14 results on '"Elizabeth D. Larson"'
Search Results
2. Low-level repressive histone marks fine-tune gene transcription in neural stem cells
- Author
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Arjun Rajan, Lucas Anhezini, Noemi Rives-Quinto, Jay Y Chhabra, Megan C Neville, Elizabeth D Larson, Stephen F Goodwin, Melissa M Harrison, and Cheng-Yu Lee
- Subjects
Drosophila ,neuroblast ,Notch ,polycomb repressive complex 2 ,asymmetric division ,fine-tuning ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Coordinated regulation of gene activity by transcriptional and translational mechanisms poise stem cells for a timely cell-state transition during differentiation. Although important for all stemness-to-differentiation transitions, mechanistic understanding of the fine-tuning of gene transcription is lacking due to the compensatory effect of translational control. We used intermediate neural progenitor (INP) identity commitment to define the mechanisms that fine-tune stemness gene transcription in fly neural stem cells (neuroblasts). We demonstrate that the transcription factor FruitlessC (FruC) binds cis-regulatory elements of most genes uniquely transcribed in neuroblasts. Loss of fruC function alone has no effect on INP commitment but drives INP dedifferentiation when translational control is reduced. FruC negatively regulates gene expression by promoting low-level enrichment of the repressive histone mark H3K27me3 in gene cis-regulatory regions. Identical to fruC loss-of-function, reducing Polycomb Repressive Complex 2 activity increases stemness gene activity. We propose low-level H3K27me3 enrichment fine-tunes gene transcription in stem cells, a mechanism likely conserved from flies to humans.
- Published
- 2023
- Full Text
- View/download PDF
3. GAF is essential for zygotic genome activation and chromatin accessibility in the early Drosophila embryo
- Author
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Marissa M Gaskill, Tyler J Gibson, Elizabeth D Larson, and Melissa M Harrison
- Subjects
transcription ,zygotic genome activation ,maternal-to-zygotic transition ,pioneer factor ,chromatin ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Following fertilization, the genomes of the germ cells are reprogrammed to form the totipotent embryo. Pioneer transcription factors are essential for remodeling the chromatin and driving the initial wave of zygotic gene expression. In Drosophila melanogaster, the pioneer factor Zelda is essential for development through this dramatic period of reprogramming, known as the maternal-to-zygotic transition (MZT). However, it was unknown whether additional pioneer factors were required for this transition. We identified an additional maternally encoded factor required for development through the MZT, GAGA Factor (GAF). GAF is necessary to activate widespread zygotic transcription and to remodel the chromatin accessibility landscape. We demonstrated that Zelda preferentially controls expression of the earliest transcribed genes, while genes expressed during widespread activation are predominantly dependent on GAF. Thus, progression through the MZT requires coordination of multiple pioneer-like factors, and we propose that as development proceeds control is gradually transferred from Zelda to GAF.
- Published
- 2021
- Full Text
- View/download PDF
4. Cell-type-specific chromatin occupancy by the pioneer factor Zelda drives key developmental transitions in Drosophila
- Author
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Ostgaard Cm, Hamm Dc, Choul-Gyun Lee, Schnell Jm, Tyler J. Gibson, Elizabeth D. Larson, Hideyuki Komori, and Melissa M. Harrison
- Subjects
animal structures ,Science ,General Physics and Astronomy ,Embryonic Development ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Neuroblast ,Animals ,Drosophila Proteins ,Progenitor cell ,Enhancer ,Progenitor ,Multidisciplinary ,Receptors, Notch ,Stem Cells ,Pioneer factor ,fungi ,Drosophila embryogenesis ,Gene Expression Regulation, Developmental ,Nuclear Proteins ,Cell Differentiation ,General Chemistry ,Neural stem cell ,Chromatin ,humanities ,Cell biology ,Drosophila melanogaster - Abstract
During Drosophila embryogenesis, the essential pioneer factor Zelda defines hundreds of cis-regulatory regions and in doing so reprograms the zygotic transcriptome. While Zelda is essential later in development, it is unclear how the ability of Zelda to define cis-regulatory regions is shaped by cell-type-specific chromatin architecture. Asymmetric division of neural stem cells (neuroblasts) in the fly brain provide an excellent paradigm for investigating the cell-type-specific functions of this pioneer factor. We show that Zelda synergistically functions with Notch to maintain neuroblasts in an undifferentiated state. Zelda misexpression reprograms progenitor cells to neuroblasts, but this capacity is limited by transcriptional repressors critical for progenitor commitment. Zelda genomic occupancy in neuroblasts is reorganized as compared to the embryo, and this reorganization is correlated with differences in chromatin accessibility and cofactor availability. We propose that Zelda regulates essential transitions in the neuroblasts and embryo through a shared gene-regulatory network driven by cell-type-specific enhancers., The pioneer transcription factor Zelda is essential for the reprogramming of germ cells to totipotent cells of the early Drosophila embryo. Here the authors examine the function of Zelda later in development in the larval brain to show that Zelda promotes the undifferentiated stem-cell fate. They further identify factors that limit the reprogramming capacity of this pioneer factor.
