scholarly journals NAD+-dependent deacetylase SIRT1 is essential for meiotic progression and controls repair-recombination efficiency

2019 ◽  
Author(s):  
Harshita Kaul ◽  
Shaunak Deota ◽  
Amit Fulzele ◽  
Anne Gonzalez-de-Peredo ◽  
Ullas Kolthur-Seetharam
Keyword(s):  
Critical Role ◽  
Genotoxic Stress ◽  
Mrn Complex ◽  
Meiotic Progression ◽  
Recombination Efficiency ◽  
Molecular Events ◽  
Repair Efficiency ◽  
Spatio Temporal ◽  
Recombination Checkpoint ◽  
Downstream Processes

AbstractMeiotic components and their functions have been extensively studied. Yet, the interplay between molecular factors and regulation of their functions that is brought about by post-translational modifications, specifically (de)-acetylation, is not well characterized. SIRT1, a NAD+-dependent deacetylase has been previously shown to be necessary for spermatogenesis. However, whether it has any role to play in mammalian meiosis remains to be uncovered. Our findings identify SIRT1 as a key determinant of meiotic progression. Knocking out SIRT1 specifically in meiocytes (SIRT1Δmeio) led to a delay in progression through pachytene and repair of double strand breaks. Interestingly, despite these deficits, meiotic loss of SIRT1 did not affect synapsis nor did it lead to pachytene arrest or apoptosis. Moreover, our results demonstrate that SIRT1 is required for regulating crossover frequency and its absence results in higher crossover events. Therefore, our study brings to the fore a novel regulatory factor/mechanism that is necessary for coupling of synapsis and recombination. This is noteworthy since mutations in core meiotic components result in gross defects in synapsis, repair and recombination, and very few studies have reported the differential regulation of these processes. Further, exposing SIRT1Δmeio to low/moderate doses of ©-irradiation indicated that SIRT1 might be involved in eliciting recombination checkpoint arrest and in its absence pachytene cells progress to diplotene stage, unlike in the SIRT1WT mice. Importantly, exogenous damage resulted in enhanced retention of ©H2AX in SIRT1Δmeio diplotene cells, reiterating the critical role that SIRT1 plays in regulating repair efficiency/kinetics. Molecularly, we find that SIRT1 interacts with MRN complex and lack of SIRT1 causes hyperacetylation of several non-histone proteins including the MRN components. Given that SIRT1Δmeio mice mimic MRN hypomorphs, we propose that SIRT1-dependent deacetylation of these proteins is crucial for normal meiotic progression. Taken together, our study uncovers a previously unappreciated role of SIRT1 in meiotic progression.Author SummaryMeiosis is a key process in germ cell development that is essential for generating genetic diversity via recombination. It involves precise spatio-temporal orchestration of various molecular events such as chromosomal synapsis, repair and recombination. Whereas the core meiotic components are well known, upstream factors that might be important for regulating their functions and also couple the downstream processes are less explored. In this paper, we report that SIRT1, a NAD+-dependent deacetylase, is necessary for meiotic progression by identifying its role in coupling of synapsis and recombination. By generating a meiosis specific knockout of SIRT1, we show that its absence in spermatocytes leads to inefficient/delayed repair and progression through pachytene. We have also uncovered that SIRT1 exerts control over recombination (cross over) frequency. Interestingly, our findings demonstrate that SIRT1 provides protection against exogenous genotoxic stress possibly by eliciting meiotic checkpoints. Thus, this study provides both cellular and molecular insights into the importance of SIRT1 mediated protein deacetylation in governing meiosis in mammals.

scholarly journals Whole Transcriptome Analysis of Hypertension Induced Cardiac Injury Using Deep Sequencing

2016 ◽  
Vol 38 (2) ◽  
pp. 670-682 ◽  
Author(s):  
Tao-Tao Li ◽  
Xiao-Yan Li ◽  
Li-Xin Jia ◽  
Jing Zhang ◽  
Wen-Mei Zhang ◽  
...  
Keyword(s):  
Transcriptome Analysis ◽  
Cell Activation ◽  
Critical Role ◽  
Cardiac Injury ◽  
Interaction Network ◽  
Receptor Interaction ◽  
Rna Seq ◽  
Cardiac Inflammation ◽  
Molecular Events ◽  
Focal Adhesion Protein

