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1.
Cell ; 186(23): 4996-5014.e24, 2023 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-37949056

RESUMEN

A formal demonstration that mammalian pluripotent stem cells possess preimplantation embryonic cell-like (naive) pluripotency is the generation of chimeric animals through early embryo complementation with homologous cells. Whereas such naive pluripotency has been well demonstrated in rodents, poor chimerism has been achieved in other species including non-human primates due to the inability of the donor cells to match the developmental state of the host embryos. Here, we have systematically tested various culture conditions for establishing monkey naive embryonic stem cells and optimized the procedures for chimeric embryo culture. This approach generated an aborted fetus and a live chimeric monkey with high donor cell contribution. A stringent characterization pipeline demonstrated that donor cells efficiently (up to 90%) incorporated into various tissues (including the gonads and placenta) of the chimeric monkeys. Our results have major implications for the study of primate naive pluripotency and genetic engineering of non-human primates.


Asunto(s)
Células Madre Embrionarias , Ingeniería Genética , Haplorrinos , Animales , Femenino , Embarazo , Haplorrinos/genética , Nacimiento Vivo , Mamíferos , Células Madre Pluripotentes , Primates , Ingeniería Genética/métodos
2.
Nature ; 628(8008): 527-533, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38600389

RESUMEN

Topology1-3 and interactions are foundational concepts in the modern understanding of quantum matter. Their nexus yields three important research directions: (1) the competition between distinct interactions, as in several intertwined phases, (2) the interplay between interactions and topology that drives the phenomena in twisted layered materials and topological magnets, and (3) the coalescence of several topological orders to generate distinct novel phases. The first two examples have grown into major areas of research, although the last example remains mostly unexplored, mainly because of the lack of a material platform for experimental studies. Here, using tunnelling microscopy, photoemission spectroscopy and a theoretical analysis, we unveil a 'hybrid' topological phase of matter in the simple elemental-solid arsenic. Through a unique bulk-surface-edge correspondence, we uncover that arsenic features a conjoined strong and higher-order topology that stabilizes a hybrid topological phase. Although momentum-space spectroscopy measurements show signs of topological surface states, real-space microscopy measurements unravel a unique geometry of topologically induced step-edge conduction channels revealed on various natural nanostructures on the surface. Using theoretical models, we show that the existence of gapless step-edge states in arsenic relies on the simultaneous presence of both a non-trivial strong Z2 invariant and a non-trivial higher-order topological invariant, which provide experimental evidence for hybrid topology. Our study highlights pathways for exploring the interplay of different band topologies and harnessing the associated topological conduction channels in engineered quantum or nano-devices.

3.
Nature ; 609(7927): 490-495, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36104552

RESUMEN

A hallmark of strongly correlated quantum materials is the rich phase diagram resulting from competing and intertwined phases with nearly degenerate ground-state energies1,2. A well-known example is the copper oxides, in which a charge density wave (CDW) is ordered well above and strongly coupled to the magnetic order to form spin-charge-separated stripes that compete with superconductivity1,2. Recently, such rich phase diagrams have also been shown in correlated topological materials. In 2D kagome lattice metals consisting of corner-sharing triangles, the geometry of the lattice can produce flat bands with localized electrons3,4, non-trivial topology5-7, chiral magnetic order8,9, superconductivity and CDW order10-15. Although CDW has been found in weakly electron-correlated non-magnetic AV3Sb5 (A = K, Rb, Cs)10-15, it has not yet been observed in correlated magnetic-ordered kagome lattice metals4,16-21. Here we report the discovery of CDW in the antiferromagnetic (AFM) ordered phase of kagome lattice FeGe (refs. 16-19). The CDW in FeGe occurs at wavevectors identical to that of AV3Sb5 (refs. 10-15), enhances the AFM ordered moment and induces an emergent anomalous Hall effect22,23. Our findings suggest that CDW in FeGe arises from the combination of electron-correlations-driven AFM order and van Hove singularities (vHSs)-driven instability possibly associated with a chiral flux phase24-28, in stark contrast to strongly correlated copper oxides1,2 and nickelates29-31, in which the CDW precedes or accompanies the magnetic order.

