launch complex differentiation programs, using mechanisms that are only partly understood. Drosophila female germline stem cells (GSCs) perpetuate without change over evolutionary time and generate cystoblast daughters that develop into nurse cells and oocytes. Cystoblasts initiate differentiation by generating a transient syncytial state, the germline cyst, and by increasing pericentromeric H3K9me3 modification, actions likely to suppress transposable element activity. Relatively open GSC chromatin is further restricted by Polycomb repression of testis or somatic cell-expressed genes briefly active in early female germ cells. Subsequently, Neijre/CBP and Myc help upregulate growth and reprogram GSC metabolism by altering mitochondrial transmembrane transport, gluconeogenesis, and other processes. In all these respects GSC differentiation resembles development of the totipotent zygote. We propose that the totipotent stem cell state was shaped by the need to resist transposon activity over evolutionary timescales.
    Keywords:  D. melanogaster; Polycomb repression; developmental biology; evolution; germ cell; oocyte; stem cell; transposable element
    DOI:  https://doi.org/10.7554/eLife.90509
  12. Stem Cell Reports. 2023 Sep 28. pii: S2213-6711(23)00368-5. [Epub ahead of print]
    Complex haploinsufficiency in pluripotent cells yields somatic cells with DNA methylation abnormalities and pluripotency induction defects.
    Rachel Lasry, Noam Maoz, Albert W Cheng, Nataly Yom Tov, Elisabeth Kulenkampff, Meir Azagury, Hui Yang, Cora Ople, Styliani Markoulaki, Dina A Faddah, Kirill Makedonski, Dana Orzech, Ofra Sabag, Rudolf Jaenisch, Yosef Buganim.
      A complete knockout of a single key pluripotency gene may drastically affect embryonic stem cell function and epigenetic reprogramming. In contrast, elimination of only one allele of a single pluripotency gene is mostly considered harmless to the cell. To understand whether complex haploinsufficiency exists in pluripotent cells, we simultaneously eliminated a single allele in different combinations of two pluripotency genes (i.e., Nanog+/-;Sall4+/-, Nanog+/-;Utf1+/-, Nanog+/-;Esrrb+/- and Sox2+/-;Sall4+/-). Although these double heterozygous mutant lines similarly contribute to chimeras, fibroblasts derived from these systems show a significant decrease in their ability to induce pluripotency. Tracing the stochastic expression of Sall4 and Nanog at early phases of reprogramming could not explain the seen delay or blockage. Further exploration identifies abnormal methylation around pluripotent and developmental genes in the double heterozygous mutant fibroblasts, which could be rescued by hypomethylating agent or high OSKM levels. This study emphasizes the importance of maintaining two intact alleles for pluripotency induction.
    Keywords:  haploinsufficiency; knockin/knockout targeting approach; methylation; nuclear transfer; pluripotent stem cells; reporter genes; reprogramming; stochastic expression; tracing system
    DOI:  https://doi.org/10.1016/j.stemcr.2023.09.009
  13. Curr Opin Cell Biol. 2023 Oct 11. pii: S0955-0674(23)00103-5. [Epub ahead of print]85 102254
    Notch-mediated cellular interactions between vascular cells.
    Henar Cuervo, Severin Mühleder, Irene García-Gónzalez, Rui Benedito.
      Vessel formation and differentiation to a proper hierarchical vasculature requires a coordinated effort from endothelial and mural cells. Over the last decade Notch was identified as a key player in this process by promoting vascular arterialization and modulating endothelial tip-stalk phenotypes. Recent work has identified that Notch fine-tunes the diverse endothelial phenotypes through regulation of canonical cell-cycle and metabolism regulators, such as ERK and Myc. During arterialization, Notch signaling inhibits the cell-cycle and metabolism of endothelial cells which coincides with the acquisition of arterial identity. During angiogenesis, the same molecular machinery prevents the hypermitogenic arrest and excessive sprouting of vessels. Notch also signals in pericytes and smooth muscle cells promoting vascular coverage and maturation. Here, we will review the latest findings on how Notch signals regulate the differentiation and interactions among vascular cells during organ development and homeostasis.
