bims-ginsta Biomed News
on Genome instability
Issue of 2024–05–05
fifteen papers selected by
Jinrong Hu, National University of Singapore
  1. Mechanics of human embryo compaction.
  2. Lumen expansion is initially driven by apical actin polymerization followed by osmotic pressure in a human epiblast model.
  3. Dissecting gene activation and chromatin remodeling dynamics in single human cells undergoing reprogramming.
  4. The Wnt-dependent master regulator NKX1-2 controls mouse pre-implantation development.
  5. BMP7 promotes cardiomyocyte regeneration in zebrafish and adult mice.
  6. Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK activation.
  7. Mitochondrially-associated actin waves maintain organelle homeostasis and equitable inheritance.
  8. Multimodal decoding of human liver regeneration.
  9. Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.
  10. Mitochondrial transfer mediates endothelial cell engraftment through mitophagy.
  11. Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease.
  12. Transient Zn2+ deficiency induces replication stress and compromises daughter cell proliferation.
  13. CDK4/6 activity is required during G2 arrest to prevent stress-induced endoreplication.
  14. Combinatorial interpretation of BMP and WNT controls the decision between primitive streak and extraembryonic fates.
  15. Alternative splicing of a chromatin modifier alters the transcriptional regulatory programs of stem cell maintenance and neuronal differentiation.
  1. Nature. 2024 May 01.
    Mechanics of human embryo compaction.
    Julie Firmin, Nicolas Ecker, Diane Rivet Danon, Özge Özgüç, Virginie Barraud Lange, Hervé Turlier, Catherine Patrat, Jean-Léon Maître.
      The shaping of human embryos begins with compaction, during which cells come into close contact1,2. Assisted reproductive technology studies indicate that human embryos fail compaction primarily because of defective adhesion3,4. On the basis of our current understanding of animal morphogenesis5,6, other morphogenetic engines, such as cell contractility, could be involved in shaping human embryos. However, the molecular, cellular and physical mechanisms driving human embryo morphogenesis remain uncharacterized. Using micropipette aspiration on human embryos donated to research, we have mapped cell surface tensions during compaction. This shows a fourfold increase of tension at the cell-medium interface whereas cell-cell contacts keep a steady tension. Therefore, increased tension at the cell-medium interface drives human embryo compaction, which is qualitatively similar to compaction in mouse embryos7. Further comparison between human and mouse shows qualitatively similar but quantitively different mechanical strategies, with human embryos being mechanically least efficient. Inhibition of cell contractility and cell-cell adhesion in human embryos shows that, whereas both cellular processes are required for compaction, only contractility controls the surface tensions responsible for compaction. Cell contractility and cell-cell adhesion exhibit distinct mechanical signatures when faulty. Analysing the mechanical signature of naturally failing embryos, we find evidence that non-compacting or partially compacting embryos containing excluded cells have defective contractility. Together, our study shows that an evolutionarily conserved increase in cell contractility is required to generate the forces driving the first morphogenetic movement shaping the human body.
    DOI:  https://doi.org/10.1038/s41586-024-07351-x
  2. Cell Stem Cell. 2024 May 02. pii: S1934-5909(24)00097-3. [Epub ahead of print]31(5): 640-656.e8
    Lumen expansion is initially driven by apical actin polymerization followed by osmotic pressure in a human epiblast model.
    Dhiraj Indana, Andrei Zakharov, Youngbin Lim, Alexander R Dunn, Nidhi Bhutani, Vivek B Shenoy, Ovijit Chaudhuri.
      Post-implantation, the pluripotent epiblast in a human embryo forms a central lumen, paving the way for gastrulation. Osmotic pressure gradients are considered the drivers of lumen expansion across development, but their role in human epiblasts is unknown. Here, we study lumenogenesis in a pluripotent-stem-cell-based epiblast model using engineered hydrogels. We find that leaky junctions prevent osmotic pressure gradients in early epiblasts and, instead, forces from apical actin polymerization drive lumen expansion. Once the lumen reaches a radius of ∼12 μm, tight junctions mature, and osmotic pressure gradients develop to drive further growth. Computational modeling indicates that apical actin polymerization into a stiff network mediates initial lumen expansion and predicts a transition to pressure-driven growth in larger epiblasts to avoid buckling. Human epiblasts show transcriptional signatures consistent with these mechanisms. Thus, actin polymerization drives lumen expansion in the human epiblast and may serve as a general mechanism of early lumenogenesis.
