scholarly journals The C. elegans SET-2 histone methyltransferase maintains germline fate by preventing progressive transcriptomic deregulation across generations

2019 ◽  
Author(s):  
Valérie J. Robert ◽  
Andrew K. Knutson ◽  
Andreas Rechtsteiner ◽  
Gaël Yvert ◽  
Susan Strome ◽  
...  
Keyword(s):  
Principal Component Analysis ◽  
Cell Fate ◽  
Germ Cells ◽  
Expression Profiling ◽  
Histone H3 ◽  
Principal Component ◽  
Transcriptional Program ◽  
C Elegans ◽  
Chromatin Regulator ◽  
Germline Genes

AbstractChromatin factors contribute to germline maintenance by preserving a germline-appropriate transcriptional program. In the absence of the conserved histone H3 Lys4 (H3K4) methyltransferase SET-2, C. elegans germ cells progressively lose their identity over generations, leading to sterility. How this transgenerational loss of fertility results from the absence of SET-2 is unknown. Here we performed expression profiling across generations on germlines from mutant animals lacking SET-2 activity. We found that gene deregulation occurred in 2 steps: a priming step in early generations progressing to loss of fertility in later generations. By performing Within-Class Analysis (WCA), a derivative of Principal Component Analysis, we identified transcriptional signatures associated with SET-2 inactivation, both at the priming step and later on during loss of fertility. Further analysis showed that repression of germline genes, derepression of somatic programs, and X-chromosome desilencing through interference with PRC2-dependent repression, are priming events driving loss of germline identity in the absence of SET-2. Decreasing expression of identified priming genes, including the C/EBP homologue cebp-1 and TGF-β pathway components, was sufficient to delay the onset of sterility, suggesting that they individually contribute to the loss of germ cell fate. Altogether, our findings illustrate how the loss of a chromatin regulator at one generation can progressively deregulate multiple transcriptional and signaling programs, ultimately leading to loss of appropriate cell fate.

scholarly journals Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline

Development ◽  
1999 ◽  
Vol 126 (5) ◽  
pp. 1011-1022 ◽  
Author(s):  
T.L. Gumienny ◽  
E. Lambie ◽  
E. Hartwieg ◽  
H.R. Horvitz ◽  
M.O. Hengartner
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Germ Cell ◽  
Somatic Cell ◽  
Cell Fate ◽  
Germ Cells ◽  
Mapk Pathway ◽  
Apoptotic Cell ◽  
C Elegans ◽  
Pathway Activation

Development of the nematode Caenorhabditis elegans is highly reproducible and the fate of every somatic cell has been reported. We describe here a previously uncharacterized cell fate in C. elegans: we show that germ cells, which in hermaphrodites can differentiate into sperm and oocytes, also undergo apoptotic cell death. In adult hermaphrodites, over 300 germ cells die, using the same apoptotic execution machinery (ced-3, ced-4 and ced-9) as the previously described 131 somatic cell deaths. However, this machinery is activated by a distinct pathway, as loss of egl-1 function, which inhibits somatic cell death, does not affect germ cell apoptosis. Germ cell death requires ras/MAPK pathway activation and is used to maintain germline homeostasis. We suggest that apoptosis eliminates excess germ cells that acted as nurse cells to provide cytoplasmic components to maturing oocytes.

scholarly journals FACT sets a barrier for cell fate reprogramming inC. elegansand Human

2017 ◽  
Author(s):  
Ena Kolundzic ◽  
Andreas Ofenbauer ◽  
Bora Uyar ◽  
Anne Sommermeier ◽  
Stefanie Seelk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Chromatin Accessibility ◽  
Genetic Screen ◽  
Cellular Reprogramming ◽  
Stable Gene ◽  
C Elegans ◽  
Chromatin Regulator ◽  
Evolutionarily Conserved ◽  
Stable Gene Expression

The chromatin regulator FACT (Facilitates Chromatin Transcription) is essential for ensuring stable gene expression by promoting transcription. In a genetic screen usingC. eleganswe identified that FACT maintains cell identities and acts as a barrier for transcription factor-mediated cell fate reprogramming. Strikingly, FACTs role as a reprogramming barrier is conserved in humans as we show that FACT depletion enhances reprogramming of fibroblasts into stem cells and neurons. Such activity of FACT is unexpected since known reprogramming barriers typically repress gene expression by silencing chromatin. In contrast, FACT is a positive regulator of gene expression suggesting an unprecedented link of cell fate maintenance with counteracting alternative cell identities. This notion is supported by ATAC-seq analysis showing that FACT depletion results in decreased but also increased chromatin accessibility for transcription factors. Our findings identify FACT as a cellular reprogramming barrier inC. elegansand in Human, revealing an evolutionarily conserved mechanism for cell fate protection.