    DOI:  https://doi.org/10.1016/j.ceb.2023.102254
  14. Nat Commun. 2023 Oct 13. 14(1): 6454
    Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction.
    Angélica María Sabogal-Guáqueta, Alejandro Marmolejo-Garza, Marina Trombetta-Lima, Asmaa Oun, Jasmijn Hunneman, Tingting Chen, Jari Koistinaho, Sarka Lehtonen, Arjan Kortholt, Justina C Wolters, Barbara M Bakker, Bart J L Eggen, Erik Boddeke, Amalia Dolga.
      Metabolic reprogramming is a hallmark of the immune cells in response to inflammatory stimuli. This metabolic process involves a switch from oxidative phosphorylation (OXPHOS) to glycolysis or alterations in other metabolic pathways. However, most of the experimental findings have been acquired in murine immune cells, and little is known about the metabolic reprogramming of human microglia. In this study, we investigate the transcriptomic, proteomic, and metabolic profiles of mouse and iPSC-derived human microglia challenged with the TLR4 agonist LPS. We demonstrate that both species display a metabolic shift and an overall increased glycolytic gene signature in response to LPS treatment. The metabolic reprogramming is characterized by the upregulation of hexokinases in mouse microglia and phosphofructokinases in human microglia. This study provides a direct comparison of metabolism between mouse and human microglia, highlighting the species-specific pathways involved in immunometabolism and the importance of considering these differences in translational research.
    DOI:  https://doi.org/10.1038/s41467-023-42096-7
  15. J Clin Invest. 2023 Oct 10. pii: e168447. [Epub ahead of print]
    Bone-derived PDGF-BB drives brain vascular calcification in male mice.
    Jiekang Wang, Ching-Lien Fang, Kathleen Noller, Zhiliang Wei, Guanqiao Liu, Ke Shen, Kangping Song, Xu Cao, Mei Wan.
      Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large vessel calcifications in peripheral tissue is well-studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contribute to cerebrovascular calcification in male mice. Aged male mice exhibited higher serum PDGF-BB levels and a significantly higher incidence of brain calcification compared to young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevation of serum PDGF-BB levels and recapitulated age-associated thalamic calcification. Conversely, mice with preosteoclast-specific Pdgfb deletion displayed diminished age-associated thalamic calcification. In an ex vivo cerebral microvascular culture system, PDGF-BB dose-dependently promoted vascular calcification. Analysis of osteogenic gene array and single-cell RNA sequencing revealed that PDGF-BB upregulates multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRβ (pPDGFRβ) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of the osteoblast differentiation genes in pericytes and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induces brain vascular calcification by activating the pPDGFRβ/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.
    Keywords:  Bone Biology; Microcirculation; Neurological disorders; Osteoclast/osteoblast biology; Vascular Biology
    DOI:  https://doi.org/10.1172/JCI168447
  16. Development. 2023 Oct 01. pii: dev202084. [Epub ahead of print]150(19):
    Clearing the slate: RNA turnover to enable cell-state switching?
    Elizabeth R Westbrook, Hugh Z Ford, Vlatka Antolović, Jonathan R Chubb.
      The distribution of mRNA in tissue is determined by the balance between transcription and decay. Understanding the control of RNA decay during development has been somewhat neglected compared with transcriptional control. Here, we explore the potential for mRNA decay to trigger rapid cell-state transitions during development, comparing a bistable switch model of cell-state conversion with experimental evidence from different developmental systems. We also consider another potential role for large-scale RNA decay that has emerged from studies of stress-induced cell-state transitions, in which removal of mRNA unblocks the translation machinery to prioritise the synthesis of proteins that establish the new cell state.
    Keywords:  Cell state transition; RNA decay; Ribosome competition
    DOI:  https://doi.org/10.1242/dev.202084
  17. Nat Commun. 2023 Oct 13. 14(1): 6433
    Chromatin organization drives the search mechanism of nuclear factors.
    Matteo Mazzocca, Alessia Loffreda, Emanuele Colombo, Tom Fillot, Daniela Gnani, Paola Falletta, Emanuele Monteleone, Serena Capozi, Edouard Bertrand, Gaelle Legube, Zeno Lavagnino, Carlo Tacchetti, Davide Mazza.