    Keywords:  actin; computational modeling; embryogenesis; engineered hydrogels; human epiblast model; induced pluripotent stem cells; lumen; morphogenesis; osmotic pressure; tissue biophysics
    DOI:  https://doi.org/10.1016/j.stem.2024.03.016
  3. Cell Rep. 2024 May 02. pii: S2211-1247(24)00498-4. [Epub ahead of print]43(5): 114170
    Dissecting gene activation and chromatin remodeling dynamics in single human cells undergoing reprogramming.
    Jose A Martinez-Sarmiento, Maria Pia Cosma, Melike Lakadamyali.
      During cell fate transitions, cells remodel their transcriptome, chromatin, and epigenome; however, it has been difficult to determine the temporal dynamics and cause-effect relationship between these changes at the single-cell level. Here, we employ the heterokaryon-mediated reprogramming system as a single-cell model to dissect key temporal events during early stages of pluripotency conversion using super-resolution imaging. We reveal that, following heterokaryon formation, the somatic nucleus undergoes global chromatin decompaction and removal of repressive histone modifications H3K9me3 and H3K27me3 without acquisition of active modifications H3K4me3 and H3K9ac. The pluripotency gene OCT4 (POU5F1) shows nascent and mature RNA transcription within the first 24 h after cell fusion without requiring an initial open chromatin configuration at its locus. NANOG, conversely, has significant nascent RNA transcription only at 48 h after cell fusion but, strikingly, exhibits genomic reopening early on. These findings suggest that the temporal relationship between chromatin compaction and gene activation during cellular reprogramming is gene context dependent.
    Keywords:  CP: Molecular biology; CP: Stem cell research; Nanog; Oct4; cellular reprogramming; chromatin; pluripotency; single-molecule FISH; super-resolution microscopy
    DOI:  https://doi.org/10.1016/j.celrep.2024.114170
  4. Stem Cell Reports. 2024 Apr 26. pii: S2213-6711(24)00110-3. [Epub ahead of print]
    The Wnt-dependent master regulator NKX1-2 controls mouse pre-implantation development.
    Shoma Nakagawa, Davide Carnevali, Xiangtian Tan, Mariano J Alvarez, David-Emlyn Parfitt, Umberto Di Vicino, Karthik Arumugam, William Shin, Sergi Aranda, Davide Normanno, Ruben Sebastian-Perez, Chiara Cannatá, Paola Cortes, Maria Victoria Neguembor, Michael M Shen, Andrea Califano, Maria Pia Cosma.
      Embryo size, specification, and homeostasis are regulated by a complex gene regulatory and signaling network. Here we used gene expression signatures of Wnt-activated mouse embryonic stem cell (mESC) clones to reverse engineer an mESC regulatory network. We identify NKX1-2 as a novel master regulator of preimplantation embryo development. We find that Nkx1-2 inhibition reduces nascent RNA synthesis, downregulates genes controlling ribosome biogenesis, RNA translation, and transport, and induces severe alteration of nucleolus structure, resulting in the exclusion of RNA polymerase I from nucleoli. In turn, NKX1-2 loss of function leads to chromosome missegregation in the 2- to 4-cell embryo stages, severe decrease in blastomere numbers, alterations of tight junctions (TJs), and impairment of microlumen coarsening. Overall, these changes impair the blastocoel expansion-collapse cycle and embryo cavitation, leading to altered lineage specification and developmental arrest.
    Keywords:  NKX1-2; RNA polymerase I; Wnt signaling; embryonic stem cell; master regulator analysis; mouse embryo; nucleolus; ribosome biogenesis; systems biology
    DOI:  https://doi.org/10.1016/j.stemcr.2024.04.004
  5. Cell Rep. 2024 Apr 27. pii: S2211-1247(24)00490-X. [Epub ahead of print]43(5): 114162
    BMP7 promotes cardiomyocyte regeneration in zebrafish and adult mice.
