bims-ginsta Biomed News
on Genome instability
Issue of 2024–12–15
23 papers selected by
Jinrong Hu, National University of Singapore
  1. Somatic polyploidy supports biosynthesis and tissue function by increasing transcriptional output.
  2. TBP bookmarks and preserves neural stem cell fate memory by orchestrating local chromatin architecture.
  3. EOMES establishes mesoderm and endoderm differentiation potential through SWI/SNF-mediated global enhancer remodeling.
  4. Actin-based deformations of the nucleus control mouse multiciliated ependymal cell differentiation.
  5. Cells transit through a quiescent-like state to convert to neurons at high rates.
  6. Design principles to tailor Hsp104 therapeutics.
  7. CRL3ARMC5 ubiquitin ligase and Integrator phosphatase form parallel mechanisms to control early stages of RNA Pol II transcription.
  8. Morphogenesis and regeneration share a conserved core transition cell state program that controls lung epithelial cell fate.
  9. Temporal dynamics of BMP/Nodal ratio drive tissue-specific gastrulation morphogenesis.
  10. Transposable element exonization generates a reservoir of evolving and functional protein isoforms.
  11. Enforced activation of the CREB/KDM2B axis prevents alcohol-induced embryonic developmental delay.
  12. Rhythmic forces shaping the zebrafish cardiac system.
  13. Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos.
  14. Lamin B1-dependent regulation of human separase in mitosis.
  15. Pharmacologically inducing regenerative cardiac cells by small molecule drugs.
  16. PDGFRA is a conserved HAND2 effector during early cardiac development.
  17. IL-23R is a senescence-linked circulating and tissue biomarker of aging.
  18. Microbiota-derived short-chain fatty acids determine stem cell characteristics of gastric chief cells.
  19. In situ analysis reveals the TRiC duty cycle and PDCD5 as an open-state cofactor.
  20. Hallmarks of female reproductive aging in physiologic aging mice.
  21. An injury-induced mesenchymal-epithelial cell niche coordinates regenerative responses in the lung.
  22. The cells are all-right: Regulation of the Lefty genes by separate enhancers in mouse embryonic stem cells.
  23. A new understanding of tissue biology from MS-based proteomics at single-cell resolution.
  1. J Cell Biol. 2025 Mar 03. pii: e202403154. [Epub ahead of print]224(3):
    Somatic polyploidy supports biosynthesis and tissue function by increasing transcriptional output.
    Alexander T Lessenger, Jan M Skotheim, Mathew P Swaffer, Jessica L Feldman.
      Cell size and biosynthetic capacity generally increase with increased DNA content. Somatic polyploidy has therefore been proposed to be an adaptive strategy to increase cell size in specialized tissues with high biosynthetic demands. However, if and how DNA concentration limits cellular biosynthesis in vivo is not well understood. Here, we show that polyploidy in the Caenorhabditis elegans intestine is critical for cell growth and yolk biosynthesis, a central role of this organ. Artificially lowering the DNA/cytoplasm ratio by reducing polyploidization in the intestine gave rise to smaller cells with dilute mRNA. Highly expressed transcripts were more sensitive to this mRNA dilution, whereas lowly expressed genes were partially compensated-in part by loading more RNA Polymerase II on the remaining genomes. Polyploidy-deficient animals produced fewer and slower-growing offspring, consistent with reduced synthesis of highly expressed yolk proteins. DNA-dilute cells had normal total protein concentration, which we propose is achieved by increasing the expression of translational machinery at the expense of specialized, cell-type-specific proteins.
    DOI:  https://doi.org/10.1083/jcb.202403154
  2. Mol Cell. 2024 Dec 05. pii: S1097-2765(24)00944-4. [Epub ahead of print]
    TBP bookmarks and preserves neural stem cell fate memory by orchestrating local chromatin architecture.
    Yuying Shen, Kun Liu, Jie Liu, Jingwen Shen, Tongtong Ye, Runxiang Zhao, Rulan Zhang, Yan Song.
      Mitotic bookmarking has been posited as an important strategy for cells to faithfully propagate their fate memory through cell generations. However, the physiological significance and regulatory mechanisms of mitotic bookmarking in neural development remain unexplored. Here, we identified TATA-binding protein (TBP) as a crucial mitotic bookmarker for preserving the fate memory of Drosophila neural stem cells (NSCs). Phosphorylation by the super elongation complex (SEC) is important for TBP to retain as discrete foci at mitotic chromosomes of NSCs to effectively transmit their fate memory. TBP depletion leads to drastic NSC loss, whereas TBP overexpression enhances the ability of SEC to induce neural progenitor dedifferentiation and tumorigenesis. Importantly, TBP achieves its mitotic retention through recruiting the chromatin remodeler EP400, which in turn increases local chromatin accessibility via depositing H2A.Z. Thus, local chromatin remodeling ensures mitotic bookmarking, which may represent a general principle underlying the preservation of cell fate memory.