Background/Aims: Hypertension plays a critical role in the cardiac inflammation and injury. However, the mechanism of how hypertension causes the cardiac injury at a molecular level remains to be elucidated. Methods: RNA-Seq has been demonstrated to be an effective approach for transcriptome analysis, which is essential to reveal the molecular constituents of cells and tissues. In this study, we investigated the global molecular events associated with the mechanism of hypertension induced cardiac injury using RNA-Seq analysis. Results: Our results showed that totally 1,801 genes with different expression variations were identified after Ang II infusion at 1, 3 and 7 days. Go analysis showed that the top 5 high enrichment Go terms were response to stress, response to wounding, cellular component organization, cell activation and defense response. KEGG pathway analysis revealed the top 5 significantly overrepresented pathways were associated with ECM-receptor interaction, focal adhesion, protein digestion and absorption, phagosome and asthma. Moreover, protein-protein interaction network analysis indicated that ubiquitin C may play a key role in the processes of hypertension-induced cardiac injury. Conclusion: Our study provides a comprehensive understanding of the transcriptome events in hypertension-induced cardiac pathology.

scholarly journals Acceleration of mesoderm development and expansion of hematopoietic progenitors in differentiating ES cells by the mouse Mix-like homeodomain transcription factor

Blood ◽  
2006 ◽  
Vol 107 (8) ◽  
pp. 3122-3130 ◽  
Author(s):  
Stephen Willey ◽  
Angel Ayuso-Sacido ◽  
Hailan Zhang ◽  
Stuart T. Fraser ◽  
Kenneth E. Sahr ◽  
...  
Keyword(s):  
Es Cells ◽  
Critical Role ◽  
Embryonic Stem ◽  
Homeobox Gene ◽  
Embryoid Bodies ◽  
Hematopoietic Progenitors ◽  
Adult Type ◽  
Mesoderm Development ◽  
Molecular Events ◽  
Organ Systems

Abstract The cellular and molecular events underlying the formation and differentiation of mesoderm to derivatives such as blood are critical to our understanding of the development and function of many tissues and organ systems. How different mesodermal populations are set aside to form specific lineages is not well understood. Although previous genetic studies in the mouse embryo have pointed to a critical role for the homeobox gene Mix-like (mMix) in gastrulation, its function in mesoderm development remains unclear. Hematopoietic defects have been identified in differentiating embryonic stem cells in which mMix was genetically inactivated. Here we show that conditional induction of mMix in embryonic stem cell–derived embryoid bodies results in the early activation of mesodermal markers prior to expression of Brachyury/T and acceleration of the mesodermal developmental program. Strikingly, increased numbers of mesodermal, hemangioblastic, and hematopoietic progenitors form in response to premature activation of mMix. Differentiation to primitive (embryonic) and definitive (adult type) blood cells proceeds normally and without an apparent bias in the representation of different hematopoietic cell fates. Therefore, the mouse Mix gene functions early in the recruitment and/or expansion of mesodermal progenitors to the hemangioblastic and hematopoietic lineages.

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 UvrD Helicase Suppresses Recombination and DNA Damage-Induced Deletions

2006 ◽  
Vol 188 (15) ◽  
pp. 5450-5459 ◽  
Author(s):  
Josephine Kang ◽  
Martin J. Blaser
Keyword(s):  
Dna Damage ◽  
Mismatch Repair ◽  
Excision Repair ◽  
Critical Role ◽  
Genotoxic Stress ◽  
Recombinational Repair ◽  
Dna Repeats ◽  
H Pylori ◽  
High Level

ABSTRACT UvrD, a highly conserved helicase involved in mismatch repair, nucleotide excision repair (NER), and recombinational repair, plays a critical role in maintaining genomic stability and facilitating DNA lesion repair in many prokaryotic species. In this report, we focus on the UvrD homolog in Helicobacter pylori, a genetically diverse organism that lacks many known DNA repair proteins, including those involved in mismatch repair and recombinational repair, and that is noted for high levels of inter- and intragenomic recombination and mutation. H. pylori contains numerous DNA repeats in its compact genome and inhabits an environment rich in DNA-damaging agents that can lead to increased rearrangements between such repeats. We find that H. pylori UvrD functions to repair DNA damage and limit homologous recombination and DNA damage-induced genomic rearrangements between DNA repeats. Our results suggest that UvrD and other NER pathway proteins play a prominent role in maintaining genome integrity, especially after DNA damage; thus, NER may be especially critical in organisms such as H. pylori that face high-level genotoxic stress in vivo.

scholarly journals S-Palmitoylation determines TMEM55B-dependent positioning of lysosomes

2021 ◽  
Author(s):  
Sönke Rudnik ◽  
Saskia Heybrock ◽  
Paul Saftig ◽  
Markus Damme
Keyword(s):  
Molecular Motors ◽  
Protein Complexes ◽  
Critical Role ◽  
Adaptor Protein ◽  
Retrograde Transport ◽  
Microtubule Motors ◽  
Lysosomal Sorting ◽  
Sorting Motif ◽  
Spatio Temporal