    Chiara Bongiovanni, Hanna Bueno-Levy, Denise Posadas Pena, Irene Del Bono, Carmen Miano, Stefano Boriati, Silvia Da Pra, Francesca Sacchi, Simone Redaelli, Max Bergen, Donatella Romaniello, Francesca Pontis, Riccardo Tassinari, Laura Kellerer, Ilaria Petraroia, Martina Mazzeschi, Mattia Lauriola, Carlo Ventura, Stephan Heermann, Gilbert Weidinger, Eldad Tzahor, Gabriele D'Uva.
      Zebrafish have a lifelong cardiac regenerative ability after damage, whereas mammals lose this capacity during early postnatal development. This study investigated whether the declining expression of growth factors during postnatal mammalian development contributes to the decrease of cardiomyocyte regenerative potential. Besides confirming the proliferative ability of neuregulin 1 (NRG1), interleukin (IL)1b, receptor activator of nuclear factor kappa-Β ligand (RANKL), insulin growth factor (IGF)2, and IL6, we identified other potential pro-regenerative factors, with BMP7 exhibiting the most pronounced efficacy. Bmp7 knockdown in neonatal mouse cardiomyocytes and loss-of-function in adult zebrafish during cardiac regeneration reduced cardiomyocyte proliferation, indicating that Bmp7 is crucial in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression in regenerating zebrafish or administration at post-mitotic juvenile and adult mouse stages, in vitro and in vivo following myocardial infarction, enhanced cardiomyocyte cycling. Mechanistically, BMP7 stimulated proliferation through BMPR1A/ACVR1 and ACVR2A/BMPR2 receptors and downstream SMAD5, ERK, and AKT signaling. Overall, BMP7 administration is a promising strategy for heart regeneration.
    Keywords:  AKT; BMP7; CP: Developmental biology; CP: Stem cell research; ERK; SMAD5; cardiac injuries; cardiomyocyte proliferation; heart regeneration; mice; regenerative growth factors; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2024.114162
  6. Nat Cell Biol. 2024 Apr 30.
    Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK activation.
    Tianchi Xin, Sara Gallini, Haoyang Wei, David G Gonzalez, Catherine Matte-Martone, Hiroki Machida, Hironobu Fujiwara, H Amalia Pasolli, Kathleen C Suozzi, Lauren E Gonzalez, Sergi Regot, Valentina Greco.
      Tissue regeneration and maintenance rely on coordinated stem cell behaviours. This orchestration can be impaired by oncogenic mutations leading to cancer. However, it is largely unclear how oncogenes perturb stem cells' orchestration to disrupt tissue. Here we used intravital imaging to investigate the mechanisms by which oncogenic Kras mutation causes tissue disruption in the hair follicle. Through longitudinally tracking hair follicles in live mice, we found that KrasG12D, a mutation that can lead to squamous cell carcinoma, induces epithelial tissue deformation in a spatiotemporally specific manner, linked with abnormal cell division and migration. Using a reporter mouse capture real-time ERK signal dynamics at the single-cell level, we discovered that KrasG12D, but not a closely related mutation HrasG12V, converts ERK signal in stem cells from pulsatile to sustained. Finally, we demonstrated that interrupting sustained ERK signal reverts KrasG12D-induced tissue deformation through modulating specific features of cell migration and division.
    DOI:  https://doi.org/10.1038/s41556-024-01413-y
  7. Curr Opin Cell Biol. 2024 Apr 30. pii: S0955-0674(24)00043-7. [Epub ahead of print]88 102364
    Mitochondrially-associated actin waves maintain organelle homeostasis and equitable inheritance.
    Stephen M Coscia, Andrew S Moore, Yvette C Wong, Erika L F Holzbaur.