- Published
- 2021
5. Low-level repressive histone marks fine-tune stemness gene transcription in neural stem cells
- Author
-
Arjun Rajan, Lucas Anhezini, Noemi Rives-Quinto, Megan C. Neville, Elizabeth D. Larson, Stephen F. Goodwin, Melissa M. Harrison, and Cheng-Yu Lee
- Abstract
Coordinated regulation of stemness gene activity by transcriptional and translational mechanisms poise stem cells for a timely cell-state transition during differentiation. Although important for all stemness-to-differentiation transitions, mechanistic understanding of the fine-tuning of stemness gene transcription is lacking due to the compensatory effect of translational control. We used intermediate neural progenitor (INP) identity commitment to define the mechanisms that fine-tune stemness gene transcription in fly neural stem cells (neuroblasts). We demonstrate that the transcription factor FruitlessC(FruC) bindscis-regulatory elements of most genes uniquely transcribed in neuroblasts. Loss offruCfunction alone has no effect on INP commitment but drives INP dedifferentiation when translational control is reduced. FruCnegatively regulates gene expression by promoting low-level enrichment of the repressive histone mark H3K27me3 in genecis-regulatory regions. Identical tofruCloss-of-function, reducing Polycomb Repressive Complex 2 activity increases stemness gene activity. We propose low-level H3K27me3 enrichment fine-tunes stemness gene transcription in stem cells, a mechanism likely conserved from flies to humans.
- Published
- 2022
6. Premature translation of the Drosophila zygotic genome activator Zelda is not sufficient to precociously activate gene expression
- Author
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Elizabeth D Larson, Hideyuki Komori, Zoe A Fitzpatrick, Samuel D Krabbenhoft, Cheng-Yu Lee, and Melissa Harrison
- Subjects
DNA-Binding Proteins ,Transcriptional Activation ,Drosophila melanogaster ,Genetics ,Animals ,Drosophila Proteins ,Gene Expression ,Gene Expression Regulation, Developmental ,Nuclear Proteins ,Drosophila ,RNA, Messenger ,Molecular Biology ,Genetics (clinical) - Abstract
Following fertilization, the unified germ cells rapidly transition to a totipotent embryo. Maternally deposited mRNAs encode the proteins necessary for this reprogramming as the zygotic genome remains transcriptionally quiescent during the initial stages of development. The transcription factors required to activate the zygotic genome are among these maternally deposited mRNAs and are robustly translated following fertilization. In Drosophila, the mRNA encoding Zelda, the major activator of the zygotic genome, is not translated until 1 h after fertilization. Here we demonstrate that zelda translation is repressed in the early embryo by the TRIM-NHL protein Brain tumor (BRAT). BRAT also regulates Zelda levels in the larval neuroblast lineage. In the embryo, BRAT-mediated translational repression is regulated by the Pan Gu kinase, which is triggered by egg activation. The Pan Gu kinase phosphorylates translational regulators, suggesting that Pan Gu kinase activity alleviates translational repression of zelda by BRAT and coupling translation of zelda with that of other regulators of early embryonic development. Using the premature translation of zelda in embryos lacking BRAT activity, we showed that early translation of a zygotic genome activator is not sufficient to drive precocious gene expression. Instead, Zelda-target genes showed increased expression at the time they are normally activated. We propose that transition through early development requires the integration of multiple processes, including the slowing of the nuclear division cycle and activation of the zygotic genome. These processes are coordinately controlled by Pan Gu kinase-mediated regulation of translation.
