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Nature cell biology
2022 May 26
Chan, JJ;Zhang, B;Chew, XH;Salhi, A;Kwok, ZH;Lim, CY;Desi, N;Subramaniam, N;Siemens, A;Kinanti, T;Ong, S;Sanchez-Mejias, A;Ly, PT;An, O;Sundar, R;Fan, X;Wang, S;Siew, BE;Lee, KC;Chong, CS;Lieske, B;Cheong, WK;Goh, Y;Fam, WN;Ooi, MG;Koh, BTH;Iyer, SG;Ling, WH;Chen, J;Yoong, BK;Chanwat, R;Bonney, GK;Goh, BKP;Zhai, W;Fullwood, MJ;Wang, W;Tan, KK;Chng, WJ;Dan, YY;Pitt, JJ;Roca, X;Guccione, E;Vardy, LA;Chen, L;Gao, X;Chow, PKH;Yang, H;Tay, Y;
PMID: 35618746 | DOI: 10.1038/s41556-022-00913-z
Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3' UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3' UTR splicing remains poorly understood as splicing studies have traditionally focused on protein-coding alterations. Here we systematically map the pan-cancer landscape of 3' UTR splicing and present this in SpUR ( http://www.cbrc.kaust.edu.sa/spur/home/ ). 3' UTR splicing is widespread, upregulated in cancers, correlated with poor prognosis and more prevalent in oncogenes. We show that antisense oligonucleotide-mediated inhibition of 3' UTR splicing efficiently reduces oncogene expression and impedes tumour progression. Notably, CTNNB1 3' UTR splicing is the most consistently dysregulated event across cancers. We validate its upregulation in hepatocellular carcinoma and colon adenocarcinoma, and show that the spliced 3' UTR variant is the predominant contributor to its oncogenic functions. Overall, our study highlights the importance of 3' UTR splicing in cancer and may launch new avenues for RNA-based anti-cancer therapeutics.
Nature cell biology
2022 May 01
Eroglu, E;Yen, CYT;Tsoi, YL;Witman, N;Elewa, A;Joven Araus, A;Wang, H;Szattler, T;Umeano, CH;Sohlmér, J;Goedel, A;Simon, A;Chien, KR;
PMID: 35550612 | DOI: 10.1038/s41556-022-00902-2
The contribution of the epicardium, the outermost layer of the heart, to cardiac regeneration has remained controversial due to a lack of suitable analytical tools. By combining genetic marker-independent lineage-tracing strategies with transcriptional profiling and loss-of-function methods, we report here that the epicardium of the highly regenerative salamander species Pleurodeles waltl has an intrinsic capacity to differentiate into cardiomyocytes. Following cryoinjury, CLDN6+ epicardium-derived cells appear at the lesion site, organize into honeycomb-like structures connected via focal tight junctions and undergo transcriptional reprogramming that results in concomitant differentiation into de novo cardiomyocytes. Ablation of CLDN6+ differentiation intermediates as well as disruption of their tight junctions impairs cardiac regeneration. Salamanders constitute the evolutionarily closest species to mammals with an extensive ability to regenerate heart muscle and our results highlight the epicardium and tight junctions as key targets in efforts to promote cardiac regeneration.
Nature methods
2022 May 26
Nielsen, AF;Bindereif, A;Bozzoni, I;Hanan, M;Hansen, TB;Irimia, M;Kadener, S;Kristensen, LS;Legnini, I;Morlando, M;Jarlstad Olesen, MT;Pasterkamp, RJ;Preibisch, S;Rajewsky, N;Suenkel, C;Kjems, J;
PMID: 35618955 | DOI: 10.1038/s41592-022-01487-2
Circular RNAs (circRNAs) are formed in all domains of life and via different mechanisms. There has been an explosion in the number of circRNA papers in recent years; however, as a relatively young field, circRNA biology has an urgent need for common experimental standards for isolating, analyzing, expressing and depleting circRNAs. Here we propose a set of guidelines for circRNA studies based on the authors' experience. This Perspective will specifically address the major class of circRNAs in Eukarya that are generated by a spliceosome-catalyzed back-splicing event. We hope that the implementation of best practice principles for circRNA research will help move the field forward and allow a better functional understanding of this fascinating group of RNAs.
