Project acronym DEVOMIND
Project How do infants mentalize? Bringing a neuroimaging approach to the puzzle of early mindreading.
Researcher (PI) Victoria SOUTHGATE
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Consolidator Grant (CoG), SH4, ERC-2016-COG
Summary Human social interaction and learning depends on making the right inferences about other people’s thoughts, a process commonly called mentalizing, or Theory of Mind, a cognitive achievement which several decades of research concluded was reached at around age 4. The last 10 years has radically changed this view, and innovative new paradigms suggest that even preverbal infants can think about others’ minds. This new developmental data has created arguably one of the biggest puzzles in the history of developmental science: How can infants be mentalizing when years of research have shown that a) pre-schoolers fail at mentalizing tasks and b) mentalizing depends on the development of cognitive control, language, and brain maturation? The key issue is whether behaviour that looks like infant mentalizing really is mentalizing, or might infants’ success belie alternative processes? The most powerful strategy for resolving this puzzle is to look to brain activity. By applying the same methods and paradigms across infancy and early childhood, DEVOMIND will investigate whether infants’ success on mentalizing tasks recruits the same network of brain regions, and neural processes, that we know are involved in success in older children and adults. In the second half of the project, we will use our neural indicators of mentalizing to test a completely novel hypothesis in which infants’ success is possible because they have a limited ability to distinguish self from other. Although novel, this hypothesis deserves to be tested because it has the potential to explain both infants’ success and preschoolers’ failures under a single, unified theory. By bringing a neuroimaging approach to the puzzle of early mentalizing, DEVOMIND will allow us to move beyond the current impasse, and to generate a new theory of Theory of Mind.
Summary
Human social interaction and learning depends on making the right inferences about other people’s thoughts, a process commonly called mentalizing, or Theory of Mind, a cognitive achievement which several decades of research concluded was reached at around age 4. The last 10 years has radically changed this view, and innovative new paradigms suggest that even preverbal infants can think about others’ minds. This new developmental data has created arguably one of the biggest puzzles in the history of developmental science: How can infants be mentalizing when years of research have shown that a) pre-schoolers fail at mentalizing tasks and b) mentalizing depends on the development of cognitive control, language, and brain maturation? The key issue is whether behaviour that looks like infant mentalizing really is mentalizing, or might infants’ success belie alternative processes? The most powerful strategy for resolving this puzzle is to look to brain activity. By applying the same methods and paradigms across infancy and early childhood, DEVOMIND will investigate whether infants’ success on mentalizing tasks recruits the same network of brain regions, and neural processes, that we know are involved in success in older children and adults. In the second half of the project, we will use our neural indicators of mentalizing to test a completely novel hypothesis in which infants’ success is possible because they have a limited ability to distinguish self from other. Although novel, this hypothesis deserves to be tested because it has the potential to explain both infants’ success and preschoolers’ failures under a single, unified theory. By bringing a neuroimaging approach to the puzzle of early mentalizing, DEVOMIND will allow us to move beyond the current impasse, and to generate a new theory of Theory of Mind.
Max ERC Funding
1 761 190 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym HISTONEMEMORY
Project New and Old Histones in Epigenetic Cell Memory
Researcher (PI) Anja Groth
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Consolidator Grant (CoG), LS1, ERC-2016-COG
Summary Cell type specific organization of DNA into chromatin is an important determinant of gene expression and cell identity. During cell division, epigenetic information in chromatin must be transmitted to daughter cells in order to maintain cell identity or commit to a developmental program. However, it remains unknown how epigenetic states are inherited during cell division. Elucidating molecular mechanisms underlying epigenetic cell memory thus represents a major challenge in biology critical to understand development and disease.
Chromatin undergoes genome-wide disruption during DNA replication and histone marks are diluted 2-fold due to new histone deposition. Yet, how this impacts on establishment and maintenance of gene expression programs is not known. I hypothesize that chromatin replication represents a critical window for epigenetic cell memory and cell fate decisions, and predict that three histone-based processes play critical roles in guarding cell identity: 1) new histone deposition to regulate nucleosome occupancy and transcription factor (TF) binding, 2) accurate transmission of old modified histones by dedicated recycling machinery, and 3) recruitment of regulatory proteins to new and old histones to direct epigenome maintenance. To dissect these events mechanistically and test causal roles in cell fate decisions, I propose a research program integrating explorative proteomics and histone chaperone structure-function analysis with stem cell biology and new cutting-edge genomic tools developed by my research group.