scholarly journals Neuronal regulated Ire1-dependent mRNA decay controls germline differentiation in C. elegans

2020 ◽  
Author(s):  
Mor Levi-Ferber ◽  
Rewayd Shalash ◽  
Adrien Le-Thomas ◽  
Yehuda Salzberg ◽  
Maor Shurgi ◽  
...  
Keyword(s):  
Er Stress ◽  
Tumor Cells ◽  
Cell Fate ◽  
Germ Cells ◽  
Mrna Decay ◽  
Neuronal Circuit ◽  
C Elegans ◽  
Animal Physiology ◽  
Molecular Events ◽  
Germline Differentiation

Understanding the molecular events that regulate cell pluripotency versus acquisition of differentiated somatic cell fate is fundamentally important. Studies in C. elegans demonstrate that knockout of the germline-specific translation repressor gld-1, causes germ cells within tumorous gonads to form germline-derived teratoma. Previously we demonstrated that ER stress enhances this phenotype to suppress germline tumor progression (Levi-Ferber M, 2015). Here, we identify a neuronal circuit that non-autonomously suppresses germline differentiation, and show that it communicates with the gonad via the neurotransmitter serotonin to limit somatic differentiation of the tumorous germline. ER stress controls this circuit through regulated IRE-1-dependent mRNA decay of transcripts encoding the neuropeptide FLP-6. Depletion of FLP-6 disrupts the circuit's integrity and hence its ability to prevent somatic-fate acquisition by germline tumor cells. Our findings reveal mechanistically how ER stress enhances ectopic germline differentiation, and demonstrate that RIDD can affect animal physiology by controlling a specific neuronal circuit.

scholarly journals The zinc-finger transcription factor LSL-1 is a major regulator of the germline transcriptional program in C. elegans

2021 ◽  
Author(s):  
David Rodriguez-Crespo ◽  
Magali Nanchen ◽  
Shweta Rajopadhye ◽  
Chantal Wicky
Keyword(s):  
Meiotic Prophase ◽  
Genome Stability ◽  
Primordial Germ Cell ◽  
Somatic Cells ◽  
Specific Gene ◽  
Loss Of Function ◽  
Transcriptional Program ◽  
Germline Development ◽  
C Elegans ◽  
Germline Genes

Specific gene transcriptional programs are required to ensure proper proliferation and differentiation processes underlying the production of specialized cells during development. Gene activity is mainly regulated by the concerted action of transcription factors and chromatin proteins. In the nematode C. elegans, mechanisms that silence improper transcriptional programs in germline and somatic cells have been well studied, however, how are tissue specific sets of genes turned on is less known. LSL-1 is herein defined as a novel crucial transcriptional regulator of germline genes in C. elegans. LSL-1 is first detected in the P4 blastomere and remains present at all stages of germline development, from primordial germ cell proliferation to the end of meiotic prophase. lsl-1 loss-of-function mutants exhibit many defects including meiotic prophase progression delay, a high level of germline apoptosis, and production of almost no functional gametes. Transcriptomic analysis and ChIP-seq data show that LSL-1 binds to promoters and acts as a transcriptional activator of germline genes involved in various processes, including homologous chromosome pairing, recombination, and genome stability. Furthermore, we show that LSL-1 functions by antagonizing the action of the heterochromatin proteins HPL-2/HP1 and LET-418/Mi2 known to be involved in the repression of germline genes in somatic cells. Based on our results, we propose LSL-1 to be a major regulator of the germline transcriptional program during development.

scholarly journals Collapse of Global Neuronal States in Caenorhabditis elegans under Isoflurane Anesthesia

2020 ◽  
Vol 133 (1) ◽  
pp. 133-144 ◽  
Author(s):  
Mehraj R. Awal ◽  
Gregory S. Wirak ◽  
Christopher V. Gabel ◽  
Christopher W. Connor
Keyword(s):  
Principal Component Analysis ◽  
Caenorhabditis Elegans ◽  
Neuronal Activity ◽  
High Frequency ◽  
Dynamic Range ◽  
Functional Organization ◽  
Principal Component ◽  
Component Analysis ◽  
C Elegans ◽  
Light Sheet Microscopy