    Keywords:  Drosophila melanogaster; EP400; H2A.Z; TBP; cell fate memory; chromatin remodeler; mitotic bookmarking; mitotic retention; neural development; neural stem cell
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.019
  3. Dev Cell. 2024 Dec 05. pii: S1534-5807(24)00696-8. [Epub ahead of print]
    EOMES establishes mesoderm and endoderm differentiation potential through SWI/SNF-mediated global enhancer remodeling.
    Chiara M Schröder, Lea Zissel, Sophie-Luise Mersiowsky, Mehmet Tekman, Simone Probst, Katrin M Schüle, Sebastian Preissl, Oliver Schilling, H Th Marc Timmers, Sebastian J Arnold.
      Mammalian pluripotent cells first segregate into neuroectoderm (NE), or mesoderm and endoderm (ME), characterized by lineage-specific transcriptional programs and chromatin states. To date, the relationship between transcription factor activities and dynamic chromatin changes that guide cell specification remains ill-defined. In this study, we employ mouse embryonic stem cell differentiation toward ME lineages to reveal crucial roles of the Tbx factor Eomes to globally establish ME enhancer accessibility as the prerequisite for ME lineage competence and ME-specific gene expression. EOMES cooperates with the SWItch/sucrose non-fermentable (SWI/SNF) complex to drive chromatin rewiring that is essential to overcome default NE differentiation, which is favored by asymmetries in chromatin accessibility at pluripotent state. Following global ME enhancer remodeling, ME-specific gene transcription is controlled by additional signals such as Wnt and transforming growth factor β (TGF-β)/NODAL, as a second layer of gene expression regulation, which can be mechanistically separated from initial chromatin remodeling activities.
    Keywords:  Eomes; SWI/SNF complex; Tbx factors; cell fate decision; chromatin accessibility; enhancer regulation; epigenetic remodeling; gastrulation
    DOI:  https://doi.org/10.1016/j.devcel.2024.11.014
  4. Dev Cell. 2024 Dec 06. pii: S1534-5807(24)00673-7. [Epub ahead of print]
    Actin-based deformations of the nucleus control mouse multiciliated ependymal cell differentiation.
    Marianne Basso, Alexia Mahuzier, Syed Kaabir Ali, Anaïs Marty, Marion Faucourt, Ana-Maria Lennon-Duménil, Ayush Srivastava, Michella Khoury Damaa, Alexia Bankolé, Alice Meunier, Ayako Yamada, Julie Plastino, Nathalie Spassky, Nathalie Delgehyr.
      Ependymal cells (ECs) are multiciliated cells in the brain that contribute to cerebrospinal fluid flow. ECs are specified during embryonic stages but differentiate later in development. Their differentiation depends on genes such as GEMC1 and MCIDAS in conjunction with E2F4/5 as well as on cell-cycle-related factors. In the mouse brain, we observe that nuclear deformation accompanies EC differentiation. Tampering with these deformations either by decreasing F-actin levels or by severing the link between the nucleus and the actin cytoskeleton blocks differentiation. Conversely, increasing F-actin by knocking out the Arp2/3 complex inhibitor Arpin or artificially deforming the nucleus activates differentiation. These data are consistent with actin polymerization triggering nuclear deformation and jump starting the signaling that produces ECs. A player in this process is the retinoblastoma 1 (RB1) protein, whose phosphorylation prompts MCIDAS activation. Overall, this study identifies a role for actin-based mechanical inputs to the nucleus as controlling factors in cell differentiation.
    Keywords:  LINC complex; MCIDAS; actin; cell cycle; differentiation; ependymal cell; mechanotransduction; multiciliated; nucleus; retinoblastoma
    DOI:  https://doi.org/10.1016/j.devcel.2024.11.008
  5. bioRxiv. 2024 Nov 25. pii: 2024.11.22.624928. [Epub ahead of print]
    Cells transit through a quiescent-like state to convert to neurons at high rates.
    A Beitz, Jmy Teves, C Oakes, C Johnstone, N Wang, J M Brickman, K E Galloway.
      While transcription factors (TFs) provide essential cues for directing and redirecting cell fate, TFs alone are insufficient to drive cells to adopt alternative fates. Rather, transcription factors rely on receptive cell states to induce novel identities. Cell state emerges from and is shaped by cellular history and the activity of diverse processes. Here, we define the cellular and molecular properties of a highly receptive state amenable to transcription factor-mediated direct conversion from fibroblasts to induced motor neurons. Using a well-defined model of direct conversion to a post-mitotic fate, we identify the highly proliferative, receptive state that transiently emerges during conversion. Through examining chromatin accessibility, histone marks, and nuclear features, we find that cells reprogram from a state characterized by global reductions in nuclear size and transcriptional activity. Supported by globally increased levels of H3K27me3, cells enter a quiescent-like state of reduced RNA metabolism and elevated expression of REST and p27, markers of quiescent neural stem cells. From this transient state, cells convert to neurons at high rates. Inhibition of Ezh2, the catalytic subunit of PRC2 that deposits H3K27me3, abolishes conversion. Our work offers a roadmap to identify global changes in cellular processes that define cells with different conversion potentials that may generalize to other cell-fate transitions.