The spatio-temporal cellular distribution of lysosomes depends on active transport mainly driven by microtubule-motors such as kinesins and dynein. Different protein complexes attach these molecular motors to their vesicular cargo: TMEM55B, as an integral lysosomal membrane protein, is a component of such a complex mediating the retrograde transport of lysosomes by establishing an interaction with the cytosolic scaffold protein JIP4 and dynein/dynactin. Here we show that TMEM55B and its paralog TMEM55A are S-palmitoylated proteins and lipidated at multiple cysteine-residues. Mutation of all cysteines in TMEM55B prevents S-palmitoylation and causes the retention of the mutated protein in the Golgi-apparatus. Consequently, non-palmitoylated TMEM55B is no longer able to modulate lysosomal positioning and the perinuclear clustering of lysosomes. Additional mutagenesis of the dileucine-based lysosomal sorting motif in non-palmitoylated TMEM55B leads to partial missorting to the plasma membrane instead of retention in the Golgi, implicating a direct effect of S-palmitoylation on the adaptor-protein-dependent sorting of TMEM55B. Our data suggest a critical role of S-palmitoylation on the trafficking of TMEM55B and TMEM55B-dependent lysosomal positioning.

scholarly journals MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence and angiogenic signaling

2017 ◽  
Author(s):  
Cristina Espinosa-Diez ◽  
RaeAnna Wilson ◽  
Namita Chatterjee ◽  
Clayton Hudson ◽  
Rebecca Ruhl ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Targeted Delivery ◽  
Genotoxic Stress ◽  
Telomerase Activity ◽  
Loss Of Function ◽  
Mrn Complex ◽  
Vegf Signaling

AbstractMicroRNAs contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic signaling that is buffered by two distinct microRNAs. We demonstrate that genotoxic stress-induced miR-494 and miR-99b inhibit the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Functionally, gain and loss of function experiments show that miR-494 and miR-99b affect telomerase activity, activate p21 and Rb pathways and diminish angiogenic sproutingin vitroandin vivo. Genetic and pharmacological disruption of VEGFR-2 signaling and the MRN complex reveal a surprising co-dependency of these pathways in regulating endothelial senescence and proliferation. Vascular-targeted delivery of miR-494 decreases both growth factor-induced and tumor angiogenesis in mouse models. Mechanistically, disruption of the MRN complex induced CD44, a known driver of senescence and regulator of VEGF signaling in addition to suppressing IL-13 a stimulator of VEGF signaling. Our work identifies a putative miR-facilitated mechanism by which endothelial cells can be insulated against VEGF signaling to facilitate the onset of senescence and highlight the potential of targeting DNA repair to disrupt pathological angiogenesis.

scholarly journals NF-κB signaling dynamics is controlled by a dose-sensing autoregulatory loop

2019 ◽  
Vol 12 (579) ◽  
pp. eaau3568 ◽  
Author(s):  
Mialy M. DeFelice ◽  
Helen R. Clark ◽  
Jacob J. Hughey ◽  
Inbal Maayan ◽  
Takamasa Kudo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell Analysis ◽  
Interleukin 1 ◽  
Expression Patterns ◽  
Critical Role ◽  
Signal Propagation ◽  
Innate Immune ◽  
Signaling Dynamics ◽  
Molecular Events ◽  
Dose Dependent

Over the last decade, multiple studies have shown that signaling proteins activated in different temporal patterns, such as oscillatory, transient, and sustained, can result in distinct gene expression patterns or cell fates. However, the molecular events that ensure appropriate stimulus- and dose-dependent dynamics are not often understood and are difficult to investigate. Here, we used single-cell analysis to dissect the mechanisms underlying the stimulus- and dose-encoding patterns in the innate immune signaling network. We found that Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling dynamics relied on a dose-dependent, autoinhibitory loop that rendered cells refractory to further stimulation. Using inducible gene expression and optogenetics to perturb the network at different levels, we identified IL-1R–associated kinase 1 (IRAK1) as the dose-sensing node responsible for limiting signal flow during the innate immune response. Although the kinase activity of IRAK1 was not required for signal propagation, it played a critical role in inhibiting the nucleocytoplasmic oscillations of the transcription factor NF-κB. Thus, protein activities that may be “dispensable” from a topological perspective can nevertheless be essential in shaping the dynamic response to the external environment.

scholarly journals The Emerging Role of Ten-Eleven Translocation 1 in Epigenetic Responses to Environmental Exposures