Nature immunology
2022 May 12
Doke, T;Abedini, A;Aldridge, DL;Yang, YW;Park, J;Hernandez, CM;Balzer, MS;Shrestra, R;Coppock, G;Rico, JMI;Han, SY;Kim, J;Xin, S;Piliponsky, AM;Angelozzi, M;Lefebvre, V;Siracusa, MC;Hunter, CA;Susztak, K;
PMID: 35552540 | DOI: 10.1038/s41590-022-01200-7
Inflammation is an important component of fibrosis but immune processes that orchestrate kidney fibrosis are not well understood. Here we apply single-cell sequencing to a mouse model of kidney fibrosis. We identify a subset of kidney tubule cells with a profibrotic-inflammatory phenotype characterized by the expression of cytokines and chemokines associated with immune cell recruitment. Receptor-ligand interaction analysis and experimental validation indicate that CXCL1 secreted by profibrotic tubules recruits CXCR2+ basophils. In mice, these basophils are an important source of interleukin-6 and recruitment of the TH17 subset of helper T cells. Genetic deletion or antibody-based depletion of basophils results in reduced renal fibrosis. Human kidney single-cell, bulk gene expression and immunostaining validate a function for basophils in patients with kidney fibrosis. Collectively, these studies identify basophils as contributors to the development of renal fibrosis and suggest that targeting these cells might be a useful clinical strategy to manage chronic kidney disease.
Nature neuroscience
2022 May 01
Tsai, NY;Wang, F;Toma, K;Yin, C;Takatoh, J;Pai, EL;Wu, K;Matcham, AC;Yin, L;Dang, EJ;Marciano, DK;Rubenstein, JL;Wang, F;Ullian, EM;Duan, X;
PMID: 35524141 | DOI: 10.1038/s41593-022-01068-8
The mouse visual system serves as an accessible model to understand mammalian circuit wiring. Despite rich knowledge in retinal circuits, the long-range connectivity map from distinct retinal ganglion cell (RGC) types to diverse brain neuron types remains unknown. In this study, we developed an integrated approach, called Trans-Seq, to map RGCs to superior collicular (SC) circuits. Trans-Seq combines a fluorescent anterograde trans-synaptic tracer, consisting of codon-optimized wheat germ agglutinin fused to mCherry, with single-cell RNA sequencing. We used Trans-Seq to classify SC neuron types innervated by genetically defined RGC types and predicted a neuronal pair from αRGCs to Nephronectin-positive wide-field neurons (NPWFs). We validated this connection using genetic labeling, electrophysiology and retrograde tracing. We then used transcriptomic data from Trans-Seq to identify Nephronectin as a determinant for selective synaptic choice from αRGC to NPWFs via binding to Integrin α8β1. The Trans-Seq approach can be broadly applied for post-synaptic circuit discovery from genetically defined pre-synaptic neurons.
Nature neuroscience
2022 May 01
Cai, X;Liu, H;Feng, B;Yu, M;He, Y;Liu, H;Liang, C;Yang, Y;Tu, L;Zhang, N;Wang, L;Yin, N;Han, J;Yan, Z;Wang, C;Xu, P;Wu, Q;Tong, Q;He, Y;Xu, Y;
PMID: 35501380 | DOI: 10.1038/s41593-022-01062-0
Midbrain dopamine (DA) and serotonin (5-HT) neurons regulate motivated behaviors, including feeding, but less is known about how these circuits may interact. In this study, we found that DA neurons in the mouse ventral tegmental area bidirectionally regulate the activity of 5-HT neurons in the dorsal raphe nucleus (DRN), with weaker stimulation causing DRD2-dependent inhibition and overeating, while stronger stimulation causing DRD1-dependent activation and anorexia. Furthermore, in the activity-based anorexia (ABA) paradigm, which is a mouse model mimicking some clinical features of human anorexia nervosa (AN), we observed a DRD2 to DRD1 shift of DA neurotransmission on 5-HTDRN neurons, which causes constant activation of these neurons and contributes to AN-like behaviors. Finally, we found that systemic administration of a DRD1 antagonist can prevent anorexia and weight loss in ABA. Our results revealed regulation of feeding behavior by stimulation strength-dependent interactions between DA and 5-HT neurons, which may contribute to the pathophysiology of AN.
Cell stem cell
2022 May 05
Jacob, JM;Di Carlo, SE;Stzepourginski, I;Lepelletier, A;Ndiaye, PD;Varet, H;Legendre, R;Kornobis, E;Benabid, A;Nigro, G;Peduto, L;
PMID: 35523143 | DOI: 10.1016/j.stem.2022.04.005
After birth, the intestine undergoes major changes to shift from an immature proliferative state to a functional intestinal barrier. By combining inducible lineage tracing and transcriptomics in mouse models, we identify a prodifferentiation PDGFRαHigh intestinal stromal lineage originating from postnatal LTβR+ perivascular stromal progenitors. The genetic blockage of this lineage increased the intestinal stem cell pool while decreasing epithelial and immune maturation at weaning age, leading to reduced postnatal growth and dysregulated repair responses. Ablating PDGFRα in the LTBR stromal lineage demonstrates that PDGFRα has a major impact on the lineage fate and function, inducing a transcriptomic switch from prostemness genes, such as Rspo3 and Grem1, to prodifferentiation factors, including BMPs, retinoic acid, and laminins, and on spatial organization within the crypt-villus and repair responses. Our results show that the PDGFRα-induced transcriptomic switch in intestinal stromal cells is required in the first weeks after birth to coordinate postnatal intestinal maturation and function.