    Highlights: Proliferation drives cells to a compact nuclear state that is receptive to TF-mediated conversion.Increased receptivity to TFs corresponds to reduced nuclear volumes.Reprogrammable cells display global, genome-wide increases in H3K27me3.High levels of H3K27me3 support cells' transits through a state of altered RNA metabolism.Inhibition of Ezh2 increases nuclear size, reduces the expression of the quiescence marker p27.Acute inhibition of Ezh2 abolishes motor neuron conversion.
    One Sentence Summary: Cells transit through a quiescent-like state characterized by global reductions in nuclear size and transcriptional activity to convert to neurons at high rates.
    DOI:  https://doi.org/10.1101/2024.11.22.624928
  6. Cell Rep. 2024 Dec 12. pii: S2211-1247(24)01356-1. [Epub ahead of print]43(12): 115005
    Design principles to tailor Hsp104 therapeutics.
    JiaBei Lin, Peter J Carman, Craig W Gambogi, Nathan M Kendsersky, Edward Chuang, Stephanie N Gates, Adam L Yokom, Alexandrea N Rizo, Daniel R Southworth, James Shorter.
      The hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated proteins. However, how ATP- or ADP-specific MD configurations regulate Hsp104 hexamers remains poorly understood. Here, we define an ATP-specific network of interprotomer contacts between nucleotide-binding domain 1 (NBD1) and MD helix L1, which tunes Hsp70 collaboration. Manipulating this network can (1) reduce Hsp70 collaboration without enhancing activity, (2) generate Hsp104 hypomorphs that collaborate selectively with class B Hsp40s, (3) produce Hsp70-independent potentiated variants, or (4) create species barriers between Hsp104 and Hsp70. Conversely, ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity, and their perturbation frequently potentiates Hsp104. Importantly, adjusting an NBD1:MD helix L1 rheostat via rational design enables finely tuned collaboration with Hsp70 to safely potentiate Hsp104, minimize off-target toxicity, and counteract FUS and TDP-43 proteinopathies in human cells. Thus, we establish design principles to tailor Hsp104 therapeutics.
    Keywords:  ALS/FTD; CP: Molecular biology; FUS; Hsp104; Hsp70; TDP-43; disaggregase; neurodegeneration; protein engineering
    DOI:  https://doi.org/10.1016/j.celrep.2024.115005
  7. Mol Cell. 2024 Dec 05. pii: S1097-2765(24)00949-3. [Epub ahead of print]
    CRL3ARMC5 ubiquitin ligase and Integrator phosphatase form parallel mechanisms to control early stages of RNA Pol II transcription.
    Roberta Cacioppo, Alexander Gillis, Iván Shlamovitz, Andrew Zeller, Daniela Castiblanco, Alastair Crisp, Benjamin Haworth, Angela Arabiotorre, Pegah Abyaneh, Yu Bao, Julian E Sale, Scott Berry, Ana Tufegdžić Vidaković.
      Control of RNA polymerase II (RNA Pol II) through ubiquitylation is essential for the DNA-damage response. Here, we reveal a distinct ubiquitylation pathway in human cells, mediated by CRL3ARMC5, that targets excessive and defective RNA Pol II molecules at the initial stages of the transcription cycle. Upon ARMC5 loss, RNA Pol II accumulates in the free pool and in the promoter-proximal zone but is not permitted into elongation. We identify Integrator subunit 8 (INTS8) as a gatekeeper preventing the release of excess RNA Pol II molecules into gene bodies. Combined loss of ARMC5 and INTS8 has detrimental effects on cell growth and results in the uncontrolled release of excessive RNA Pol II complexes into early elongation, many of which are transcriptionally incompetent and fail to reach the ends of genes. These findings uncover CRL3ARMC5 and Integrator as two distinct pathways acting in parallel to monitor the quantity and quality of transcription complexes before they are licensed into elongation.
    Keywords:  ARMC5; CUL3; INTS8; Integrator; RNA polymerase II; elongation; pausing; promoter-proximal; transcription; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.024
  8. Dev Cell. 2024 Dec 09. pii: S1534-5807(24)00699-3. [Epub ahead of print]
    Morphogenesis and regeneration share a conserved core transition cell state program that controls lung epithelial cell fate.