2020 ◽  
Vol 13 ◽  
pp. 251686572091015 ◽  
Author(s):  
Tao Zhu ◽  
Anthony P Brown ◽  
Hong Ji
Keyword(s):  
Therapeutic Potential ◽  
Critical Role ◽  
Environmental Exposures ◽  
Epidemiological Studies ◽  
Epigenetic Changes ◽  
Molecular Processes ◽  
Molecular Events ◽  
Negative Impacts ◽  
The Impact

Mounting evidence from epidemiological studies and animal models has linked exposures to environmental factors to changes in epigenetic markers, especially in DNA methylation. These epigenetic changes may lead to dysregulation of molecular processes and functions and mediate the impact of environmental exposures in complex diseases. However, detailed molecular events that result in epigenetic changes following exposures remain unclear. Here, we review the emerging evidence supporting a critical role of ten-eleven translocation 1 (TET1) in mediating these processes. Targeting TET1 and its associated pathways may have therapeutic potential in alleviating negative impacts of environmental exposures, preventing and treating exposure-related diseases.

scholarly journals Mouse centric and pericentric satellite repeats form distinct functional heterochromatin

2004 ◽  
Vol 166 (4) ◽  
pp. 493-505 ◽  
Author(s):  
Mounia Guenatri ◽  
Delphine Bailly ◽  
Christèle Maison ◽  
Geneviève Almouzni
Keyword(s):  
Critical Role ◽  
Repetitive Sequences ◽  
Micrococcal Nuclease ◽  
Temporal Isolation ◽  
Heterochromatin Protein ◽  
Histone Methyltransferases ◽  
Centromeric Function ◽  
Satellite Repeats ◽  
Chromatid Cohesion ◽  
Spatio Temporal

Heterochromatin is thought to play a critical role for centromeric function. However, the respective contributions of the distinct repetitive sequences found in these regions, such as minor and major satellites in the mouse, have remained largely unsolved. We show that these centric and pericentric repeats on the chromosomes have distinct heterochromatic characteristics in the nucleus. Major satellites from different chromosomes form clusters associated with heterochromatin protein 1α, whereas minor satellites are individual entities associated with centromeric proteins. Both regions contain methylated histone H3 (Me-K9 H3) but show different micrococcal nuclease sensitivities. A dinucleosome repeating unit is found specifically associated with major satellites. These domains replicate asynchronously, and chromatid cohesion is sustained for a longer time in major satellites compared with minor satellites. Such prolonged cohesion in major satellites is lost in the absence of Suv39h histone methyltransferases. Thus, we define functionally independent centromeric subdomains, which spatio-temporal isolation is proposed to be important for centromeric cohesion and dissociation during chromosome segregation.

scholarly journals Seasonal resource categorisation and behavioural adaptation among non-human primates: Implications for hominin carnivory in the Early Pleistocene

2021 ◽  
Author(s):  
James Clark ◽  
Gonzalo José Linares Matás
Keyword(s):  
Nonhuman Primates ◽  
Behavioural Change ◽  
Critical Role ◽  
Early Pleistocene ◽  
Fallback Foods ◽  
Resource Quality ◽  
Behavioural Adaptation ◽  
Temporal Relationships ◽  
Different Populations ◽  
Spatio Temporal

Seasonality plays a critical role in determining the yearly dietary variability of many nonhuman primates living in tropical and subtropical environments. Much previous research has emphasised the seasonal importance of both preferred resources—eaten whenever available—and fallback foods—eaten during periods of scarcity to compensate for an insufficient availability of preferred resources. However, previous discussions of this dichotomy have often overlooked why different populations of the same taxon may exhibit a different level of engagement with identical resources, especially those that require some degree of technological investment by virtue of being embedded. Similarly, not enough attention has been given to diachronic trends in the incorporation of novel resources to seasonal consumption patterns among non-human primates.In this paper, we present a framework for understanding the spatio-temporal relationships between preferred and fallback resources in a more systematic way, explicitly through the lens of landscape knowledge and seasonal fluctuations in quality and availability. We argue it is the interplay between resource quality and the available knowledge pertaining to its exploitation that will determine the categorisation of a resource. In this regard, the accumulation of further information through encounter, experimentation, and behavioural (including technological) innovation enables resources with high nutritional potential to attain preferred status. We end with an exploration of the gradual consolidation of the hominin carnivory niche in the Early Pleistocene of East Africa, to demonstrate the utility of our framework—specifically the interplay between seasonality and the concept of landscape knowledge—for understanding behavioural change in the archaeological record.

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