- Published
- 2022
7. Premature translation of the zygotic genome activator Zelda is not sufficient to precociously activate gene expression
- Author
-
Elizabeth D. Larson, Hideyuki Komori, Zoe A. Fitzpatrick, Samuel D. Krabbenhoft, Cheng-Yu Lee, and Melissa Harrison
- Abstract
Following fertilization, the unified germ cells rapidly transition to a totipotent embryo. Maternally deposited mRNAs encode the proteins necessary for this reprogramming as the zygotic genome remains transcriptionally quiescent during the initial stages of development. The transcription factors required to activate the zygotic genome are among these maternally deposited mRNAs and are robustly translated following fertilization. In Drosophila, the mRNA encoding Zelda, the major activator of the zygotic genome, is not translated until one hour after fertilization. Here we demonstrate that zelda translation is repressed following fertilization by the TRIM-NHL protein Brain tumor (BRAT). BRAT also regulates Zelda levels in the larval neuroblast lineage. In the embryo, BRAT-mediated translational repression is regulated by the Pan Gu (PNG) kinase, which is triggered by egg activation. The PNG kinase phosphorylates translational regulators, suggesting that PNG kinase activity alleviates translational repression of zelda by BRAT and coupling translation of zelda with that of other regulators of early embryonic development. Using the premature translation of zelda in embryos lacking BRAT activity, we showed that early translation of a zygotic genome activator is not sufficient to drive precocious gene expression. Instead, Zelda-target genes showed increased expression at the time they are normally activated. We propose that transition through early development requires the integration of multiple processes, including the slowing of the nuclear division cycle and activation of the zygotic genome. These processes are coordinately controlled by PNG kinase-mediated regulation of translation.
- Published
- 2022
8. Attachment Security and Continuing Bonds: The Mediating Role of Meaning-Made in Bereavement
- Author
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Brandy L. Tidwell, Jacob A. Bentley, and Elizabeth D. Larson
- Subjects
050103 clinical psychology ,Social Psychology ,media_common.quotation_subject ,Bond ,05 social sciences ,Attachment security ,Psychiatry and Mental health ,0501 psychology and cognitive sciences ,Grief ,Meaning (existential) ,Pshychiatric Mental Health ,Function (engineering) ,Psychology ,Social psychology ,Social Sciences (miscellaneous) ,media_common - Abstract
Attachment security plays an important function in the grieving process. This study aimed to explore how individual differences in attachment security and meaning-made predict continuing bonds expr...