    Xiangyi Ke, Benjamin van Soldt, Lukas Vlahos, Yizhuo Zhou, Jun Qian, Joel George, Claudia Capdevila, Ian Glass, Kelley Yan, Andrea Califano, Wellington V Cardoso.
      Transitional cell states are at the crossroads of crucial developmental and regenerative events, yet little is known about how these states emerge and influence outcomes. The alveolar and airway epithelia arise from distal lung multipotent progenitors, which undergo cell fate transitions to form these distinct compartments. The identification and impact of cell states in the developing lung are poorly understood. Here, we identified a population of Icam1/Nkx2-1 epithelial progenitors harboring a transitional state program remarkably conserved in humans and mice during lung morphogenesis and regeneration. Lineage-tracing and functional analyses reveal their role as progenitors to both airways and alveolar cells and the requirement of this transitional program to make distal lung progenitors competent to undergo airway cell fate specification. The identification of a common progenitor cell state in vastly distinct processes suggests a unified program reiteratively regulating outcomes in development and regeneration.
    Keywords:  epithelial cell fate; human lung development; lung repair-regeneration; morphogenesis; organoids; single-cell analysis; stem cell; transitional cell state
    DOI:  https://doi.org/10.1016/j.devcel.2024.11.017
  9. Development. 2024 Dec 09. pii: dev.202931. [Epub ahead of print]
    Temporal dynamics of BMP/Nodal ratio drive tissue-specific gastrulation morphogenesis.
    Alyssa A Emig, Megan Hansen, Sandra Grimm, Cristian Coarfa, Nathan D Lord, Margot Kossmann Williams.
      Anteroposterior (AP) elongation of the vertebrate body plan is driven by convergence and extension (C&E) gastrulation movements in both the mesoderm and neuroectoderm, but how or whether molecular regulation of C&E differs between tissues remains an open question. Using a zebrafish explant model of AP axis extension, we show that C&E of the neuroectoderm and mesoderm can be uncoupled ex vivo, and that morphogenesis of individual tissues results from distinct morphogen signaling dynamics. Using precise temporal manipulation of BMP and Nodal signaling, we identify a critical developmental window during which high or low BMP/Nodal ratios induce neuroectoderm- or mesoderm-driven C&E, respectively. Increased BMP activity similarly enhances C&E specifically in the ectoderm of intact zebrafish gastrulae, highlighting the in vivo relevance of our findings. Together, these results demonstrate that temporal dynamics of BMP and Nodal morphogen signaling activate distinct morphogenetic programs governing C&E gastrulation movements within individual tissues.
    Keywords:  BMP; Convergent extension; Gastrulation; Morphogenesis; Nodal; Zebrafish
    DOI:  https://doi.org/10.1242/dev.202931
  10. Cell. 2024 Dec 09. pii: S0092-8674(24)01328-X. [Epub ahead of print]
    Transposable element exonization generates a reservoir of evolving and functional protein isoforms.
    Yago A Arribas, Blandine Baudon, Maxime Rotival, Guadalupe Suárez, Pierre-Emmanuel Bonté, Vanessa Casas, Apollinaire Roubert, Paul Klein, Elisa Bonnin, Basma Mchich, Patricia Legoix, Sylvain Baulande, Benjamin Sadacca, Julien Diharce, Joshua J Waterfall, Catherine Etchebest, Montserrat Carrascal, Christel Goudot, Lluís Quintana-Murci, Marianne Burbage, Antonela Merlotti, Sebastian Amigorena.
      Alternative splicing enhances protein diversity in different ways, including through exonization of transposable elements (TEs). Recent transcriptomic analyses identified thousands of unannotated spliced transcripts with exonizing TEs, but their contribution to the proteome and biological relevance remains unclear. Here, we use transcriptome assembly, ribosome profiling, and proteomics to describe a population of 1,227 unannotated TE exonizing isoforms generated by mRNA splicing and recurrent in human populations. Despite being shorter and lowly expressed, these isoforms are shared between individuals and efficiently translated. Functional analyses show stable expression, specific cellular localization, and, in some cases, modified functions. Exonized TEs are rich in ancient genes, whereas the involved splice sites are recent and can be evolutionarily conserved. In addition, exonized TEs contribute to the secondary structure of the emerging isoforms, supporting their functional relevance. We conclude that TE-spliced isoforms represent a diversity reservoir of functional proteins on which natural selection can act.
    Keywords:  cryptic splice sites; exon birth; non-canonical proteome; protein evolution; protein isoforms; protein structure; proteomics; ribosome profiling; transposable elements; unannotated splicing
    DOI:  https://doi.org/10.1016/j.cell.2024.11.011
  11. Cell Rep. 2024 Dec 10. pii: S2211-1247(24)01426-8. [Epub ahead of print]43(12): 115075
    Enforced activation of the CREB/KDM2B axis prevents alcohol-induced embryonic developmental delay.