American journal of respiratory and critical care medicine
2022 May 03
Cunningham, CM;Li, M;Ruffenach, G;Doshi, M;Aryan, L;Hong, J;Park, J;Hrncir, H;Medzikovic, L;Umar, S;Arnold, AP;Eghbali, M;
PMID: 35504005 | DOI: 10.1164/rccm.202110-2309OC
Idiopathic pulmonary arterial hypertension (PAH) is a terminal pulmonary vascular disease characterized by increased pressure, right ventricular failure and death. PAH exhibits a striking sex bias and is up to 4x more prevalent in females. Understanding the molecular basis behind sex differences could help uncover novel therapies.We previously discovered the Y-Chromosome is protective against hypoxia-induced experimental PH which may contribute to sex differences in PAH. Here, we identify the gene responsible for Y-Chromosome protection, investigate key downstream autosomal genes, and demonstrate a novel preclinical therapy. Methods, Measurements and Main Results: To test the effect of Y-Chromosome genes on PH development, we knocked down each Y-Chromosome gene expressed in the lung via intratracheal instillation of siRNA in gonadectomized male mice exposed to hypoxia. Knockdown of Y-Chromosome gene Uty resulted in more severe PH measured by increased right ventricular pressure and decreased pulmonary artery acceleration time. RNA-sequencing revealed an increase in proinflammatory chemokines Cxcl9 and Cxcl10 as a result of Uty knockdown. We found CXCL9 and CXCL10 significantly upregulated in human PAH lungs, with more robust upregulation in PAH females. Treatment of human pulmonary artery endothelial cells with CXCL9 and CXCL10 triggered apoptosis. Inhibition of CXCL9 and CXCL10 expression in male Uty knockout mice and CXCL9 and CXCL10 activity in female rats significantly reduced PH severity.Uty, is protective against PH. Reduction of Uty expression results in increased expression of proinflammatory chemokines CXCL9 and CXCL10 which trigger endothelial cell death and PH. Inhibition of Cxcl9 and Cxcl10 rescues PH development in multiple experimental models.
Advanced Functional Materials
2022 May 24
McLaughlin, S;Sedlakova, V;Zhang, Q;McNeill, B;Smyth, D;Seymour, R;Davis, D;Ruel, M;Brand, M;Alarcon, E;Suuronen, E;
| DOI: 10.1002/adfm.202204076
Methylglyoxal (MG) production after myocardial infarction (MI) leads to advanced glycation end-product formation, adverse remodeling, and loss of cardiac function. The extracellular matrix (ECM) is a main target for MG glycation. This suggests that ECM-mimicking biomaterial therapies may protect the post-MI environment by removing MG. In this study, mechanisms by which a recombinant human collagen type I hydrogel therapy confers cardioprotection are investigated. One-week post-MI, mice receive intramyocardial injection of hydrogel or PBS. The hydrogel improves border zone contractility after 2 days, which is maintained for 28 days. RNA sequencing shows that hydrogel treatment decreases the expression of erythroid differentiation regulator 1, a factor associated with apoptosis. Hydrogel treatment reduces cardiomyocyte apoptosis and oxidative stress at 2 days with greater myocardial salvage seen at 28 days. The hydrogel located at the epicardial surface is modified by MG, and less MG-modified proteins are observed in the underlying myocardium of hydrogel-treated mice. Biomaterials that can be a target for MG glycation may act as a sponge to remove MG from the myocardium post-MI. This leads to less oxidative stress, greater survival and contractility of cardiomyocytes, which altogether suggests a novel mechanism by which biomaterials improve function of the infarcted heart.
Molecular cell
2022 May 05
Liedmann, S;Liu, X;Guy, CS;Crawford, JC;Rodriguez, DA;Kuzuoğlu-Öztürk, D;Guo, A;Verbist, KC;Temirov, J;Chen, MJ;Ruggero, D;Zhang, H;Thomas, PG;Green, DR;
PMID: 35597236 | DOI: 10.1016/j.molcel.2022.04.016
Activated CD8+ T lymphocytes differentiate into heterogeneous subsets. Using super-resolution imaging, we found that prior to the first division, dynein-dependent vesicular transport polarized active TORC1 toward the microtubule-organizing center (MTOC) at the proximal pole. This active TORC1 was physically associated with active eIF4F, required for the translation of c-myc mRNA. As a consequence, c-myc-translating polysomes polarized toward the cellular pole proximal to the immune synapse, resulting in localized c-myc translation. Upon division, the TORC1-eIF4A complex preferentially sorted to the proximal daughter cell, facilitating asymmetric c-Myc synthesis. Transient disruption of eIF4A activity at first division skewed long-term cell fate trajectories to memory-like function. Using a genetic barcoding approach, we found that first-division sister cells often displayed differences in transcriptional profiles that largely correlated with c-Myc and TORC1 target genes. Our findings provide mechanistic insights as to how distinct T cell fate trajectories can be established during the first division.