4.
Nature ; 605(7909): 315-324, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35314832

RESUMEN

After fertilization, the quiescent zygote experiences a burst of genome activation that initiates a short-lived totipotent state. Understanding the process of totipotency in human cells would have broad applications. However, in contrast to in mice1,2, demonstration of the time of zygotic genome activation or the eight-cell (8C) stage in in vitro cultured human cells has not yet been reported, and the study of embryos is limited by ethical and practical considerations. Here we describe a transgene-free, rapid and controllable method for producing 8C-like cells (8CLCs) from human pluripotent stem cells. Single-cell analysis identified key molecular events and gene networks associated with this conversion. Loss-of-function experiments identified fundamental roles for DPPA3, a master regulator of DNA methylation in oocytes3, and TPRX1, a eutherian totipotent cell homeobox (ETCHbox) family transcription factor that is absent in mice4. DPPA3 induces DNA demethylation throughout the 8CLC conversion process, whereas TPRX1 is a key executor of 8CLC gene networks. We further demonstrate that 8CLCs can produce embryonic and extraembryonic lineages in vitro or in vivo in the form of blastoids5 and complex teratomas. Our approach provides a resource to uncover the molecular process of early human embryogenesis.


Asunto(s)
Embrión de Mamíferos , Desarrollo Embrionario , Células Madre Pluripotentes , Cigoto , Humanos , Proteínas Cromosómicas no Histona/genética , Embrión de Mamíferos/citología , Proteínas de Homeodominio/genética , Células Madre Pluripotentes/citología , Factores de Transcripción/genética , Cigoto/citología
5.
Nature ; 612(7941): 720-724, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36477530

RESUMEN

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1-4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.


Asunto(s)
Consumo de Bebidas Alcohólicas , Predisposición Genética a la Enfermedad , Variación Genética , Internacionalidad , Herencia Multifactorial , Uso de Tabaco , Humanos , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Estudio de Asociación del Genoma Completo/métodos , Herencia Multifactorial/genética , Factores de Riesgo , Uso de Tabaco/genética , Consumo de Bebidas Alcohólicas/genética , Transcriptoma , Tamaño de la Muestra , Sitios Genéticos/genética , Europa (Continente)/etnología
6.
Immunity ; 48(4): 773-786.e5, 2018 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-29625896

RESUMEN

The molecular mechanisms whereby CD8+ T cells become "exhausted" in the tumor microenvironment remain unclear. Programmed death ligand-1 (PD-L1) is upregulated on tumor cells and PD-1-PD-L1 blockade has significant efficacy in human tumors; however, most patients do not respond, suggesting additional mechanisms underlying T cell exhaustion. B7 superfamily member 1 (B7S1), also called B7-H4, B7x, or VTCN1, negatively regulates T cell activation. Here we show increased B7S1 expression on myeloid cells from human hepatocellular carcinoma correlated with CD8+ T cell dysfunction. B7S1 inhibition suppressed development of murine tumors. Putative B7S1 receptor was co-expressed with PD-1 but not T cell immunoglobulin and mucin-domain containing-3 (Tim-3) at an activated state of early tumor-infiltrating CD8+ T cells, and B7S1 promoted T cell exhaustion, possibly through Eomes overexpression. Combinatorial blockade of B7S1 and PD-1 synergistically enhanced anti-tumor immune responses. Collectively, B7S1 initiates dysfunction of tumor-infiltrating CD8+ T cells and may be targeted for cancer immunotherapy.


Asunto(s)
Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Carcinoma Hepatocelular/inmunología , Neoplasias Hepáticas/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Células Mieloides/inmunología , Inhibidor 1 de la Activación de Células T con Dominio V-Set/metabolismo , Animales , Carcinoma Hepatocelular/patología , Modelos Animales de Enfermedad , Humanos , Neoplasias Hepáticas/patología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Dominio T Box/metabolismo , Inhibidor 1 de la Activación de Células T con Dominio V-Set/genética
7.
Proc Natl Acad Sci U S A ; 121(22): e2402135121, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38771869