    Hang Liu, Qiyu Ren, Meihan Gong, Feifei Zuo, Qian Li, Dawei Huo, Ye Yuan, Yutong Zhang, Yu Kong, Xiaozhi Liu, Cailing Lu, Xudong Wu.
      Unintentional, early pregnancy alcohol consumption affects embryonic development. During the peri-implantation stage, coinciding with the transition from naive to primed pluripotency, the long isoform of KDM2B (KDM2BLF) underlies the de novo establishment of polycomb repressive complex (PRC) functions at promoters after fertilization. However, it remains unclear whether and how ethanol exposure affects this spatiotemporal chromatin setting. Here, we show that exposing peri-implantation mouse embryos to ethanol leads to impaired post-implantation development, mirrored by the delayed exit of naive pluripotency in acetaldehyde-treated embryonic stem cells. Remarkably, these abnormalities are linked to inadequate KDM2BLF expression and compromised deposition of PRC marks, which arise from cAMP response element-binding protein (CREB) inactivation. Accordingly, pharmacological activation of CREB effectively restores pluripotency transition partly dependent on KDM2BLF in vitro and ameliorates post-implantation embryonic defects in vivo. Therefore, our study highlights the pivotal role of the CREB/KDM2B axis in chromatin configuration and developmental programming, proposing potential preventive strategies against ethanol exposure-induced detrimental effects.
    Keywords:  CP: Developmental biology; CP: Molecular biology; CREB; H3K27me3; KDM2B; PDE4 inhibitor; PRC2; acetaldehyde; ethanol exposure; pluripotency; polycomb; post-implantation
    DOI:  https://doi.org/10.1016/j.celrep.2024.115075
  12. Trends Cell Biol. 2024 Dec 10. pii: S0962-8924(24)00229-0. [Epub ahead of print]
    Rhythmic forces shaping the zebrafish cardiac system.
    Hajime Fukui, Renee Wei-Yan Chow, Choon Hwai Yap, Julien Vermot.
      The structural development of the heart depends heavily on mechanical forces, and rhythmic contractions generate essential physical stimuli during morphogenesis. Cardiac cells play a critical role in coordinating this process by sensing and responding to these mechanical forces. In vivo, cells experience rhythmic spatial and temporal variations in deformation-related stresses throughout heart development. What impact do these mechanical forces have on heart morphogenesis? Recent work in zebrafish (Danio rerio) offers important insights into this question. This review focuses on endocardial (EdCs) and myocardial cells (cardiomyocytes, CMs), key cell types in the heart, and provides a comprehensive overview of forces and tissue mechanics in zebrafish and their direct influence on cardiac cell identity.
    Keywords:  Danio rerio; cardiac valve; endothelial to mesenchymal transition; finite element modeling; tissue mechanics; trabeculation
    DOI:  https://doi.org/10.1016/j.tcb.2024.10.012
  13. Elife. 2024 Dec 09. pii: RP88916. [Epub ahead of print]12
    Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos.
    Marius Regin, Yingnan Lei, Edouard Couvreu De Deckersberg, Charlotte Janssens, Anfien Huyghebaert, Yves Guns, Pieter Verdyck, Greta Verheyen, Hilde Van de Velde, Karen Sermon, Claudia Spits.
      About 70% of human cleavage stage embryos show chromosomal mosaicism, falling to 20% in blastocysts. Chromosomally mosaic human blastocysts can implant and lead to healthy new-borns with normal karyotypes. Studies in mouse embryos and human gastruloids showed that aneuploid cells are eliminated from the epiblast by p53-mediated apoptosis while being tolerated in the trophectoderm. These observations suggest a selective loss of aneuploid cells from human embryos, but the underlying mechanisms are not yet fully understood. Here, we investigated the cellular consequences of aneuploidy in a total of 125 human blastocysts. RNA-sequencing of trophectoderm cells showed activated p53 pathway and apoptosis proportionate to the level of chromosomal imbalance. Immunostaining corroborated that aneuploidy triggers proteotoxic stress, autophagy, p53-signaling, and apoptosis independent from DNA damage. Total cell numbers were lower in aneuploid embryos, due to a decline both in trophectoderm and in epiblast/primitive endoderm cell numbers. While lower cell numbers in trophectoderm may be attributed to apoptosis, aneuploidy impaired the second lineage segregation, particularly primitive endoderm formation. This might be reinforced by retention of NANOG. Our findings might explain why fully aneuploid embryos fail to further develop and we hypothesize that the same mechanisms lead to the removal of aneuploid cells from mosaic embryos.
    Keywords:  Embryology; apoptosis; autophagy; chromosomal mosaicism; chromosomes; developmental biology; gene expression; human; p53; proteotoxic stress
    DOI:  https://doi.org/10.7554/eLife.88916
  14. bioRxiv. 2024 Nov 28. pii: 2024.11.28.625860. [Epub ahead of print]
    Lamin B1-dependent regulation of human separase in mitosis.