Molecular cell
2022 May 19
Trojanowski, J;Frank, L;Rademacher, A;Mücke, N;Grigaitis, P;Rippe, K;
PMID: 35537448 | DOI: 10.1016/j.molcel.2022.04.017
Transcription factors (TFs) consist of a DNA-binding domain and an activation domain (AD) that are frequently considered to be independent and exchangeable modules. However, recent studies report that the physicochemical properties of the AD can control TF assembly at chromatin by driving phase separation into transcriptional condensates. Here, we dissected transcription activation by comparing different synthetic TFs at a reporter gene array with real-time single-cell fluorescence microscopy. In these experiments, binding site occupancy, residence time, and coactivator recruitment in relation to multivalent TF interactions were compared. While phase separation propensity and activation strength of the AD were linked, the actual formation of liquid-like TF droplets had a neutral or inhibitory effect on transcription activation. We conclude that multivalent AD-mediated interactions enhance the transcription activation capacity of a TF by increasing its residence time in the chromatin-bound state and facilitating the recruitment of coactivators independent of phase separation.
Science immunology
2022 May 13
Lindholm, HT;Parmar, N;Drurey, C;Campillo Poveda, M;Vornewald, PM;Ostrop, J;Díez-Sanchez, A;Maizels, RM;Oudhoff, MJ;
PMID: 35559665 | DOI: 10.1126/sciimmunol.abl6543
The intestinal tract is a common site for various types of infections including viruses, bacteria, and helminths, each requiring specific modes of immune defense. The intestinal epithelium has a pivotal role in both immune initiation and effector stages, which are coordinated by lymphocyte cytokines such as IFNγ, IL-13, and IL-22. Here, we studied intestinal epithelial immune responses using organoid image analysis based on a convolutional neural network, transcriptomic analysis, and in vivo infection models. We found that IL-13 and IL-22 both induce genes associated with goblet cells, but the resulting goblet cell phenotypes are dichotomous. Moreover, only IL-13-driven goblet cells are associated with classical NOTCH signaling. We further showed that IL-13 induces the bone morphogenetic protein (BMP) pathway, which acts in a negative feedback loop on immune type 2-driven tuft cell hyperplasia. This is associated with inhibiting Sox4 expression to putatively limit the tuft cell progenitor population. Blocking ALK2, a BMP receptor, with the inhibitor dorsomorphin homolog 1 (DMH1) interrupted the feedback loop, resulting in greater tuft cell numbers both in vitro and in vivo after infection with Nippostrongylus brasiliensis. Together, this investigation of cytokine effector responses revealed an unexpected and critical role for the BMP pathway in regulating type 2 immunity, which can be exploited to tailor epithelial immune responses.
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| Description | ||
|---|---|---|
| sense Example: Hs-LAG3-sense | Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe. | |
| Intron# Example: Mm-Htt-intron2 | Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection | |
| Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G) | A mixture of multiple probe sets targeting multiple genes or transcripts | |
| No-XSp Example: Hs-PDGFB-No-XMm | Does not cross detect with the species (Sp) | |
| XSp Example: Rn-Pde9a-XMm | designed to cross detect with the species (Sp) | |
| O# Example: Mm-Islr-O1 | Alternative design targeting different regions of the same transcript or isoforms | |
| CDS Example: Hs-SLC31A-CDS | Probe targets the protein-coding sequence only | |
| EnEm | Probe targets exons n and m | |
| En-Em | Probe targets region from exon n to exon m | |
| Retired Nomenclature | ||
| tvn Example: Hs-LEPR-tv1 | Designed to target transcript variant n | |
| ORF Example: Hs-ACVRL1-ORF | Probe targets open reading frame | |
| UTR Example: Hs-HTT-UTR-C3 | Probe targets the untranslated region (non-protein-coding region) only | |
| 5UTR Example: Hs-GNRHR-5UTR | Probe targets the 5' untranslated region only | |
| 3UTR Example: Rn-Npy1r-3UTR | Probe targets the 3' untranslated region only | |
| Pan Example: Pool | A mixture of multiple probe sets targeting multiple genes or transcripts | |
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