RESUMEN

Seamless integration of microstructures and circuits on three-dimensional (3D) complex surfaces is of significance and is catalyzing the emergence of many innovative 3D curvy electronic devices. However, patterning fine features on arbitrary 3D targets remains challenging. Here, we propose a facile charge-driven electrohydrodynamic 3D microprinting technique that allows micron- and even submicron-scale patterning of functional inks on a couple of 3D-shaped dielectrics via an atmospheric-pressure cold plasma jet. Relying on the transient charging of exposed sites arising from the weakly ionized gas jet, the specified charge is programmably deposited onto the surface as a virtual electrode with spatial and time spans of ~mm in diameter and ~µs in duration to generate a localized electric field accordantly. Therefore, inks with a wide range of viscosities can be directly drawn out from micro-orifices and deposited on both two-dimensional (2D) planar and 3D curved surfaces with a curvature radius down to ~1 mm and even on the inner wall of narrow cavities via localized electrostatic attraction, exhibiting a printing resolution of ~450 nm. In addition, several conformal electronic devices were successfully printed on 3D dielectric objects. Self-aligned 3D microprinting, with stacking layers up to 1400, is also achieved due to the electrified surfaces. This microplasma-induced printing technique exhibits great advantages such as ultrahigh resolution, excellent compatibility of inks and substrates, antigravity droplet dispersion, and omnidirectional printing on 3D freeform surfaces. It could provide a promising solution for intimately fabricating electronic devices on arbitrary 3D surfaces.

8.
Proc Natl Acad Sci U S A ; 121(4): e2317058121, 2024 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-38232281

RESUMEN

Integration of methanogenic archaea with photocatalysts presents a sustainable solution for solar-driven methanogenesis. However, maximizing CH4 conversion efficiency remains challenging due to the intrinsic energy conservation and strictly restricted substrates of methanogenic archaea. Here, we report a solar-driven biotic-abiotic hybrid (biohybrid) system by incorporating cadmium sulfide (CdS) nanoparticles with a rationally designed methanogenic archaeon Methanosarcina acetivorans C2A, in which the glucose synergist protein and glucose kinase, an energy-efficient route for glucose transport and phosphorylation from Zymomonas mobilis, were implemented to facilitate nonnative substrate glucose for methanogenesis. We demonstrate that the photo-excited electrons facilitate membrane-bound electron transport chain, thereby augmenting the Na+ and H+ ion gradients across membrane to enhance adenosine triphosphate (ATP) synthesis. Additionally, this biohybrid system promotes the metabolism of pyruvate to acetyl coenzyme A (AcCoA) and inhibits the flow of AcCoA to the tricarboxylic acid (TCA) cycle, resulting in a 1.26-fold augmentation in CH4 production from glucose-derived carbon. Our results provide a unique strategy for enhancing methanogenesis through rational biohybrid design and reprogramming, which gives a promising avenue for sustainably manufacturing value-added chemicals.


Asunto(s)
Adenosina Trifosfato , Metano , Metano/metabolismo , Transporte de Electrón , Adenosina Trifosfato/metabolismo , Metabolismo Energético , Transporte Biológico , Methanosarcina/metabolismo
9.
Proc Natl Acad Sci U S A ; 121(10): e2320559121, 2024 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-38408237

RESUMEN

Basal progenitor cells serve as a stem cell pool to maintain the homeostasis of the epithelium of the foregut, including the esophagus and the forestomach. Aberrant genetic regulation in these cells can lead to carcinogenesis, such as squamous cell carcinoma (SCC). However, the underlying molecular mechanisms regulating the function of basal progenitor cells remain largely unknown. Here, we use mouse models to reveal that Hippo signaling is required for maintaining the homeostasis of the foregut epithelium and cooperates with p53 to repress the initiation of foregut SCC. Deletion of Mst1/2 in mice leads to epithelial overgrowth in both the esophagus and forestomach. Further molecular studies find that Mst1/2-deficiency promotes epithelial growth by enhancing basal cell proliferation in a Yes-associated protein (Yap)-dependent manner. Moreover, Mst1/2 deficiency accelerates the onset of foregut SCC in a carcinogen-induced foregut SCC mouse model, depending on Yap. Significantly, a combined deletion of Mst1/2 and p53 in basal progenitor cells sufficiently drives the initiation of foregut SCC. Therefore, our studies shed light on the collaborative role of Hippo signaling and p53 in maintaining squamous epithelial homeostasis while suppressing malignant transformation of basal stem cells within the foregut.