The proposed research will 1) identify novel mechanisms of histone chaperoning and deposition specific to new and old histones, 2) reveal how nucleosome assembly govern TF binding during DNA replication, and 3) address the significance of old histone recycling and new histone deposition for pluripotency and commitment. This will provide a major advance in understanding the molecular mechanisms that govern epigenetic cell memory.
Summary
Cell type specific organization of DNA into chromatin is an important determinant of gene expression and cell identity. During cell division, epigenetic information in chromatin must be transmitted to daughter cells in order to maintain cell identity or commit to a developmental program. However, it remains unknown how epigenetic states are inherited during cell division. Elucidating molecular mechanisms underlying epigenetic cell memory thus represents a major challenge in biology critical to understand development and disease.
Chromatin undergoes genome-wide disruption during DNA replication and histone marks are diluted 2-fold due to new histone deposition. Yet, how this impacts on establishment and maintenance of gene expression programs is not known. I hypothesize that chromatin replication represents a critical window for epigenetic cell memory and cell fate decisions, and predict that three histone-based processes play critical roles in guarding cell identity: 1) new histone deposition to regulate nucleosome occupancy and transcription factor (TF) binding, 2) accurate transmission of old modified histones by dedicated recycling machinery, and 3) recruitment of regulatory proteins to new and old histones to direct epigenome maintenance. To dissect these events mechanistically and test causal roles in cell fate decisions, I propose a research program integrating explorative proteomics and histone chaperone structure-function analysis with stem cell biology and new cutting-edge genomic tools developed by my research group.
The proposed research will 1) identify novel mechanisms of histone chaperoning and deposition specific to new and old histones, 2) reveal how nucleosome assembly govern TF binding during DNA replication, and 3) address the significance of old histone recycling and new histone deposition for pluripotency and commitment. This will provide a major advance in understanding the molecular mechanisms that govern epigenetic cell memory.
Max ERC Funding
1 999 750 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym PATHORISC
Project Reprogramming of small RNA function in plant-pathogen interactions
Researcher (PI) Anders Peter BRODERSEN
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Consolidator Grant (CoG), LS2, ERC-2016-COG
Summary RNA silencing relies on small RNAs that act in RNA induced silencing complexes (RISCs). RISCs use base pairing to select mRNAs or invading nucleic acids such as viruses for repression. RNA silencing may facilitate gene expression changes, for example in host-pathogen interactions. Such changes require reprogramming of RISC, since a different set of RNAs must be rapidly repressed upon pathogen perception. RISC reprogramming is non-trivial: new small RNAs must be produced and be rapidly incorporated into RISC, while unwanted repression by pre-existing RISCs must be eliminated. This project focuses on understanding three central aspects of RISC reprogramming in plant-pathogen interactions. First, we will define mechanisms that allow invading RNA, but not self-RNA, to engage in positive feedback loops for small RNA synthesis, and we will investigate the specific importance of these positive feedback loops in antiviral defense. Second, we will explore how rapid proteolysis of the central RISC component ARGONAUTE1 (AGO1) governs rapid incorporation of newly synthesized small RNA. We will also explore the hypothesis that non-RNA bound AGO1 is degraded to minimize vulnerability to pathogens that use small RNAs as virulence factors to repress host immune signaling. The relevance of these mechanisms of AGO1 proteolysis in plant immunity will be investigated. These studies take advantage of our recent discovery of proteins required specifically for turnover of AGO1. Finally, we explore the hypothesis that rapid chemical modification of mRNA by N6-adenosine methylation (m6A) may bring mRNAs with poor small RNA binding sites under RISC repression. This scenario is supported by interactions between m6A reader proteins and AGO1 discovered in current work in the group. This mechanism may enable reprogramming of RISC specificity rather than composition upon pathogen perception. Our project will fill gaps in knowledge on RNA silencing and elucidate their importance in plant immunity.
