scholarly journals Primate-specific ZNF808 is essential for pancreatic development in humans

2021 ◽  
Author(s):  
Elisa De Franco ◽  
Nick DL Owens ◽  
Hossam Montaser ◽  
Matthew N Wakeling ◽  
Jonna Saarimaki-Vire ◽  
...  
Keyword(s):  
Transposable Elements ◽  
Cell Fate ◽  
Zinc Finger Protein ◽  
Critical Role ◽  
Specific Gene ◽  
Loss Of Function ◽  
Pancreatic Development ◽  
Extreme Phenotypes ◽  
Pancreatic Agenesis

Identifying genes linked to extreme phenotypes in humans has the potential to highlight new biological processes fundamental for human development. Here we report the identification of homozygous loss of function variants in the primate-specific gene ZNF808 as a cause of pancreatic agenesis. ZNF808 is a member of the KRAB zinc finger protein (KZFPs) family, a large and rapidly evolving group of epigenetic silencers that target transposable elements. Loss of ZNF808 in vitro results in aberrant activation of many transposable elements it normally represses during early pancreas development. We show that this results in inappropriate specification of cell fate with induction of genes associated with liver endoderm and a loss of pancreatic identity. This suggests that ZNF808 and its transposable element targets play a critical role in cell fate specification during human pancreatic development. This is the first report of loss of a primate-specific gene causing a congenital developmental disease and highlights the essential role of ZNF808 for pancreatic development in humans.

scholarly journals Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson’s disease

Brain ◽  
2019 ◽  
Vol 142 (8) ◽  
pp. 2380-2401 ◽  
Author(s):  
Saurav Brahmachari ◽  
Saebom Lee ◽  
Sangjune Kim ◽  
Changqing Yuan ◽  
Senthilkumar S Karuppagounder ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Critical Role ◽  
Trna Synthetase ◽  
Loss Of Function ◽  
Substrate Protein ◽  
Finger Protein ◽  
Sporadic Parkinson’S Disease

Abstract α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson’s disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson’s disease, there is evidence that parkin is inactivated in sporadic Parkinson’s disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson’s disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson’s disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson’s disease and related α-synucleinopathies.

Abstract 82: Wnt11 Regulates Chamber Specific Neonatal Cardiomyocyte Proliferation During Perinatal Circulatory Transition

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Marlin Touma ◽  
Xuedong Kang ◽  
Fuying Gao ◽  
Yan Zhao ◽  
Reshma Biniwale ◽  
...  
Keyword(s):  
Heart Defects ◽  
Critical Role ◽  
Newborn Infants ◽  
R Package ◽  
Maturation Stage ◽  
Specific Gene ◽  
Mouse Heart ◽  
Cardiomyocyte Proliferation ◽  
Loss Of Function ◽  
Myocyte Proliferation

Background: Fetal to neonatal transition of heart involves major changes in cardiomyocytes (CMC) including proliferative capacity. However, the chamber specific CMC proliferation programs of remain poorly understood. Elucidating the mechanisms involved is critical to develop chamber specific therapies for newborn infants with single ventricle physiology and other congenital heart defects (CHDs). Methods: Transcriptomes of mouse left ventricle (LV) and right ventricle (RV) were analyzed by RNA-seq at postnatal days 0 (P0), P3 and P7. R package and Ingenuity suite were used for weighted gene co-expression network analysis (WGCNA) and gene ontology studies. Mechanistic analysis was conducted using gain and loss of function approaches. Results: Mouse neonatal cardiac transcriptome was mostly affected by developmental stage. WGCNA revealed 5 LV and 8 RV modules that were significantly correlated with maturation stage and highly preserved between both ventricles at P0 and P7. In contrast, P3 specific gene modules exhibited the largest chamber specific variations in cell signaling, involving proliferation in LV and Wnt signaling molecules, including Wnt11, in RV. Importantly, Wnt11 expression significantly decreased in cyanotic CHDs phenotypes and correlated with O2 saturation levels in hypoxemic infants with Tetralogy of Fallot (TOF). Notably, Perinatal hypoxia treatment in mice suppressed Wnt11 expression, induced CMC proliferation, downregulated Rb1 expression and enhanced Rb1 phosphorylation more robustly in RV vs. LV. Remarkably, Wnt11 inactivation was sufficient to induce myocyte proliferation in perinatal mouse heart and reduced Rb1 expression and phosphorylation in primary neonatal CMC. Importantly, downregulated Wnt11 in hypoxemic TOF infantile heart was also associated with Rb1 suppression and inversely correlated with proliferation marker Plk1 in human. Conclusion: Using integrated systems genomic and functional biology analyses of perinatal cardiac transcriptome, we revealed a previously uncharacterized function for Wnt11 in chamber specific growth and cyanotic CHD. Reduction of Wnt11 expression by hypoxia plays a critical role in neonatal CMC proliferation via modulating Rb1 expression and activity.