      Nuclear factors rapidly scan the genome for their targets, but the role of nuclear organization in such search is uncharted. Here we analyzed how multiple factors explore chromatin, combining live-cell single-molecule tracking with multifocal structured illumination of DNA density. We find that factors displaying higher bound fractions sample DNA-dense regions more exhaustively. Focusing on the tumor-suppressor p53, we demonstrate that it searches for targets by alternating between rapid diffusion in the interchromatin compartment and compact sampling of chromatin dense regions. Efficient targeting requires balanced interactions with chromatin: fusing p53 with an exogenous intrinsically disordered region potentiates p53-mediated target gene activation at low concentrations, but leads to condensates at higher levels, derailing its search and downregulating transcription. Our findings highlight the role of disordered regions on factors search and showcase a powerful method to generate traffic maps of the eukaryotic nucleus to dissect how its organization guides nuclear factors action.
    DOI:  https://doi.org/10.1038/s41467-023-42133-5
  18. Cell Rep Methods. 2023 Oct 03. pii: S2667-2375(23)00282-5. [Epub ahead of print] 100618
    Chromosome-level genome editing uncovers aneuploidy addiction in cancer.
    Siobhan O'Brien, Alice H Berger.
      Publishing in Science, Girish and colleagues achieve chromosome-level genome editing to reveal a requirement for aneuploidy in breast and melanoma cancers. Authors developed and leveraged ReDACT (restoring disomy in aneuploid cells using CRISPR targeting) to generate isogenic models of aneuploidy and demonstrate that some cancers are addicted to increased copy number of specific chromosome arms.
    DOI:  https://doi.org/10.1016/j.crmeth.2023.100618
  19. Science. 2023 Oct 13. 382(6667): eadf7044
    A comparative atlas of single-cell chromatin accessibility in the human brain.
    Yang Eric Li, Sebastian Preissl, Michael Miller, Nicholas D Johnson, Zihan Wang, Henry Jiao, Chenxu Zhu, Zhaoning Wang, Yang Xie, Olivier Poirion, Colin Kern, Antonio Pinto-Duarte, Wei Tian, Kimberly Siletti, Nora Emerson, Julia Osteen, Jacinta Lucero, Lin Lin, Qian Yang, Quan Zhu, Nathan Zemke, Sarah Espinoza, Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, Rebecca D Hodge, Sten Linnarsson, Trygve Bakken, Boaz Levi, C Dirk Keene, Jingbo Shang, Ed Lein, Allen Wang, M Margarita Behrens, Joseph R Ecker, Bing Ren.
      Recent advances in single-cell transcriptomics have illuminated the diverse neuronal and glial cell types within the human brain. However, the regulatory programs governing cell identity and function remain unclear. Using a single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq), we explored open chromatin landscapes across 1.1 million cells in 42 brain regions from three adults. Integrating this data unveiled 107 distinct cell types and their specific utilization of 544,735 candidate cis-regulatory DNA elements (cCREs) in the human genome. Nearly a third of the cCREs demonstrated conservation and chromatin accessibility in the mouse brain cells. We reveal strong links between specific brain cell types and neuropsychiatric disorders including schizophrenia, bipolar disorder, Alzheimer's disease (AD), and major depression, and have developed deep learning models to predict the regulatory roles of noncoding risk variants in these disorders.
    DOI:  https://doi.org/10.1126/science.adf7044
  20. bioRxiv. 2023 Sep 28. pii: 2023.09.28.560032. [Epub ahead of print]
    SETD2 maintains nuclear lamina stability to safeguard the genome.
    Abid Khan, James M Metts, Lucas C Collins, C Allie Mills, Kelin Li, Amanda L Brademeyer, Brittany M Bowman, M Ben Major, Jeffrey Aubé, Laura E Herring, Ian J Davis, Brian D Strahl.