Asunto(s)
Carcinoma de Células Escamosas , Transducción de Señal , Animales , Ratones , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Homeostasis , Transducción de Señal/genética , Células Madre/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Señalizadoras YAP
10.
Proc Natl Acad Sci U S A ; 121(1): e2310685120, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38147550

RESUMEN

Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR [db/db (diabetes)] and leptin [ob/ob (obese)] are not identical, and the cause remains unclear. Here, we show that db/db, but not ob/ob, mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4 (angiopoietin-like protein 4), a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1+ mesenchymal cells at the HO site, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1+ cells, or lineage ablation of LepR+ cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Together, these findings identify ANGPTL4 as a ligand for LepR to regulate the formation of acquired HO.


Asunto(s)
Leptina , Osificación Heterotópica , Animales , Ratones , Leptina/genética , Ligandos , Ratones Endogámicos C57BL , Osteogénesis , Receptores de Leptina/genética , Receptores de Leptina/metabolismo
11.
J Cell Sci ; 137(5)2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-37667859

RESUMEN

Ciliates assemble numerous microtubular structures into complex cortical patterns. During ciliate division, the pattern is duplicated by intracellular segmentation that produces a tandem of daughter cells. In Tetrahymena thermophila, the induction and positioning of the division boundary involves two mutually antagonistic factors: posterior CdaA (cyclin E) and anterior CdaI (Hippo kinase). Here, we characterized the related cdaH-1 allele, which confers a pleiotropic patterning phenotype including an absence of the division boundary and an anterior-posterior mispositioning of the new oral apparatus. CdaH is a Fused or Stk36 kinase ortholog that localizes to multiple sites that correlate with the effects of its loss, including the division boundary and the new oral apparatus. CdaH acts downstream of CdaA to induce the division boundary and drives asymmetric cytokinesis at the tip of the posterior daughter. CdaH both maintains the anterior-posterior position of the new oral apparatus and interacts with CdaI to pattern ciliary rows within the oral apparatus. Thus, CdaH acts at multiple scales, from induction and positioning of structures on the cell-wide polarity axis to local organelle-level patterning.


Asunto(s)
Tetrahymena thermophila , Tetrahymena , Tetrahymena/genética , División Celular/genética , Acetamidas , Tetrahymena thermophila/genética , Citoesqueleto
12.
Genome Res ; 33(10): 1673-1689, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37884342

RESUMEN

Ultraconserved elements (UCEs) are the most conserved regions among the genomes of evolutionarily distant species and are thought to play critical biological functions. However, some UCEs rapidly evolved in specific lineages, and whether they contributed to adaptive evolution is still controversial. Here, using an increased number of sequenced genomes with high taxonomic coverage, we identified 2191 mammalian UCEs and 5938 avian UCEs from 95 mammal and 94 bird genomes, respectively. Our results show that these UCEs are functionally constrained and that their adjacent genes are prone to widespread expression with low expression diversity across tissues. Functional enrichment of mammalian and avian UCEs shows different trends indicating that UCEs may contribute to adaptive evolution of taxa. Focusing on lineage-specific accelerated evolution, we discover that the proportion of fast-evolving UCEs in nine mammalian and 10 avian test lineages range from 0.19% to 13.2%. Notably, up to 62.1% of fast-evolving UCEs in test lineages are much more likely to result from GC-biased gene conversion (gBGC). A single cervid-specific gBGC region embracing the uc.359 allele significantly alters the expression of Nova1 and other neural-related genes in the rat brain. Combined with the altered regulatory activity of ancient gBGC-induced fast-evolving UCEs in eutherians, our results provide evidence that synergy between gBGC and selection shaped lineage-specific substitution patterns, even in the most constrained regulatory elements. In summary, our results show that gBGC played an important role in facilitating lineage-specific accelerated evolution of UCEs, and further support the idea that a combination of multiple evolutionary forces shapes adaptive evolution.