Abstract 356: Krueppel-Like Factor 15 Regulates Wnt/β-Catenin Transcription and Controls Cardiac Progenitor Cell Fate in the Postnatal Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Claudia Noack ◽  
Maria P Zafiriou ◽  
Anke Renger ◽  
Hans J Schaeffer ◽  
Martin W Bergmann ◽  
...  
Keyword(s):  
Cell Fate ◽  
Transcriptional Activation ◽  
Progenitor Cell ◽  
Cellular Localization ◽  
Target Genes ◽  
Critical Role ◽  
Isolated Cells ◽  
Cardiac Progenitor Cell

Wnt/β-catenin signaling controls adult heart remodeling partly by regulating cardiac progenitor cell (CPC) differentiation. We now identified and characterized a novel cardiac interaction of the transcription factor Krueppel-like factor 15 (KLF15) with the Wnt/β-catenin signaling on adult CPCs. In vitro mutation, reporter gene assays and co-localization studies revealed that KLF15 requires two distinct domains for nuclear localization and for repression of β-catenin-mediated transcription. KLF15 had no effect on β-catenin stability or cellular localization, but interacted with its co-factor TCF4, which is required for activation of β-catenin target gene expression. Moreover, increased TCF4 ubiquitination was induced by KLF15. In line with this finding we found KLF15 to interact with the Nemo-like kinase, which was shown to phosphorylate and target TCF4 for degradation. In vivo analyses of adult Klf15 functional knock-out (KO) vs. wild-type (WT) mice showed a cardiac β-catenin-mediated transcriptional activation and reduced TCF4 degradation along with cardiac dysfunction assessed by echocardiography (n=10). FACS analysis of the CPC enriched-population of KO vs. WT mice revealed a significant reduction of cardiogenic-committed precursors identified as Sca1+/αMHC+ (0.8±0.2% vs. 1.8±0.1%) and Tbx5+ (3.5±0.3% vs. 5.2±0.5%). In contrast, endothelial Sca1+/CD31+ cells were significantly higher in KO mice (11.3±0.4% vs. 8.6±0.4%; n≥9). In addition, Sca1+ isolated cells of Klf15 KO showed increased RNA expression of endothelial markers von Willebrand Factor, CD105, and Flk1 along with upregulation of β-catenin target genes. CPCs co-cultured on adult fibroblasts resulted in increased endothelial Flk1 cells and reduction of αMHC and Hand1 cardiogenic cells in KO vs. WT CPCs (n=9). Treating these co-cultures with Quercetin, an inhibitor of nuclear β-catenin, resulted in partial rescue of the observed phenotype. This study uncovers a critical role of KLF15 for the maintenance of cardiac tissue homeostasis. Via inhibition of β-catenin transcription, KLF15 controls cardiomyogenic cell fate similar to embryonic cardiogenesis. This knowledge may provide a tool for activation of endogenous CPCs in the postnatal heart.