      First identified in dividing cells as revolving clusters of actin filaments, these are now understood as mitochondrially-associated actin waves that are active throughout the cell cycle. These waves are formed from the polymerization of actin onto a subset of mitochondria. Within minutes, this F-actin depolymerizes while newly formed actin filaments assemble onto neighboring mitochondria. In interphase, actin waves locally fragment the mitochondrial network, enhancing mitochondrial content mixing to maintain organelle homeostasis. In dividing cells actin waves spatially mix mitochondria in the mother cell to ensure equitable partitioning of these organelles between daughter cells. Progress has been made in understanding the consequences of actin cycling as well as the underlying molecular mechanisms, but many questions remain, and here we review these elements. Also, we draw parallels between mitochondrially-associated actin cycling and cortical actin waves. These dynamic systems highlight the remarkable plasticity of the actin cytoskeleton.
    DOI:  https://doi.org/10.1016/j.ceb.2024.102364
  8. Nature. 2024 May 01.
    Multimodal decoding of human liver regeneration.
    K P Matchett, J R Wilson-Kanamori, J R Portman, C A Kapourani, F Fercoq, S May, E Zajdel, M Beltran, E F Sutherland, J B G Mackey, M Brice, G C Wilson, S J Wallace, L Kitto, N T Younger, R Dobie, D J Mole, G C Oniscu, S J Wigmore, P Ramachandran, C A Vallejos, N O Carragher, M M Saeidinejad, A Quaglia, R Jalan, K J Simpson, T J Kendall, J A Rule, W M Lee, M Hoare, C J Weston, J C Marioni, S A Teichmann, T G Bird, L M Carlin, N C Henderson.
      The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.
    DOI:  https://doi.org/10.1038/s41586-024-07376-2
  9. Cell. 2024 Apr 25. pii: S0092-8674(24)00400-8. [Epub ahead of print]
    Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.
    Xuezhao Liu, Dazhuan Eric Xin, Xiaowen Zhong, Chuntao Zhao, Zhidan Li, Liguo Zhang, Adam J Dourson, Lindsay Lee, Shreya Mishra, Arman E Bayat, Eva Nicholson, William L Seibel, Bingfang Yan, Joel Mason, Bradley J Turner, David G Gonsalvez, William Ong, Sing Yian Chew, Balaram Ghosh, Sung Ok Yoon, Mei Xin, Zhigang He, Jason Tchieu, Michael Wegner, Klaus-Armin Nave, Robin J M Franklin, Ranjan Dutta, Bruce D Trapp, Ming Hu, Matthew A Smith, Michael P Jankowski, Samantha K Barton, Xuelian He, Q Richard Lu.
      Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.
    Keywords:  Epigenetic silencing; HDAC3 Inhibition; SREBP condensation; aging; chromatin remodeling; lipid/cholesterol biosynthesis; multiple sclerosis; myelin regeneration; oligodendrocyte; small molecule
    DOI:  https://doi.org/10.1016/j.cell.2024.04.005
  10. Nature. 2024 May 01.
    Mitochondrial transfer mediates endothelial cell engraftment through mitophagy.
    Ruei-Zeng Lin, Gwang-Bum Im, Allen Chilun Luo, Yonglin Zhu, Xuechong Hong, Joseph Neumeyer, Hong-Wen Tang, Norbert Perrimon, Juan M Melero-Martin.
      Ischaemic diseases such as critical limb ischaemia and myocardial infarction affect millions of people worldwide1. Transplanting endothelial cells (ECs) is a promising therapy in vascular medicine, but engrafting ECs typically necessitates co-transplanting perivascular supporting cells such as mesenchymal stromal cells (MSCs), which makes clinical implementation complicated2,3. The mechanisms that enable MSCs to facilitate EC engraftment remain elusive. Here we show that, under cellular stress, MSCs transfer mitochondria to ECs through tunnelling nanotubes, and that blocking this transfer impairs EC engraftment. We devised a strategy to artificially transplant mitochondria, transiently enhancing EC bioenergetics and enabling them to form functional vessels in ischaemic tissues without the support of MSCs. Notably, exogenous mitochondria did not integrate into the endogenous EC mitochondrial pool, but triggered mitophagy after internalization. Transplanted mitochondria co-localized with autophagosomes, and ablation of the PINK1-Parkin pathway negated the enhanced engraftment ability of ECs. Our findings reveal a mechanism that underlies the effects of mitochondrial transfer between mesenchymal and endothelial cells, and offer potential for a new approach for vascular cell therapy.