Background A comprehensive understanding of how anesthetics facilitate a reversible collapse of system-wide neuronal function requires measurement of neuronal activity with single-cell resolution. Multineuron recording was performed in Caenorhabditis elegans to measure neuronal activity at varying depths of anesthesia. The authors hypothesized that anesthesia is characterized by dyssynchrony between neurons resulting in a collapse of organized system states. Methods Using light-sheet microscopy and transgenic expression of the calcium-sensitive fluorophore GCaMP6s, a majority of neurons (n = 120) in the C. elegans head were simultaneously imaged in vivo and neuronal activity was measured. Neural activity and system-wide dynamics were compared in 10 animals, progressively dosed at 0%, 4%, and 8% isoflurane. System-wide neuronal activity was analyzed using principal component analysis. Results Unanesthetized animals display distinct global neuronal states that are reflected in a high degree of correlation (R = 0.196 ± 0.070) between neurons and low-frequency, large-amplitude neuronal dynamics. At 4% isoflurane, the average correlation between neurons is significantly diminished (R = 0.026 ± 0.010; P < 0.0001 vs. unanesthetized) and neuron dynamics shift toward higher frequencies but with smaller dynamic range. At 8% isoflurane, interneuronal correlations indicate that neuronal activity remains uncoordinated (R = 0.053 ± 0.029; P < 0.0001 vs. unanesthetized) with high-frequency dynamics that are even further restricted. Principal component analysis of unanesthetized neuronal activity reveals distinct structure corresponding to known behavioral states. At 4% and 8% isoflurane this structure is lost and replaced with randomized dynamics, as quantified by the percentage of total ensemble variance captured by the first three principal components. In unanesthetized worms, this captured variance is high (88.9 ± 5.4%), reflecting a highly organized system, falling significantly at 4% and 8% isoflurane (57.9 ± 11.2%, P < 0.0001 vs. unanesthetized, and 76.0 ± 7.9%, P < 0.001 vs. unanesthetized, respectively) and corresponding to increased randomization and collapse of system-wide organization. Conclusions Anesthesia with isoflurane in C. elegans corresponds to high-frequency randomization of individual neuron activity, loss of coordination between neurons, and a collapse of system-wide functional organization. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals A hydraulic instability drives the cell death decision in the nematode germline

2020 ◽  
Author(s):  
N. T. Chartier ◽  
A. Mukherjee ◽  
J. Pfanzelter ◽  
S. Fürthauer ◽  
B. T. Larson ◽  
...  
Keyword(s):  
Decision Making ◽  
Cell Death ◽  
Cell Fate ◽  
Germ Cells ◽  
Cell Fate Decision ◽  
Homogeneous Population ◽  
C Elegans ◽  
The Common ◽  
Fate Decision ◽  
Cell Volumes

AbstractOocytes are large and resourceful. During oogenesis some germ cells grow, typically at the expense of others that undergo apoptosis. How germ cells are selected to live or die out of a homogeneous population remains unclear. Here we show that this cell fate decision in C. elegans is mechanical and related to tissue hydraulics. Germ cells become inflated when the pressure inside them is lower than in the common cytoplasmic pool. This condition triggers a hydraulic instability which amplifies volume differences and causes some germ cells to grow and others to shrink. Shrinking germ cells are extruded and die, as we demonstrate by reducing germ cell volumes via thermoviscous pumping. Together, this reveals a robust mechanism of mechanochemical cell fate decision making in the germline.

scholarly journals SUMOylation of the chromodomain factor MRG-1 in C. elegans affects chromatin-regulatory dynamics

2021 ◽  
Author(s):  
Gülkiz Baytek ◽  
Alexander Blume ◽  
Funda Gerceker Demirel ◽  
Selman Bulut ◽  
Philipp Mertins ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Protein Interaction ◽  
Interaction Analysis ◽  
Mammalian Species ◽  
Strong Association ◽  
Histone H3 ◽  
C Elegans ◽  
Protein Protein Interaction ◽  
Lysine Residues