The SCL Transcription Factor Supports Erythroid Cell Survival and Differentiation Downstream of the Erythropoietin Receptor.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 818-818
Author(s):  
Rachid Lahlil ◽  
Richard Martin ◽  
Peter D. Aplan ◽  
C. Glenn Begley ◽  
Jacqueline E. Damen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Survival ◽  
Cell Fate ◽  
Genetic Interaction ◽  
Fetal Liver ◽  
Erythropoietin Receptor ◽  
Erythroid Cell ◽  
Loss Of Function

Abstract Erythroid cell development critically depends on the SCL/Tal1 transcription factor and on erythropoietin signalling. In the present study, we have taken several approaches to show that the two genes operate within the same pathway to consolidate the erythroid lineage. Signaling through the erythropoietin receptor (EpoR) upregulates SCL protein levels in a clonal cell line (TF-1) in vitro, and in murine fetal liver cells in vivo, when Epor−/− cells were compared to those of wild type littermates at E12.5. In addition, we provide functional evidence for a linear pathway from EpoR to SCL that regulates erythropoiesis. Interfering with SCL induction or SCL function prevents the anti-apoptotic effect of Epo in TF-1 cells and conversely, ectopic SCL expression is sufficient to substitute for Epo to transiently maintain cell survival. In vivo, SCL gain of function complements the cellular defects in Epor−/− embryos to support cell survival and maturation during primitive and definitive erythropoiesis, as assessed by cellular and histological analyses of Epor−/− SCLtg embryos. Moreover, several erythroid specific genes that are decreased in Epor−/− embryos are rescued by the SCL transgene including glycophorinA, bH1 and bmaj globin, providing molecular confirmation of the functional and genetic interaction between Epor and SCL. Conversely, erythropoiesis becomes deficient in compound Epor+/−SCL+/− heterozygote mice, indicating that the genetic interaction between EpoR and SCL is synthetic. Finally, using EpoR mutants that harbour well defined signalling deficiencies, combined with gain and loss of function approaches for specific kinases, we identify MAPK as the major signal transduction pathway downstream of EpoR that upregulates SCL function, necessary for erythroid cell survival and differentiation. Taken together, our observations are consistent with the view that cytokines can influence cell fate by altering the dosage of lineage transcriptional regulators.

Key Mechanisms of Early Lung Development

2007 ◽  
Vol 10 (5) ◽  
pp. 335-347 ◽  
Author(s):  
Jun Kimura ◽  
Gail H. Deutsch
Keyword(s):  
Respiratory Tract ◽  
Cell Fate ◽  
Target Genes ◽  
Critical Role ◽  
Hierarchical Classification ◽  
Branching Morphogenesis ◽  
Loss Of Function ◽  
Innovative Strategies ◽  
Downstream Target ◽  
Molecular Events

Lung morphogenesis requires the integration of multiple regulatory factors, which results in a functional air-blood interface required for gas exchange at birth. The respiratory tract is composed of endodermally derived epithelium surrounded by cells of mesodermal origin. Inductive signaling between these 2 tissue compartments plays a critical role in formation and differentiation of the lung, which is mediated by evolutionarily conserved signaling families used reiteratively during lung formation, including the fibroblast growth factor, hedgehog, retinoic acid, bone morphogenetic protein, and Wnt signaling pathways. Cells coordinate their response to these signaling proteins largely through transcription factors, which determine respiratory cell fate and pattern formation via the activation and repression of downstream target genes. Gain- and loss-of-function studies in null mutant and transgenic mice models have greatly facilitated the identification and hierarchical classification of these molecular programs. In this review, we highlight select molecular events that drive key phases of pulmonary development, including specification of a lung cell fate, primary lung bud formation, tracheoesophageal septation, branching morphogenesis, and proximal-distal epithelial patterning. Understanding the genetic pathways that regulate respiratory tract development is essential to provide insight into the pathogenesis of congenital anomalies and to develop innovative strategies to treat inherited and acquired lung disease.

scholarly journals SOX2 Plays a Critical Role in the Pituitary, Forebrain, and Eye during Human Embryonic Development