Asunto(s)
Conversión Génica , Mamíferos , Animales , Ratas , Mamíferos/genética , Alelos , Aves/genética , Evolución Molecular , Antígeno Ventral Neuro-Oncológico
13.
Genome Res ; 33(8): 1284-1298, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37714713

RESUMEN

Chinese indicine cattle harbor a much higher genetic diversity compared with other domestic cattle, but their genome architecture remains uninvestigated. Using PacBio HiFi sequencing data from 10 Chinese indicine cattle across southern China, we assembled 20 high-quality partially phased genomes and integrated them into a multiassembly graph containing 148.5 Mb (5.6%) of novel sequence. We identified 156,009 high-confidence nonredundant structural variants (SVs) and 206 SV hotspots spanning ∼195 Mb of gene-rich sequence. We detected 34,249 archaic introgressed fragments in Chinese indicine cattle covering 1.93 Gb (73.3%) of the genome. We inferred an average of 3.8%, 3.2%, 1.4%, and 0.5% of introgressed sequence originating, respectively, from banteng-like, kouprey-like, gayal-like, and gaur-like Bos species, as well as 0.6% of unknown origin. Introgression from multiple donors might have contributed to the genetic diversity of Chinese indicine cattle. Altogether, this study highlights the contribution of interspecies introgression to the genomic architecture of an important livestock population and shows how exotic genomic elements can contribute to the genetic variation available for selection.


Asunto(s)
Bovinos , Rumiantes , Animales , Bovinos/genética , China , Genoma , Genómica , Rumiantes/genética
14.
Genome Res ; 33(3): 463-477, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-37310928

RESUMEN

Structural variations (SVs) are a major contributor to genetic diversity and phenotypic variations, but their prevalence and functions in domestic animals are largely unexplored. Here we generated high-quality genome assemblies for 15 individuals from genetically diverse sheep breeds using Pacific Biosciences (PacBio) high-fidelity sequencing, discovering 130.3 Mb nonreference sequences, from which 588 genes were annotated. A total of 149,158 biallelic insertions/deletions, 6531 divergent alleles, and 14,707 multiallelic variations with precise breakpoints were discovered. The SV spectrum is characterized by an excess of derived insertions compared to deletions (94,422 vs. 33,571), suggesting recent active LINE expansions in sheep. Nearly half of the SVs display low to moderate linkage disequilibrium with surrounding single-nucleotide polymorphisms (SNPs) and most SVs cannot be tagged by SNP probes from the widely used ovine 50K SNP chip. We identified 865 population-stratified SVs including 122 SVs possibly derived in the domestication process among 690 individuals from sheep breeds worldwide. A novel 168-bp insertion in the 5' untranslated region (5' UTR) of HOXB13 is found at high frequency in long-tailed sheep. Further genome-wide association study and gene expression analyses suggest that this mutation is causative for the long-tail trait. In summary, we have developed a panel of high-quality de novo assemblies and present a catalog of structural variations in sheep. Our data capture abundant candidate functional variations that were previously unexplored and provide a fundamental resource for understanding trait biology in sheep.


Asunto(s)
Estudio de Asociación del Genoma Completo , Cola (estructura animal) , Animales , Ovinos/genética , Regiones no Traducidas 5' , Alelos , Fenotipo
15.
Plant Cell ; 35(4): 1241-1258, 2023 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-36648110

RESUMEN

In Arabidopsis thaliana, female gametophyte (FG) development is accompanied by the formation and expansion of the large vacuole in the FG; this is essential for FG expansion, nuclear polar localization, and cell fate determination. Arabidopsis VACUOLELESS GAMETOPHYTES (VLG) facilitates vesicular fusion to form large vacuole in the FG, but the regulation of VLG remains largely unknown. Here, we found that gain-of-function mutation of BRASSINOSTEROID INSENSITIVE2 (BIN2) (bin2-1) increases VLG abundance to induce the vacuole formation at stage FG1, and leads to abortion of FG. Loss-of-function mutation of BIN2 and its homologs (bin2-3 bil1 bil2) reduced VLG abundance and mimicked vlg/VLG phenotypes. Knocking down VLG in bin2-1 decreased the ratio of aberrant vacuole formation at stage FG1, whereas FG1-specific overexpression of VLG mimicked the bin2-1 phenotype. VLG partially rescued the bin2-3 bil1 bil2 phenotype, demonstrating that VLG acts downstream of BIN2. Mutation of VLG residues that are phosphorylated by BIN2 altered VLG stability and a phosphorylation mimic of VLG causes similar defects as did bin2-1. Therefore, BIN2 may function by interacting with and phosphorylating VLG in the FG to enhance its stability and abundance, thus facilitating vacuole formation. Our findings provide mechanistic insight into how the BIN2-VLG module regulates the spatiotemporal formation of the large vacuole in FG development.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/fisiología , Proteínas de Arabidopsis/metabolismo , Brasinoesteroides/metabolismo , Regulación de la Expresión Génica de las Plantas/genética , Células Germinativas de las Plantas/metabolismo , Óvulo Vegetal/genética , Óvulo Vegetal/metabolismo , Fosforilación , Proteínas Quinasas/metabolismo , Transducción de Señal/genética , Vacuolas/metabolismo
16.
Nucleic Acids Res ; 52(5): 2142-2156, 2024 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-38340342