    Julien Picotto, Francesca Cipressa, Didier Busso, Giovanni Cenci, Pascale Bertrand, Gaëlle Pennarun.
      Separase plays a central role in chromosome separation during mitosis and in centrosome cycle. Tight control of separase activity is required to prevent unscheduled resolution of sister chromatid cohesion and centrosome aberrations, thereby preserving genome stability. In mammals, despite their disassembly in early mitosis, some nuclear envelope components possess mitotic roles, but links with separase activity remain unexplored. Here, we uncover a new mechanism of separase regulation involving lamin B1, a key nuclear envelope factor. We show that separase and lamin B1 associate preferentially during early stages of mitosis. Importantly, lamin B1 depletion leads to an increase in separase recruitment on chromosomes together with premature chromatid separation, a phenotype reminiscent of separase overexpression. Conversely, similar to separase depletion, lamin B1 overexpression induces formation of diplochromosomes- resulting from chromatid separation failure-, in association with centrosome amplification. Importantly, increasing separase level prevents lamin B1-induced centrosome aberrations, suggesting a separase defect at their origin. Indeed, we show that overexpression of lamin B1 leads to a decrease in the recruitment of separase to the chromosome and a delay in its activity. Taken together, this study unveils a novel mechanism of separase regulation involving the nuclear envelope factor lamin B1, that is crucial for genome integrity maintenance.
    DOI:  https://doi.org/10.1101/2024.11.28.625860
  15. Elife. 2024 Dec 09. pii: RP93405. [Epub ahead of print]13
    Pharmacologically inducing regenerative cardiac cells by small molecule drugs.
    Wei Zhou, Kezhang He, Chiyin Wang, Pengqi Wang, Dan Wang, Bowen Wang, Han Geng, Hong Lian, Tianhua Ma, Yu Nie, Sheng Ding.
      Adult mammals, unlike some lower organisms, lack the ability to regenerate damaged hearts through cardiomyocytes (CMs) dedifferentiation into cells with regenerative capacity. Developing conditions to induce such naturally unavailable cells with potential to proliferate and differentiate into CMs, that is, regenerative cardiac cells (RCCs), in mammals will provide new insights and tools for heart regeneration research. In this study, we demonstrate that a two-compound combination, CHIR99021 and A-485 (2C), effectively induces RCCs from human embryonic stem cell-derived TNNT2+ CMs in vitro, as evidenced by lineage tracing experiments. Functional analysis shows that these RCCs express a broad spectrum of cardiogenesis genes and have the potential to differentiate into functional CMs, endothelial cells, and smooth muscle cells. Importantly, similar results were observed in neonatal rat CMs both in vitro and in vivo. Remarkably, administering 2C in adult mouse hearts significantly enhances survival and improves heart function post-myocardial infarction. Mechanistically, CHIR99021 is crucial for the transcriptional and epigenetic activation of genes essential for RCC development, while A-485 primarily suppresses H3K27Ac and particularly H3K9Ac in CMs. Their synergistic effect enhances these modifications on RCC genes, facilitating the transition from CMs to RCCs. Therefore, our findings demonstrate the feasibility and reveal the mechanisms of pharmacological induction of RCCs from endogenous CMs, which could offer a promising regenerative strategy to repair injured hearts.
    Keywords:  cardiomyocytes; chemicals; heart; human; regeneration; regenerative medicine; reprogramming; stem cells
    DOI:  https://doi.org/10.7554/eLife.93405
  16. Nat Cardiovasc Res. 2024 Dec;3(12): 1531-1548
    PDGFRA is a conserved HAND2 effector during early cardiac development.
    Yanli Xu, Rupal Gehlot, Samuel J Capon, Marga Albu, Jonas Gretz, Joshua Bloomekatz, Kenny Mattonet, Dubravka Vucicevic, Sweta Talyan, Khrievono Kikhi, Stefan Günther, Mario Looso, Beth A Firulli, Miloslav Sanda, Anthony B Firulli, Scott Allen Lacadie, Deborah Yelon, Didier Y R Stainier.
      The basic helix-loop-helix transcription factor HAND2 has multiple roles during vertebrate organogenesis, including cardiogenesis. However, much remains to be uncovered about its mechanism of action. Here, we show the generation of several hand2 mutant alleles in zebrafish and demonstrate that dimerization-deficient mutants display the null phenotype but DNA-binding-deficient mutants do not. Rescue experiments with Hand2 variants using a newly identified hand2 enhancer confirmed these observations. To identify Hand2 effectors critical for cardiogenesis, we analyzed the transcriptomes of hand2 loss- and gain-of-function embryonic cardiomyocytes and tested the function of eight candidate genes in vivo; pdgfra was most effective in rescuing myocardial migration in hand2 mutants. Accordingly, we identified a putative Hand2-binding region in the zebrafish pdgfra locus that is important for its expression. In addition, Hand2 loss- and gain-of-function experiments in mouse embryonic stem cell-derived cardiac cells decreased and increased Pdgfra expression, respectively. Altogether, these results further our mechanistic understanding of HAND2 function during early cardiogenesis.