Summary
RNA silencing relies on small RNAs that act in RNA induced silencing complexes (RISCs). RISCs use base pairing to select mRNAs or invading nucleic acids such as viruses for repression. RNA silencing may facilitate gene expression changes, for example in host-pathogen interactions. Such changes require reprogramming of RISC, since a different set of RNAs must be rapidly repressed upon pathogen perception. RISC reprogramming is non-trivial: new small RNAs must be produced and be rapidly incorporated into RISC, while unwanted repression by pre-existing RISCs must be eliminated. This project focuses on understanding three central aspects of RISC reprogramming in plant-pathogen interactions. First, we will define mechanisms that allow invading RNA, but not self-RNA, to engage in positive feedback loops for small RNA synthesis, and we will investigate the specific importance of these positive feedback loops in antiviral defense. Second, we will explore how rapid proteolysis of the central RISC component ARGONAUTE1 (AGO1) governs rapid incorporation of newly synthesized small RNA. We will also explore the hypothesis that non-RNA bound AGO1 is degraded to minimize vulnerability to pathogens that use small RNAs as virulence factors to repress host immune signaling. The relevance of these mechanisms of AGO1 proteolysis in plant immunity will be investigated. These studies take advantage of our recent discovery of proteins required specifically for turnover of AGO1. Finally, we explore the hypothesis that rapid chemical modification of mRNA by N6-adenosine methylation (m6A) may bring mRNAs with poor small RNA binding sites under RISC repression. This scenario is supported by interactions between m6A reader proteins and AGO1 discovered in current work in the group. This mechanism may enable reprogramming of RISC specificity rather than composition upon pathogen perception. Our project will fill gaps in knowledge on RNA silencing and elucidate their importance in plant immunity.
Max ERC Funding
1 987 811 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym ReCAP
Project Repair capacity and genome diversity in mammals
Researcher (PI) Eva Ran Hoffmann
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Consolidator Grant (CoG), LS2, ERC-2016-COG
Summary Genome evolution is driven by the generation of diversity. In mammals, genome diversification occurs in germline during the specialised division (meiosis) in gametes, when chromosomes recombine and assort into new haploid sets as they are passed from parent to offspring. Recently, the traditional view that genome diversification occurs exclusively in the germline has been challenged by findings that mutations in early embryos may cause predisposition to childhood cancers. We are uniquely placed to explore genome diversification in the germline and early embryos due to our breakthroughs in developing single-cell genomics and reproductive technologies.
Our strategic aim is to uncover the capacity for genetic diversity in the human genome and investigate how DNA repair capacity in adult oocytes and early embryos facilitates genome stability. This will allow us to identify the selective forces that shape the genomic landscape in humans. Based on preliminary data, we hypothesize that repair capacity determines reproductive fitness of mammalian females, and that impaired repair capacity may underlie infertility, miscarriage, and congenital disorders. In Objective 1 we focus on adult oocytes, their survival in the adult ovary and the maintenance of genetic quality as women age. Objective 2 investigates genome diversification and stability in early embryos and putative ‘self-corrective’ mechanisms that restore the genetic quality of embryos. This proposal will shed light on a poorly understood area of enormous socioeconomic and medical importance.
Summary
Genome evolution is driven by the generation of diversity. In mammals, genome diversification occurs in germline during the specialised division (meiosis) in gametes, when chromosomes recombine and assort into new haploid sets as they are passed from parent to offspring. Recently, the traditional view that genome diversification occurs exclusively in the germline has been challenged by findings that mutations in early embryos may cause predisposition to childhood cancers. We are uniquely placed to explore genome diversification in the germline and early embryos due to our breakthroughs in developing single-cell genomics and reproductive technologies.
Our strategic aim is to uncover the capacity for genetic diversity in the human genome and investigate how DNA repair capacity in adult oocytes and early embryos facilitates genome stability. This will allow us to identify the selective forces that shape the genomic landscape in humans. Based on preliminary data, we hypothesize that repair capacity determines reproductive fitness of mammalian females, and that impaired repair capacity may underlie infertility, miscarriage, and congenital disorders. In Objective 1 we focus on adult oocytes, their survival in the adult ovary and the maintenance of genetic quality as women age. Objective 2 investigates genome diversification and stability in early embryos and putative ‘self-corrective’ mechanisms that restore the genetic quality of embryos. This proposal will shed light on a poorly understood area of enormous socioeconomic and medical importance.
Max ERC Funding
1 997 593 €
Duration
Start date: 2017-07-01, End date: 2022-06-30