RESUMEN

Human DNA topoisomerase 1 (Top1) is a crucial enzyme responsible for alleviating torsional stress on DNA during transcription and replication, thereby maintaining genome stability. Previous researches had found that non-working Top1 interacted extensively with chromosomal DNA in human cells. However, the reason for its retention on chromosomal DNA remained unclear. In this study, we discovered a close association between Top1 and chromosomal DNA, specifically linked to the presence of G-quadruplex (G4) structures. G4 structures, formed during transcription, trap Top1 and hinder its ability to relax neighboring DNAs. Disruption of the Top1-G4 interaction using G4 ligand relieved the inhibitory effect of G4 on Top1 activity, resulting in a further reduction of R-loop levels in cells. Additionally, the activation of Top1 through the use of a G4 ligand enhanced the toxicity of Top1 inhibitors towards cancer cells. Our study uncovers a negative regulation mechanism of human Top1 and highlights a novel pathway for activating Top1.


Asunto(s)
ADN-Topoisomerasas de Tipo I , G-Cuádruplex , Transcripción Genética , Humanos , ADN/química , Replicación del ADN , ADN-Topoisomerasas de Tipo I/metabolismo , Ligandos , Inhibidores de Topoisomerasa I/farmacología
17.
PLoS Genet ; 19(2): e1010615, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36821549

RESUMEN

The worldwide sheep population comprises more than 1000 breeds. Together, these exhibit a considerable morphological diversity, which has not been extensively investigated at the molecular level. Here, we analyze whole-genome sequencing individuals of 1,098 domestic sheep from 154 breeds, and 69 wild sheep from seven Ovis species. On average, we detected 6.8%, 1.0% and 0.2% introgressed sequence in domestic sheep originating from Iranian mouflon, urial and argali, respectively, with rare introgressions from other wild species. Interestingly, several introgressed haplotypes contributed to the morphological differentiations across sheep breeds, such as a RXFP2 haplotype from Iranian mouflon conferring the spiral horn trait, a MSRB3 haplotype from argali strongly associated with ear morphology, and a VPS13B haplotype probably originating from urial and mouflon possibly associated with facial traits. Our results reveal that introgression events from wild Ovis species contributed to the high rate of morphological differentiation in sheep breeds, but also to individual variation within breeds. We propose that long divergent haplotypes are a ubiquitous source of phenotypic variation that allows adaptation to a variable environment, and that these remain intact in the receiving population probably due to reduced recombination.


Asunto(s)
Aclimatación , Oveja Doméstica , Ovinos/genética , Animales , Oveja Doméstica/genética , Haplotipos/genética , Irán , Fenotipo
18.
Proc Natl Acad Sci U S A ; 120(13): e2210796120, 2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-36947513

RESUMEN

Rewiring of redox metabolism has a profound impact on tumor development, but how the cellular heterogeneity of redox balance affects leukemogenesis remains unknown. To precisely characterize the dynamic change in redox metabolism in vivo, we developed a bright genetically encoded biosensor for H2O2 (named HyPerion) and tracked the redox state of leukemic cells in situ in a transgenic sensor mouse. A H2O2-low (HyPerion-low) subset of acute myeloid leukemia (AML) cells was enriched with leukemia-initiating cells, which were endowed with high colony-forming ability, potent drug resistance, endosteal rather than vascular localization, and short survival. Significantly high expression of malic enzymes, including ME1/3, accounted for nicotinamide adenine dinucleotide phosphate (NADPH) production and the subsequent low abundance of H2O2. Deletion of malic enzymes decreased the population size of leukemia-initiating cells and impaired their leukemogenic capacity and drug resistance. In summary, by establishing an in vivo redox monitoring tool at single-cell resolution, this work reveals a critical role of redox metabolism in leukemogenesis and a potential therapeutic target.