    DOI:  https://doi.org/10.1038/s44161-024-00574-1
  17. Nat Aging. 2024 Dec 10.
    IL-23R is a senescence-linked circulating and tissue biomarker of aging.
    Chase M Carver, Sonia L Rodriguez, Elizabeth J Atkinson, Andrew J Dosch, Niels C Asmussen, Paul T Gomez, Ethan A Leitschuh, Jair M Espindola-Netto, Karthik B Jeganathan, Madison G Whaley, Theodore M Kamenecka, Darren J Baker, Andrew J Haak, Nathan K LeBrasseur, Marissa J Schafer.
      Cellular senescence is an aging mechanism characterized by cell cycle arrest and a senescence-associated secretory phenotype (SASP). Preclinical studies demonstrate that senolytic drugs, which target survival pathways in senescent cells, can counteract age-associated conditions that span several organs. The comparative efficacy of distinct senolytic drugs for modifying aging and senescence biomarkers in vivo has not been demonstrated. Here, we established aging- and senescence-related plasma proteins and tissue transcripts that changed in old versus young female and male mice. We investigated responsivity to acute treatment with venetoclax, navitoclax, fisetin or luteolin versus transgenic senescent cell clearance in aged p16-InkAttac mice. We discovered that age-dependent changes in plasma proteins, including IL-23R, CCL5 and CA13, were reversed by senotherapeutics, which corresponded to expression differences in tissues, particularly in the kidney. In plasma from humans across the lifespan, IL-23R increased with age. Our results reveal circulating factors as candidate mediators of senescence-associated interorgan signal transduction and translationally impactful biomarkers of systemic senescent cell burden.
    DOI:  https://doi.org/10.1038/s43587-024-00752-7
  18. Dev Cell. 2024 11 27. pii: S1534-5807(24)00672-5. [Epub ahead of print]
    Microbiota-derived short-chain fatty acids determine stem cell characteristics of gastric chief cells.
    Haengdueng Jeong, Buhyun Lee, Soo Young Cho, Yura Lee, Jiseon Kim, Sumin Hur, Kyungrae Cho, Kwang H Kim, Sung-Hee Kim, Ki Taek Nam.
      The gastric mucosa is a highly dynamic tissue that undergoes constant self-renewal through stem cell differentiation. Chief cells maintain a quiescent state in homeostasis but are responsible for regeneration after injury. Although the role of microbiome-host interactions in the intestine is well studied, less is known about these interactions in the stomach. Using the mouse organoid and germ-free mouse models, we show that microbiota-derived short-chain fatty acids (SCFAs) suppress the proliferation of chief cells in mice. This effect is mediated by activation of G-protein-coupled receptor 43. Most importantly, through metabolomics and transplantation studies, we show butyrate-producing Lactobacillus intestinalis modulates the proliferation of chief cells in mice. Our findings identify a mechanism by which the microbiota regulates the cell characteristics of chief cells, providing insight into the complex interplay between the host and its microbial environment and the mechanisms underlying gastric homeostasis, with potential therapeutic implications for gastric diseases.
    Keywords:  SCFA; chief cell; gastric stem cells; germ-free; microbe-host interaction
    DOI:  https://doi.org/10.1016/j.devcel.2024.11.007
  19. Nature. 2024 Dec 11.
    In situ analysis reveals the TRiC duty cycle and PDCD5 as an open-state cofactor.
    Huaipeng Xing, Remus R E Rosenkranz, Piere Rodriguez-Aliaga, Ting-Ting Lee, Tomáš Majtner, Stefanie Böhm, Beata Turoňová, Judith Frydman, Martin Beck.
      The ring-shaped chaperonin T-complex protein ring complex (TRiC; also known as chaperonin containing TCP-1, CCT) is an ATP-driven protein-folding machine that is essential for maintenance of cellular homeostasis1,2. Its dysfunction is related to cancer and neurodegenerative disease3,4. Despite its importance, how TRiC works in the cell remains unclear. Here we structurally analysed the architecture, conformational dynamics and spatial organization of the chaperonin TRiC in human cells using cryo-electron tomography. We resolved distinctive open, closed, substrate-bound and prefoldin-associated states of TRiC, and reconstructed its duty cycle in situ. The substrate-bound open and symmetrically closed TRiC states were equally abundant. Closed TRiC containing substrate forms distinctive clusters, indicative of spatial organization. Translation inhibition did not fundamentally change the distribution of duty cycle intermediates, but reduced substrate binding for all states as well as cluster formation. From our in-cell structures, we identified the programmed cell death protein 5 (PDCD5) as an interactor that specifically binds to almost all open but not closed TRiC, in a position that is compatible with both substrate and prefoldin binding. Our data support a model in which TRiC functions at near full occupancy to fold newly synthesized proteins inside cells. Defining the TRiC cycle and function inside cells lays the foundation to understand its dysfunction during cancer and neurodegeneration.