    DOI:  https://doi.org/10.1038/s41586-024-07340-0
  11. Cell Stem Cell. 2024 Apr 22. pii: S1934-5909(24)00129-2. [Epub ahead of print]
    Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease.
    Biao Huang, Zipeng Zeng, Sunghyun Kim, Connor C Fausto, Kari Koppitch, Hui Li, Zexu Li, Xi Chen, Jinjin Guo, Chennan C Zhang, Tianyi Ma, Pedro Medina, Megan E Schreiber, Mateo W Xia, Ariel C Vonk, Tianyuan Xiang, Tadrushi Patel, Yidan Li, Riana K Parvez, Balint Der, Jyun Hao Chen, Zhenqing Liu, Matthew E Thornton, Brendan H Grubbs, Yarui Diao, Yali Dou, Ksenia Gnedeva, Qilong Ying, Nuria M Pastor-Soler, Teng Fei, Kenneth R Hallows, Nils O Lindström, Andrew P McMahon, Zhongwei Li.
      Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here, manipulation of p38 and YAP activity allowed for long-term clonal expansion of primary mouse and human NPCs and induced NPCs (iNPCs) from human pluripotent stem cells (hPSCs). Molecular analyses demonstrated that cultured iNPCs closely resemble primary human NPCs. iNPCs generated nephron organoids with minimal off-target cell types and enhanced maturation of podocytes relative to published human kidney organoid protocols. Surprisingly, the NPC culture medium uncovered plasticity in human podocyte programs, enabling podocyte reprogramming to an NPC-like state. Scalability and ease of genome editing facilitated genome-wide CRISPR screening in NPC culture, uncovering genes associated with kidney development and disease. Further, NPC-directed modeling of autosomal-dominant polycystic kidney disease (ADPKD) identified a small-molecule inhibitor of cystogenesis. These findings highlight a broad application for the reported iNPC platform in the study of kidney development, disease, plasticity, and regeneration.
    Keywords:  CAKUT; CRISPR screen; NPC; PKD; Wilms tumor; cellular plasticity; congenital anomalies of the kidney and urinary tract; hPSC; human pluripotent stem cell; kidney organoid; nephron progenitor cell; podocyte; polycystic kidney disease
    DOI:  https://doi.org/10.1016/j.stem.2024.04.002
  12. Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2321216121
    Transient Zn2+ deficiency induces replication stress and compromises daughter cell proliferation.
    Samuel E Holtzen, Elnaz Navid, Joseph D Kainov, Amy E Palmer.
      Cells must replicate their genome quickly and accurately, and they require metabolites and cofactors to do so. Ionic zinc (Zn2+) is an essential micronutrient that is required for hundreds of cellular processes, including DNA synthesis and adequate proliferation. Deficiency in this micronutrient impairs DNA synthesis and inhibits proliferation, but the mechanism is unknown. Using fluorescent reporters to track single cells via long-term live-cell imaging, we find that Zn2+ is required at the G1/S transition and during S phase for timely completion of S phase. A short pulse of Zn2+ deficiency impairs DNA synthesis and increases markers of replication stress. These markers of replication stress are reversed upon resupply of Zn2+. Finally, we find that if Zn2+ is chelated during the mother cell's S phase, daughter cells enter a transient quiescent state, maintained by sustained expression of p21, which disappears upon reentry into the cell cycle. In summary, short pulses of mild Zn2+ deficiency in S phase specifically induce replication stress, which causes downstream proliferation impairments in daughter cells.
    Keywords:  cell cycle; replication stress; single cell; zinc; zinc deficiency
    DOI:  https://doi.org/10.1073/pnas.2321216121
  13. Science. 2024 May 03. 384(6695): eadi2421
    CDK4/6 activity is required during G2 arrest to prevent stress-induced endoreplication.
    Connor McKenney, Yovel Lendner, Adler Guerrero Zuniga, Niladri Sinha, Benjamin Veresko, Timothy J Aikin, Sergi Regot.