Asunto(s)
Peróxido de Hidrógeno , Leucemia Mieloide Aguda , Ratones , Animales , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Oxidación-Reducción , Ratones Transgénicos , Resistencia a Antineoplásicos/genética
19.
Proc Natl Acad Sci U S A ; 120(10): e2201504120, 2023 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-36867684

RESUMEN

The slow-evolving invertebrate amphioxus has an irreplaceable role in advancing our understanding of the vertebrate origin and innovations. Here we resolve the nearly complete chromosomal genomes of three amphioxus species, one of which best recapitulates the 17 chordate ancestor linkage groups. We reconstruct the fusions, retention, or rearrangements between descendants of whole-genome duplications, which gave rise to the extant microchromosomes likely existed in the vertebrate ancestor. Similar to vertebrates, the amphioxus genome gradually establishes its three-dimensional chromatin architecture at the onset of zygotic activation and forms two topologically associated domains at the Hox gene cluster. We find that all three amphioxus species have ZW sex chromosomes with little sequence differentiation, and their putative sex-determining regions are nonhomologous to each other. Our results illuminate the unappreciated interspecific diversity and developmental dynamics of amphioxus genomes and provide high-quality references for understanding the mechanisms of chordate functional genome evolution.


Asunto(s)
Anfioxos , Animales , Cromatina , Cromosomas Sexuales , Reordenamiento Génico , Familia de Multigenes
20.
J Neurosci ; 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39025678

RESUMEN

The hippocampal CA3 region plays an important role in learning and memory. CA3 pyramidal neurons (PNs) receive two prominent excitatory inputs - mossy fibers (MFs) from dentate gyrus (DG) and recurrent collaterals (RCs) from CA3 PNs - that play opposing roles in pattern separation and pattern completion, respectively. Although the dorsoventral heterogeneity of the hippocampal anatomy, physiology, and behavior has been well established, nothing is known about the dorsoventral heterogeneity of synaptic connectivity in CA3 PNs. In this study, we performed Timm's sulfide silver staining, dendritic and spine morphological analyses, and ex vivo electrophysiology in mice of both sexes to investigate the heterogeneity of MF and RC pathways along the CA3 dorsoventral axis. Our morphological analyses demonstrate that ventral CA3 (vCA3) PNs possess greater dendritic lengths and more complex dendritic arborization, compared to dorsal CA3 (dCA3) PNs. Moreover, using ChannelRhodopsin2 (ChR2)-assisted patch-clamp recording, we find that the ratio of the RC-to-MF excitatory drive onto CA3 PNs increases substantially from dCA3 to vCA3, with vCA3 PNs receiving significantly weaker MFs, but stronger RCs, excitation than dCA3 PNs. Given the distinct roles of MF versus RC inputs in pattern separation versus completion, our findings of the significant dorsoventral variations of MF and RC excitation in CA3 PNs may have important functional implications for the contribution of CA3 circuit to the dorsoventral difference in hippocampal function.Significance Statement The hippocampal CA3 region is essential for memory formation. CA3 pyramidal neurons receive recurrent collateral (RC) from CA3 and mossy fiber (MF) from dentate gyrus (DG), which have opposite functions in pattern completion (memory generalization) and separation (discrimination), respectively. Although hippocampal dorsoventral heterogeneity is well established, dorsoventral heterogeneity of CA3 connectivity is unknow. Here, we demonstrate that the ratio of RC-to-MF excitation increases substantially from dCA3 to vCA3, with vCA3 receiving significantly weaker MF, but stronger RC, excitation than dCA3. Thus, our study reveals a novel CA3-based synaptic mechanism that may offer the computational advantage for the ventral hippocampus to be more strongly involved in behaviors that require less precision but more generalization than the dorsal hippocampus.

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