2008 ◽  
Vol 93 (5) ◽  
pp. 1865-1873 ◽  
Author(s):  
Daniel Kelberman ◽  
Sandra C. P. de Castro ◽  
Shuwen Huang ◽  
John A. Crolla ◽  
Rodger Palmer ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Anterior Pituitary ◽  
De Novo ◽  
Hypogonadotropic Hypogonadism ◽  
Expression Patterns ◽  
Critical Role ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Direct Role

Abstract Context: Heterozygous, de novo mutations in the transcription factor SOX2 are associated with bilateral anophthalmia or severe microphthalmia and hypopituitarism. Variable additional abnormalities include defects of the corpus callosum and hippocampus. Objective: We have ascertained a further three patients with severe eye defects and pituitary abnormalities who were screened for mutations in SOX2. To provide further evidence of a direct role for SOX2 in hypothalamo-pituitary development, we have studied the expression of the gene in human embryonic tissues. Results: All three patients harbored heterozygous SOX2 mutations: a deletion encompassing the entire gene, an intragenic deletion (c.70_89del), and a novel nonsense mutation (p.Q61X) within the DNA binding domain that results in impaired transactivation. We also show that human SOX2 can inhibit β-catenin-driven reporter gene expression in vitro, whereas mutant SOX2 proteins are unable to repress efficiently this activity. Furthermore, we show that SOX2 is expressed throughout the human brain, including the developing hypothalamus, as well as Rathke’s pouch, the developing anterior pituitary, and the eye. Conclusions: Patients with SOX2 mutations often manifest the unusual phenotype of hypogonadotropic hypogonadism, with sparing of other pituitary hormones despite anterior pituitary hypoplasia. SOX2 expression patterns in human embryonic development support a direct involvement of the protein during development of tissues affected in these individuals. Given the critical role of Wnt-signaling in the development of most of these tissues, our data suggest that a failure to repress the Wnt-β-catenin pathway could be one of the underlying pathogenic mechanisms associated with loss-of-function mutations in SOX2.

scholarly journals P-selectin glycoprotein ligand regulates the interaction of multiple myeloma cells with the bone marrow microenvironment

Blood ◽  
2012 ◽  
Vol 119 (6) ◽  
pp. 1468-1478 ◽  
Author(s):  
Abdel Kareem Azab ◽  
Phong Quang ◽  
Feda Azab ◽  
Costas Pitsillides ◽  
Brian Thompson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Stromal Cells ◽  
Critical Role ◽  
Loss Of Function ◽  
Downstream Signaling ◽  
Target Organs ◽  
Regulation Of Growth

Abstract Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in the pathogenesis of MM and in the development of drug resistance by MM cells. Selectins are involved in extravasation and homing of leukocytes to target organs. In the present study, we focused on adhesion dynamics that involve P-selectin glycoprotein ligand-1 (PSGL-1) on MM cells and its interaction with selectins in the BM microenvironment. We show that PSGL-1 is highly expressed on MM cells and regulates the adhesion and homing of MM cells to cells in the BM microenvironment in vitro and in vivo. This interaction involves both endothelial cells and BM stromal cells. Using loss-of-function studies and the small-molecule pan-selectin inhibitor GMI-1070, we show that PSGL-1 regulates the activation of integrins and downstream signaling. We also document that this interaction regulates MM-cell proliferation in coculture with BM microenvironmental cells and the development of drug resistance. Furthermore, inhibiting this interaction with GMI-1070 enhances the sensitization of MM cells to bortezomib in vitro and in vivo. These data highlight the critical contribution of PSGL-1 to the regulation of growth, dissemination, and drug resistance in MM in the context of the BM microenvironment.

scholarly journals Single-Cell RNA Sequencing Reveals Regulatory Mechanism for Trophoblast Cell-Fate Divergence in Human Peri-Implantation Embryo