      Cell cycle events are coordinated by cyclin-dependent kinases (CDKs) to ensure robust cell division. CDK4/6 and CDK2 regulate the growth 1 (G1) to synthesis (S) phase transition of the cell cycle by responding to mitogen signaling, promoting E2F transcription and inhibition of the anaphase-promoting complex. We found that this mechanism was still required in G2-arrested cells to prevent cell cycle exit after the S phase. This mechanism revealed a role for CDK4/6 in maintaining the G2 state, challenging the notion that the cell cycle is irreversible and that cells do not require mitogens after passing the restriction point. Exit from G2 occurred during ribotoxic stress and was actively mediated by stress-activated protein kinases. Upon relief of stress, a significant fraction of cells underwent a second round of DNA replication that led to whole-genome doubling.
    DOI:  https://doi.org/10.1126/science.adi2421
  14. Cell Syst. 2024 Apr 26. pii: S2405-4712(24)00116-9. [Epub ahead of print]
    Combinatorial interpretation of BMP and WNT controls the decision between primitive streak and extraembryonic fates.
    Elena Camacho-Aguilar, Sumin T Yoon, Miguel A Ortiz-Salazar, Siqi Du, M Cecilia Guerra, Aryeh Warmflash.
      BMP signaling is essential for mammalian gastrulation, as it initiates a cascade of signals that control self-organized patterning. As development is highly dynamic, it is crucial to understand how time-dependent combinatorial signaling affects cellular differentiation. Here, we show that BMP signaling duration is a crucial control parameter that determines cell fates upon the exit from pluripotency through its interplay with the induced secondary signal WNT. BMP signaling directly converts cells from pluripotent to extraembryonic fates while simultaneously upregulating Wnt signaling, which promotes primitive streak and mesodermal specification. Using live-cell imaging of signaling and cell fate reporters together with a simple mathematical model, we show that this circuit produces a temporal morphogen effect where, once BMP signal duration is above a threshold for differentiation, intermediate and long pulses of BMP signaling produce specification of mesoderm and extraembryonic fates, respectively. Our results provide a systems-level picture of how these signaling pathways control the landscape of early human development.
    Keywords:  cell differentiation; embryonic stem cells; gastrulation; live-cell imaging; mathematical modeling; regulatory network; signaling
    DOI:  https://doi.org/10.1016/j.cels.2024.04.001
  15. Cell Stem Cell. 2024 May 02. pii: S1934-5909(24)00128-0. [Epub ahead of print]31(5): 754-771.e6
    Alternative splicing of a chromatin modifier alters the transcriptional regulatory programs of stem cell maintenance and neuronal differentiation.
    Mohammad Nazim, Chia-Ho Lin, An-Chieh Feng, Wen Xiao, Kyu-Hyeon Yeom, Mulin Li, Allison E Daly, Xianglong Tan, Ha Vu, Jason Ernst, Michael F Carey, Stephen T Smale, Douglas L Black.
      Development of embryonic stem cells (ESCs) into neurons requires intricate regulation of transcription, splicing, and translation, but how these processes interconnect is not understood. We found that polypyrimidine tract binding protein 1 (PTBP1) controls splicing of DPF2, a subunit of BRG1/BRM-associated factor (BAF) chromatin remodeling complexes. Dpf2 exon 7 splicing is inhibited by PTBP1 to produce the DPF2-S isoform early in development. During neuronal differentiation, loss of PTBP1 allows exon 7 inclusion and DPF2-L expression. Different cellular phenotypes and gene expression programs were induced by these alternative DPF2 isoforms. We identified chromatin binding sites enriched for each DPF2 isoform, as well as sites bound by both. In ESC, DPF2-S preferential sites were bound by pluripotency factors. In neuronal progenitors, DPF2-S sites were bound by nuclear factor I (NFI), while DPF2-L sites were bound by CCCTC-binding factor (CTCF). DPF2-S sites exhibited enhancer modifications, while DPF2-L sites showed promoter modifications. Thus, alternative splicing redirects BAF complex targeting to impact chromatin organization during neuronal development.
    Keywords:  BAF complex; DPF2; PTBP1; alternative splicing; chromatin remodeling; embryonic stem cell; histone modification; mammalian SWI/SNF complex; neuronal differentiation; transcription
    DOI:  https://doi.org/10.1016/j.stem.2024.04.001
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