      Histone methyltransferases play essential roles in the organization and function of chromatin. They are also frequently mutated in human diseases including cancer 1 . One such often mutated methyltransferase, SETD2, associates co-transcriptionally with RNA polymerase II and catalyzes histone H3 lysine 36 trimethylation (H3K36me3) - a modification that contributes to gene transcription, splicing, and DNA repair 2 . While studies on SETD2 have largely focused on the consequences of its catalytic activity, the non-catalytic functions of SETD2 are largely unknown. Here we report a catalysis-independent function of SETD2 in maintaining nuclear lamina stability and genome integrity. We found that SETD2, via its intrinsically disordered N-terminus, associates with nuclear lamina proteins including lamin A/C, lamin B1, and emerin. Depletion of SETD2, or deletion of its N-terminus, resulted in widespread nuclear morphology abnormalities and genome stability defects that were reminiscent of a defective nuclear lamina. Mechanistically, the N-terminus of SETD2 facilitates the association of the mitotic kinase CDK1 with lamins, thereby promoting lamin phosphorylation and depolymerization required for nuclear envelope disassembly during mitosis. Taken together, our findings reveal an unanticipated link between the N-terminus of SETD2 and nuclear lamina organization that may underlie how SETD2 acts as a tumor suppressor.
    DOI:  https://doi.org/10.1101/2023.09.28.560032
  21. Nat Commun. 2023 Oct 12. 14(1): 6416
    SUN1/2 controls macrophage polarization via modulating nuclear size and stiffness.
    Shi Jiao, Chuanchuan Li, Fenghua Guo, Jinjin Zhang, Hui Zhang, Zhifa Cao, Wenjia Wang, Wenbo Bu, Mobin Lin, Junhong Lü, Zhaocai Zhou.
      Alteration of the size and stiffness of the nucleus triggered by environmental cues are thought to be important for eukaryotic cell fate and function. However, it remains unclear how context-dependent nuclear remodeling occurs and reprograms gene expression. Here we identify the nuclear envelope proteins SUN1/2 as mechano-regulators of the nucleus during M1 polarization of the macrophage. Specifically, we show that LPS treatment decreases the protein levels of SUN1/2 in a CK2-βTrCP-dependent manner to shrink and soften the nucleus, therefore altering the chromatin accessibility for M1-associated gene expression. Notably, the transmembrane helix of SUN1/2 is solely required and sufficient for the nuclear mechano-remodeling. Consistently, SUN1/2 depletion in macrophages facilitates their phagocytosis, tissue infiltration, and proinflammatory cytokine production, thereby boosting the antitumor immunity in mice. Thus, our study demonstrates that, in response to inflammatory cues, SUN1/2 proteins act as mechano-regulators to remodel the nucleus and chromatin for M1 polarization of the macrophage.
    DOI:  https://doi.org/10.1038/s41467-023-42187-5
  22. Science. 2023 Oct 13. 382(6667): 168-169
    A family portrait of human brain cells.
    Alyssa Weninger, Paola Arlotta.
      A cell census provides information on the source of human brain specialization.
    DOI:  https://doi.org/10.1126/science.adk4857
  23. Science. 2023 Oct 13. 382(6667): eadf1226
    Comprehensive cell atlas of the first-trimester developing human brain.
    Emelie Braun, Miri Danan-Gotthold, Lars E Borm, Ka Wai Lee, Elin Vinsland, Peter Lönnerberg, Lijuan Hu, Xiaofei Li, Xiaoling He, Žaneta Andrusivová, Joakim Lundeberg, Roger A Barker, Ernest Arenas, Erik Sundström, Sten Linnarsson.
      The adult human brain comprises more than a thousand distinct neuronal and glial cell types, a diversity that emerges during early brain development. To reveal the precise sequence of events during early brain development, we used single-cell RNA sequencing and spatial transcriptomics and uncovered cell states and trajectories in human brains at 5 to 14 postconceptional weeks (pcw). We identified 12 major classes that are organized as ~600 distinct cell states, which map to precise spatial anatomical domains at 5 pcw. We described detailed differentiation trajectories of the human forebrain and midbrain and found a large number of region-specific glioblasts that mature into distinct pre-astrocytes and pre-oligodendrocyte precursor cells. Our findings reveal the establishment of cell types during the first trimester of human brain development.
    DOI:  https://doi.org/10.1126/science.adf1226
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