- Published
- 2020
9. Author response: GAF is essential for zygotic genome activation and chromatin accessibility in the early Drosophila embryo
- Author
-
Melissa M. Harrison, Tyler J. Gibson, Marissa M Gaskill, and Elizabeth D. Larson
- Subjects
biology ,Maternal to zygotic transition ,Embryo ,Drosophila (subgenus) ,biology.organism_classification ,Chromatin ,Cell biology - Published
- 2021
10. GAF is essential for zygotic genome activation and chromatin accessibility in the early Drosophila embryo
- Author
-
Melissa Harrison, Tyler J. Gibson, Elizabeth D. Larson, and Marissa M Gaskill
- Subjects
0301 basic medicine ,Transcriptional Activation ,pioneer factor ,Embryo, Nonmammalian ,Zygote ,QH301-705.5 ,Science ,maternal-to-zygotic transition ,Biology ,Genome ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Drosophila Proteins ,Biology (General) ,Gene ,Organism ,zygotic genome activation ,General Immunology and Microbiology ,D. melanogaster ,General Neuroscience ,fungi ,Pioneer factor ,food and beverages ,Embryo ,General Medicine ,Chromosomes and Gene Expression ,Chromatin ,DNA-Binding Proteins ,030104 developmental biology ,Drosophila melanogaster ,Evolutionary biology ,Maternal to zygotic transition ,chromatin ,Medicine ,transcription ,Reprogramming ,030217 neurology & neurosurgery ,Research Article ,Transcription Factors - Abstract
Following fertilization, the genomes of the germ cells are reprogrammed to form the totipotent embryo. Pioneer transcription factors are essential for remodeling the chromatin and driving the initial wave of zygotic gene expression. In Drosophila melanogaster, the pioneer factor Zelda is essential for development through this dramatic period of reprogramming, known as the maternal-to-zygotic transition (MZT). However, it was unknown whether additional pioneer factors were required for this transition. We identified an additional maternally encoded factor required for development through the MZT, GAGA Factor (GAF). GAF is necessary to activate widespread zygotic transcription and to remodel the chromatin accessibility landscape. We demonstrated that Zelda preferentially controls expression of the earliest transcribed genes, while genes expressed during widespread activation are predominantly dependent on GAF. Thus, progression through the MZT requires coordination of multiple pioneer-like factors, and we propose that as development proceeds control is gradually transferred from Zelda to GAF., eLife digest Most cells in an organism share the exact same genetic information, yet they still adopt distinct identities. This diversity emerges because only a selection of genes is switched on at any given time in a cell. Proteins that latch onto DNA control this specificity by activating certain genes at the right time. However, to perform this role they first need to physically access DNA: this can be difficult as the genetic information is tightly compacted so it can fit in a cell. A group of proteins can help to unpack the genome to uncover the genes that can then be accessed and activated. While these ‘pioneer factors’ can therefore shape the identity of a cell, much remains unknown about how they can work together to do so. For instance, the pioneer factor Zelda is essential in early fruit fly development, as it enables the genetic information of the egg and sperm to undergo dramatic reprogramming and generate a new organism. Yet, it was unclear whether additional helpers were required for this transition. Using this animal system, Gaskill, Gibson et al. identified GAGA Factor as a protein which works with Zelda to open up and reprogram hundreds of different sections along the genome of fruit fly embryos. This tag-team effort started with Zelda being important initially to activate genes; regulation was then handed over for GAGA Factor to continue the process. Without either protein, the embryo died. Getting a glimpse into early genetic events during fly development provides insights that are often applicable to other animals such as fish and mammals. Ultimately, this research may help scientists to understand how things can go wrong in human embryos.
- Published
- 2021
11. Pioneering the developmental frontier
- Author
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Elizabeth D. Larson, Melissa M. Harrison, and Audrey J. Marsh
- Subjects
Context (language use) ,Biology ,Genome ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Gene expression ,Nucleosome ,Animals ,Humans ,Gene Regulatory Networks ,Regulatory Elements, Transcriptional ,Molecular Biology ,Transcription factor ,Organism ,030304 developmental biology ,0303 health sciences ,Pioneer factor ,Gene Expression Regulation, Developmental ,Cell Biology ,DNA ,humanities ,Nucleosomes ,chemistry ,Evolutionary biology ,030217 neurology & neurosurgery ,Protein Binding ,Transcription Factors - Abstract
Coordinated changes in gene expression allow for the single fertilized oocyte to develop into a complex, multi-cellular organism. These changes in expression are controlled by transcription factors that gain access to discrete cis-regulatory elements in the genome, allowing them to activate gene expression. While nucleosomes present barriers to transcription-factor occupancy, pioneer transcription factors have unique properties that allow them to bind DNA in the context of nucleosomes, define cis-regulatory elements and facilitate the subsequent binding of additional factors that determine gene expression. In this capacity, pioneer factors act at the top of gene regulatory networks to control developmental transitions. Nonetheless, developmental context also influences pioneer-factor binding and activity. Here we discuss the interplay between pioneer factors and development, both their role in driving developmental transitions and the influence that cellular environment has on pioneer-factor binding and activity.