2019 ◽  
Author(s):  
Bo Lv ◽  
Qin An ◽  
Qiao Zeng ◽  
Ping Lu ◽  
Xianmin Zhu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cellular Differentiation ◽  
Regulatory Mechanism ◽  
Bioinformatic Analysis ◽  
Loss Of Function ◽  
Trophoblast Differentiation ◽  
T Box ◽  
Development And Differentiation ◽  
Post Implantation

AbstractMultipotent trophoblasts undergo dynamic morphological movement and cellular differentiation after embryonic implantation to generate placenta. However, the mechanism controlling trophoblast development and differentiation during peri-implantation development remains elusive. In this study, we modeled human embryo peri-implantation development from blastocyst to early post-implantation stages by using an in vitro coculture system, and profiled the transcriptome of individual trophoblast cells from these embryos. We revealed the genetic networks regulating peri-implantation trophoblast development. While determining when trophoblast differentiation happens, our bioinformatic analysis identified T-box transcription factor 3 (TBX3) as a key regulator for the differentiation of cytotrophoblast into syncytiotrophoblast. The function of TBX3 in trophoblast differentiation is then validated by a loss-of-function experiment. In conclusion, our results provided a valuable resource to study the regulation of trophoblasts development and differentiation during human peri-implantation development.

scholarly journals Capsule carbohydrate structure determines virulence in Acinetobacter baumannii

2021 ◽  
Vol 17 (2) ◽  
pp. e1009291
Author(s):  
Yuli Talyansky ◽  
Travis B. Nielsen ◽  
Jun Yan ◽  
Ulrike Carlino-Macdonald ◽  
Gisela Di Venanzio ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Bacterial Pathogen ◽  
Specific Gene ◽  
Dependent Manner ◽  
Bacterial Burden ◽  
Carbohydrate Structure ◽  
Loss Of Function ◽  
Capsule Assembly

Acinetobacter baumannii is a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and displayed higher bacterial burden and lethality in vivo. Gtr6+ strains were phagocytized more readily and caused lower bacterial burden and no clinical illness in vivo. We found that the CR3 receptor mediated phagocytosis of gtr6+, but not gtr6-, strains in a complement-dependent manner. Furthermore, hypovirulent gtr6+ strains demonstrated increased virulence in vivo when CR3 function was abrogated. In summary, loss-of-function in a single capsule assembly gene dramatically altered virulence by inhibiting complement deposition and recognition by phagocytes across multiple A. baumannii strains. Thus, capsular structure can determine virulence among A. baumannii strains by altering bacterial interactions with host complement-mediated opsonophagocytosis.

scholarly journals Knockdown of EIF3H inhibits the development and progression of pancreatic cancer by regulating cell proliferation and apoptosis in vitro

2022 ◽  
Vol 67 (4) ◽  
pp. 83-90
Author(s):  
Yuqiang Shan ◽  
Wencheng Kong ◽  
Akao Zhu ◽  
Jiangtao Li ◽  
Huicheng Jin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Critical Role ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Loss Of Function ◽  
Eukaryotic Translation ◽  
Proliferation Capacity ◽  
Pancreatic Cancer Cells

Nowadays, pancreatic cancer has been recognized as one of the most fatal malignancies worldwide, the molecular mechanism of which is still not fully understood. In this study, we aimed to uncover the fundamental functions of the eukaryotic translation initiation factor 3H subunit (EIF3H) in the development and progression of pancreatic cancer. Firstly, the results of immunohistochemical (IHC) staining revealed that EIF3H was highly expressed in pancreatic cancer. Moreover, lentiviruses were used to deliver shRNAs into pancreatic cancer cells for silencing EIF3H. Furthermore, the loss-of-function assays demonstrated that knockdown of EIF3H could inhibit the progression of pancreatic cancer cells by reducing proliferation capacity, promoting apoptosis, arresting cell cycle in G2 and suppressing cell migration. In summary, EIF3H may play a critical role in the development and progression of pancreatic cancer, which possesses the potential to act as a therapeutic target for pancreatic cancer treatment.

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