AbstractEpigenetic mechanisms to control chromatin accessibility and structure is important for gene expression in eukaryotic cells. Chromatin regulation ensures proper development and cell fate specification but is also essential later in life. Modifications of histone proteins as an integral component of chromatin can promote either gene expression or repression, respectively. Proteins containing specific domains such as the chromodomain recognize mono-, di- or tri-methylated lysine residues on histone H3. The chromodomain protein MRG-1 in Caenorhabditis elegans is the ortholog of mammalian MRG15, which belongs to the MORF4 Related Gene (MRG) family in humans. In C. elegans MRG-1 predominantly binds methylated histone H3 lysine residues at position 36 (H3K36me3). MRG-1 is important during germline maturation and for safeguarding the germ cell identity. However, it lacks enzymatic activity and depends on protein-protein interaction to cooperate with other factors to regulate chromatin. To elucidate the variety of MRG-1 interaction partners we performed in-depth protein-protein interaction analysis using immunoprecipitations coupled with mass-spectrometry. Besides previously described and novel interactions with other proteins, we also detected a strong association with the Small Ubiquitin-like Modifier (SUMO). Since SUMO is known to be attached to proteins in order to modulate the target proteins activity we assessed whether MRG-1 is post-translationally modified by SUMOylation. Notably, we provide evidence that MRG-1 is indeed SUMOylated and that this post-translational modification influences the chromatin-binding profile of MRG-1 in the C. elegans genome. Our presented study hints towards an important role of SUMOylation in the context of epigenetic regulation via the chromodomain protein MRG-1, which may be a conserved phenomenon also in mammalian species.

TRA-1A regulates transcription of fog-3, which controls germ cell fate in C. elegans

Development ◽  
2000 ◽  
Vol 127 (14) ◽  
pp. 3119-3129 ◽  
Author(s):  
P. Chen ◽  
R.E. Ellis
Keyword(s):  
Transcriptional Regulation ◽  
Sexual Identity ◽  
Cell Fate ◽  
Zinc Finger ◽  
Germ Cells ◽  
Zinc Finger Protein ◽  
Rt Pcr ◽  
C Elegans ◽  
Finger Protein

In C. elegans, the zinc-finger protein TRA-1A is thought to be the final arbiter of somatic sexual identity. We show that fog-3, which is required for germ cells to become sperm rather than oocytes, is a target of TRA-1A. First, northern analyses and RT-PCR experiments indicate that expression of fog-3 is controlled by tra-1. Second, studies of double mutants show that this control could be direct. Third, the fog-3 promoter contains multiple sites that bind TRA-1A in gel shift assays, and mutations in these sites alter activity of fog-3 in vivo. These results establish fog-3 as one of the first known targets of transcriptional regulation by TRA-1A. Furthermore, they show that tra-1 controls a terminal regulator of sexual fate in germ cells, just as it is thought to do in the soma.

Transformation of the germ line into muscle in mes-1 mutant embryos of C. elegans

Development ◽  
1995 ◽  
Vol 121 (9) ◽  
pp. 2961-2972 ◽  
Author(s):  
S. Strome ◽  
P. Martin ◽  
E. Schierenberg ◽  
J. Paulsen
Keyword(s):  
Cell Fate ◽  
Germ Cells ◽  
Germ Line ◽  
Primordial Germ Cells ◽  
Primordial Germ Cell ◽  
Wild Type ◽  
C Elegans ◽  
Stem Cell Divisions ◽  
Asymmetric Partitioning

Mutations in the maternal-effect sterile gene mes-1 cause the offspring of homozygous mutant mothers to develop into sterile adults. Lineage analysis revealed that mutant offspring are sterile because they fail to form primordial germ cells during embryogenesis. In wild-type embryos, the primordial germ cell P4 is generated via a series of four unequal stem-cell divisions of the zygote. mes-1 embryos display a premature and progressive loss of polarity in these divisions: P0 and P1 undergo apparently normal unequal divisions and cytoplasmic partitioning, but P2 (in some embryos) and P3 (in most embryos) display defects in cleavage asymmetry and fail to partition lineage-specific components to only one daughter cell. As an apparent consequence of these defects, P4 is transformed into a muscle precursor, like its somatic sister cell D, and generates up to 20 body muscle cells instead of germ cells. Our results show that the wild-type mes-1 gene participates in promoting unequal germ-line divisions and asymmetric partitioning events and thus the determination of cell fate in early C. elegans embryos.

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