- Published
- 2020
12. GAF is essential for zygotic genome activation and chromatin accessibility in the earlyDrosophilaembryo
- Author
-
Marissa M Gaskill, Elizabeth D. Larson, Tyler J. Gibson, and Melissa Harrison
- Subjects
Transcription (biology) ,Pioneer factor ,Maternal to zygotic transition ,Biology ,Drosophila melanogaster ,biology.organism_classification ,Transcription factor ,Reprogramming ,Gene ,Chromatin ,Cell biology - Abstract
Following fertilization, the genomes of the germ cells are reprogrammed to form the totipotent embryo. Pioneer transcription factors are essential for remodeling the chromatin and driving the initial wave of zygotic gene expression. InDrosophila melanogaster, the pioneer factor Zelda is essential for development through this dramatic period of reprogramming, known as the maternal- to-zygotic transition (MZT). However, it was unknown whether additional pioneer factors were required for this transition. We identified an additional maternally encoded factor required for development through the MZT, GAGA Factor (GAF). GAF is necessary to activate widespread zygotic transcription and to remodel the chromatin accessibility landscape. We demonstrated that Zelda preferentially controls expression of the earliest transcribed genes, while genes expressed during widespread activation are predominantly dependent on GAF. Thus, progression through the MZT requires coordination of multiple pioneer-like factors, and we propose that as development proceeds control is gradually transferred from Zelda to GAF.
- Published
- 2020
13. A conserved maternal-specific repressive domain in Zelda revealed by Cas9-mediated mutagenesis inDrosophila melanogaster
- Author
-
Kelsey E. Marshall, Eliana R. Bondra, Elizabeth D. Larson, Markus Nevil, Danielle C. Hamm, and Melissa M. Harrison
- Subjects
0301 basic medicine ,Cancer Research ,Embryology ,Transcription, Genetic ,Zygote ,Biochemistry ,Genome ,Conserved sequence ,0302 clinical medicine ,Genome editing ,Transcription (biology) ,Invertebrate Genomics ,Drosophila Proteins ,Genetics (clinical) ,Regulation of gene expression ,Zinc finger ,Genetics ,0303 health sciences ,biology ,Drosophila Melanogaster ,Messenger RNA ,Eukaryota ,Gene Expression Regulation, Developmental ,Genomics ,Animal Models ,Cell biology ,Insects ,Nucleic acids ,Experimental Organism Systems ,Drosophila ,Drosophila melanogaster ,Research Article ,lcsh:QH426-470 ,Arthropoda ,DNA transcription ,Protein domain ,Research and Analysis Methods ,03 medical and health sciences ,Model Organisms ,Protein Domains ,Point Mutation ,Animals ,Molecular Biology ,Transcription factor ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Embryos ,Organisms ,Biology and Life Sciences ,Proteins ,biology.organism_classification ,Invertebrates ,lcsh:Genetics ,030104 developmental biology ,Animal Genomics ,Mutation ,RNA ,Gene expression ,Developmental biology ,030217 neurology & neurosurgery ,Developmental Biology ,Transcription Factors - Abstract
In nearly all metazoans, the earliest stages of development are controlled by maternally deposited mRNAs and proteins. The zygotic genome becomes transcriptionally active hours after fertilization. Transcriptional activation during this maternal-to-zygotic transition (MZT) is tightly coordinated with the degradation of maternally provided mRNAs. In Drosophila melanogaster, the transcription factor Zelda plays an essential role in widespread activation of the zygotic genome. While Zelda expression is required both maternally and zygotically, the mechanisms by which it functions to remodel the embryonic genome and prepare the embryo for development remain unclear. Using Cas9-mediated genome editing to generate targeted mutations in the endogenous zelda locus, we determined the functional relevance of protein domains conserved amongst Zelda orthologs. We showed that neither a conserved N-terminal zinc finger nor an acidic patch were required for activity. Similarly, a previously identified splice isoform of zelda is dispensable for viability. By contrast, we identified a highly conserved zinc-finger domain that is essential for the maternal, but not zygotic functions of Zelda. Animals homozygous for mutations in this domain survived to adulthood, but embryos inheriting these loss-of-function alleles from their mothers died late in embryogenesis. These mutations did not interfere with the capacity of Zelda to activate transcription in cell culture. Unexpectedly, these mutations generated a hyperactive form of the protein and enhanced