    DOI:  https://doi.org/10.1038/s41586-024-08321-z
  20. Nat Aging. 2024 Dec;4(12): 1711-1730
    Hallmarks of female reproductive aging in physiologic aging mice.
    Julia L Balough, Shweta S Dipali, Karen Velez, T Rajendra Kumar, Francesca E Duncan.
      The female reproductive axis is one of the first organ systems to age, which has consequences for fertility and overall health. Here, we provide a comprehensive overview of the biological process of female reproductive aging across reproductive organs, tissues and cells based on research with widely used physiologic aging mouse models, and describe the mechanisms that underpin these phenotypes. Overall, aging is associated with dysregulation of the hypothalamic-pituitary-ovarian axis, perturbations of the ovarian stroma, reduced egg quantity and quality, and altered uterine morphology and function that contributes to reduced capacity for fertilization and impaired embryo development. Ultimately, these age-related phenotypes contribute to altered pregnancy outcomes and adverse consequences in offspring. Conserved mechanisms of aging, as well as those unique to the reproductive system, underlie these phenotypes. The knowledge of such mechanisms will lead to development of therapeutics to extend female reproductive longevity and support endocrine function and overall health.
    DOI:  https://doi.org/10.1038/s43587-024-00769-y
  21. Science. 2024 Dec 13. 386(6727): eado5561
    An injury-induced mesenchymal-epithelial cell niche coordinates regenerative responses in the lung.
    Dakota L Jones, Michael P Morley, Xinyuan Li, Yun Ying, Gan Zhao, Sarah E Schaefer, Luis R Rodriguez, Fabian L Cardenas-Diaz, Shanru Li, Su Zhou, Ullas V Chembazhi, Mijeong Kim, Chen Shen, Ana Nottingham, Susan M Lin, Edward Cantu, Joshua M Diamond, Maria C Basil, Andrew E Vaughan, Edward E Morrisey.
      Severe lung injury causes airway basal stem cells to migrate and outcompete alveolar stem cells, resulting in dysplastic repair. We found that this "stem cell collision" generates an injury-induced tissue niche containing keratin 5+ epithelial cells and plastic Pdgfra+ mesenchymal cells. Single-cell analysis revealed that the injury-induced niche is governed by mesenchymal proliferation and Notch signaling, which suppressed Wnt/Fgf signaling in the injured niche. Conversely, loss of Notch signaling rewired alveolar signaling patterns to promote functional regeneration and gas exchange. Signaling patterns in injury-induced niches can differentiate fibrotic from degenerative human lung diseases through altering the direction of Wnt/Fgf signaling. Thus, we have identified an injury-induced niche in the lung with the ability to discriminate human lung disease phenotypes.
    DOI:  https://doi.org/10.1126/science.ado5561
  22. PLoS Genet. 2024 Dec 13. 20(12): e1011513
    The cells are all-right: Regulation of the Lefty genes by separate enhancers in mouse embryonic stem cells.
    Tiegh Taylor, Hongyu Vicky Zhu, Sakthi D Moorthy, Nawrah Khader, Jennifer A Mitchell.
      Enhancers play a critical role in regulating precise gene expression patterns essential for development and cellular identity; however, how gene-enhancer specificity is encoded within the genome is not clearly defined. To investigate how this specificity arises within topologically associated domains (TAD), we performed allele-specific genome editing of sequences surrounding the Lefty1 and Lefty2 paralogs in mouse embryonic stem cells. The Lefty genes arose from a tandem duplication event and these genes interact with each other in chromosome conformation capture assays which place these genes within the same TAD. Despite their physical proximity, we demonstrate that these genes are primarily regulated by separate enhancer elements. Through CRISPR-Cas9 mediated deletions to remove the intervening chromatin between the Lefty genes, we reveal a distance-dependent dosage effect of the Lefty2 enhancer on Lefty1 expression. These findings indicate a role for chromatin distance in insulating gene expression domains in the Lefty locus in the absence of architectural insulation.
    DOI:  https://doi.org/10.1371/journal.pgen.1011513
  23. Nat Methods. 2024 Dec;21(12): 2220-2222
    A new understanding of tissue biology from MS-based proteomics at single-cell resolution.
    Thierry M Nordmann, Andreas Mund, Matthias Mann.
      
    DOI:  https://doi.org/10.1038/s41592-024-02541-x
This page is being maintained by Thomas Krichel. It was last updated on 2025‒01‒26 at 8:56.