Zelda-dependent gene expression. These data have defined a protein domain critical for controlling Zelda activity during the MZT, but dispensable for its roles later in development, for the first time separating the maternal and zygotic requirements for Zelda. This demonstrates that highly regulated levels of Zelda activity are required for establishing the developmental program during the MZT. We propose that tightly regulated gene expression is essential to navigate the MZT and that failure to precisely execute this developmental program leads to embryonic lethality., Author summary Following fertilization, the one-celled zygote must be rapidly reprogrammed to enable the development of a new, unique organism. During these initial stages of development there is little or no transcription of the zygotic genome, and maternally deposited products control this process. Among the essential maternal products are mRNAs that encode transcription factors required for preparing the zygotic genome for transcriptional activation. This ensures that there is a precisely coordinated hand-off from maternal to zygotic control. In Drosophila melanogaster, the transcription factor Zelda is essential for activating the zygotic genome and coupling this activation to the degradation of the maternally deposited products. Nonetheless, the mechanism by which Zelda functions remains unclear. Here we used Cas9-mediated genome engineering to determine the functional requirements for highly conserved domains within Zelda. We identified a domain required specifically for Zelda’s role in reprogramming the early embryonic genome, but not essential for its functions later in development. Surprisingly, this domain restricts the ability of Zelda to activate transcription. These data demonstrate that Zelda activity is tightly regulated, and we propose that precise regulation of both the timing and levels of genome activation is required for the embryo to successfully transition from maternal to zygotic control.
- Published
- 2017
14. A conserved maternal-specific repressive domain in Zelda revealed by Cas9-mediated mutagenesis in Drosophila melanogaster.
- Author
-
Danielle C Hamm, Elizabeth D Larson, Markus Nevil, Kelsey E Marshall, Eliana R Bondra, and Melissa M Harrison
- Subjects
Genetics ,QH426-470 - Abstract
In nearly all metazoans, the earliest stages of development are controlled by maternally deposited mRNAs and proteins. The zygotic genome becomes transcriptionally active hours after fertilization. Transcriptional activation during this maternal-to-zygotic transition (MZT) is tightly coordinated with the degradation of maternally provided mRNAs. In Drosophila melanogaster, the transcription factor Zelda plays an essential role in widespread activation of the zygotic genome. While Zelda expression is required both maternally and zygotically, the mechanisms by which it functions to remodel the embryonic genome and prepare the embryo for development remain unclear. Using Cas9-mediated genome editing to generate targeted mutations in the endogenous zelda locus, we determined the functional relevance of protein domains conserved amongst Zelda orthologs. We showed that neither a conserved N-terminal zinc finger nor an acidic patch were required for activity. Similarly, a previously identified splice isoform of zelda is dispensable for viability. By contrast, we identified a highly conserved zinc-finger domain that is essential for the maternal, but not zygotic functions of Zelda. Animals homozygous for mutations in this domain survived to adulthood, but embryos inheriting these loss-of-function alleles from their mothers died late in embryogenesis. These mutations did not interfere with the capacity of Zelda to activate transcription in cell culture. Unexpectedly, these mutations generated a hyperactive form of the protein and enhanced Zelda-dependent gene expression. These data have defined a protein domain critical for controlling Zelda activity during the MZT, but dispensable for its roles later in development, for the first time separating the maternal and zygotic requirements for Zelda. This demonstrates that highly regulated levels of Zelda activity are required for establishing the developmental program during the MZT. We propose that tightly regulated gene expression is essential to navigate the MZT and that failure to precisely execute this developmental program leads to embryonic lethality.
- Published
- 2017
- Full Text
- View/download PDF
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