EMBL Seminars

Abstract
Recent studies have revealed striking similarities between the neurohormonal circuits that govern insect metamorphosis and mammalian puberty. As these circuits become better defined by experiments in different organisms, quantitative models can play an important role in organizing diverse datasets and predicting circuit responses to genetic and environmental perturbations. I will present our recent steps in this direction inDrosophila, one of the leading systems in the integrative analysis of the juvenile-to-adult transition. Our approach is based on a combination of mathematical modeling and optogenetic perturbations of a key signaling node that has been implicated in quantitative control of both insect metamorphosis and mammalian puberty. The established approach quantifies a threshold of the irreversible commitment to metamorphosis and can be used explore other aspects of organism growth and maturation.

Communities in the research sector are diverse and form in different ways for a myriad of reasons, yet often researchers find themselves disconnected from one another. Community building is one way to address this disconnect, it is the act of bringing people together under a common goal. In this webinar, Piv Gopalasingam, EMBL-EBI scientific training officer and EMBL Staff Association co-Chair, will introduce the skills you can develop and utilise to build and maintain a community, provide tips and tricks to help assess your group’s needs, and discuss common pitfalls to avoid.

Speakers: Piv Gopalasingam, EMBL-EBI scientific training officer and EMBL Staff Association co-Chair

Connection details
Zoom*: please register at https://embl-org.zoom.us/webinar/register/WN_jCXJMjqiSLWY9rdAPrA-sw 

Please note that the talk will be recorded.
*For the Q&A section, as a zoom participant, please use the Q&A function and the host will read out the questions.

Abstract
[My laboratory investigates fundamental questions of cell division and size control during vertebrate development. We leverage frogs of the genus Xenopus that span in genome size from diploid (2n, Xenopus tropicalis) to dodecaploid (12n, Xenopus longipes) to investigate consequences of the conserved relationship between genome size and cell size on embryogenesis and explore the molecular basis and physiological consequences of scaling relationships. A unique feature of Xenopus systems is the ability to reconstitute assembly of the meiotic or mitotic spindle in vitro using cytoplasmic extracts. By combining cell biological, biochemical, and bioinformatic approaches in embryos and extract systems, we are currently investigating mechanisms of oocyte growth, the incidence of aneuploidy during embryogenesis, adaptation of the cell division machinery to increased ploidy, chromosome mis-segregation in inviable hybrids, and the cellular basis of metabolic scaling. Our studies aim to reveal fundamental principles of spindle assembly and biological size control, and the molecular basis of variation that contributes to genomic instability and evolution.].

About the speaker
[Professor Rebecca W. Heald is a leading biochemist and a professor in the Department of Molecular and Cell Biology, 
 

Abstract

Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disease that exclusively affects

elderly people. Here, we used direct conversion of primarily sporadic AD patient fibroblasts into

induced neurons (iNs) to generate an age-equivalent neuronal model. Patient-derived iNs exhibit

strong AD-specific transcriptome neuronal signatures characterized by down-regulation of mature

functional and morphological properties and up-regulation of immature neuronal and neural stem

cell-associated pathways. Mapping AD and control iNs to longitudinal transcriptome data from

maturing human neurons demonstrated that AD iNs are fully converted into iNs, but reflect a dedifferentiated

neuronal identity. Epigenetic landscape profiling revealed an aberrant cellular

program underlying their immature neuronal state, which shares similarities with malignant

transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we

generated iPSC neurons from the small cohort, which, indeed, showed non-significant diseaserelated

transcriptome signatures. This is consistent with epigenetic aging clock and brain

oncogenesis mapping, which indicated that unlike iPSC neurons, iNs more closely reflect adult

and old brain stages, rendering them a valuable tool for studying adult-specific, age-related

neurodegeneration. In this model, AD-related neuronal changes appear less as a mere

accumulation of damaging events, but rather an age-dependent cellular program that impairs

neuronal identity.
 

Abstract
Our research focuses on the role of RAF kinases in transmitting signals within the RAS-RAF-MEK-ERK (RAS/ERK) cascade. Hyperactivation of the RAS/ERK pathway caused by activating mutations in RAS and RAF is a major driver of tumor formation in ~30% of all cancers1. Improving our understanding on the regulation of the RAS/ERK pathway is of paramount importance for the development of next-generation therapeutics.  

The RAF family comprises three catalytically active isoforms (ARAF, BRAF, CRAF) and two pseudokinase isoforms (KSR1, KSR2), which adopts dimers conformation to activate RAF catalytic outputs2. Our goal is to investigate the molecular mechanisms governing the dimerisation of KSRs with RAFs. Our investigation uncovered an allosteric mechanism driving KSR1:BRAF heterodimerization and BRAF activation, which depends on MEK binding to KSR and on the interactions between the N-Terminal domains of KSRs and BRAF3. Additionally, we revealed how the scaffold proteins CNK and HYP potentiate this KSR-dependent mechanism through the formation of an unexpected CNK:HYP:MEK:KSR quaternary complex4.

Employing integrative structural biology techniques combining NMR, X-Ray crystallography and cryo-EM alongside biochemical analyses, we aim to deepen our understanding of the pivotal role of the pseudokinase KSR in regulating the RAF kinases, providing novel insights into the multi-layered regulation of the oncogenic RAS/ERK signaling pathway.

1Lavoie H et.al., Nat Rev Mol Cell Biol (2015) - 10.1038/nrm3979 
2Rajakulendran T et.al., Nature (2009) -10.1038/nature08314
3Lavoie H et.al., Nature. (2018) -10.1038/nature25478
4Maisonneuve P et.al., Nat Struct & Mol Biol (2024) -10.1038/s41594-024-01233-6

Connection details
Zoom*: https://embl-org.zoom.us/j/97170620085?pwd=LklFaC4gFmlJHvw5tMSbT2vqaKsaNV.1   
Webinar ID: 971 7062 0085
Passcode: 717935

Please note that the talk will be recorded.
*For the FAQ section, as a zoom participant, please use either the chat function (the host will read out your question) or the “raise your hand” function and turn on your microphone.

Abstract
To be announced

Connection details
Zoom*: https://embl-org.zoom.us/j/97170620085?pwd=LklFaC4gFmlJHvw5tMSbT2vqaKsaNV.1  
Webinar ID: 971 7062 0085
Passcode: 717935

Please note that the talk will be recorded.
*For the FAQ section, as a zoom participant, please use either the chat function (the host will read out your question) or the “raise your hand” function and turn on your microphone.

Abstract

Epigenetic components regulate many biological phenomena during development and normal physiology. When dysregulated, epigenetic components can also accompany or drive diseases. One main class of epigenetic components are Polycomb group proteins. Originally, Polycomb proteins were shown to silence gene expression. We found that this function involves the regulation of 3D chromosome folding and we found that Polycomb components can induce the formation of long-distance interactions or chromatin loops that may play instructive roles in gene regulation as well as serve as scaffolding elements that contribute to enhancer-promoter specificity. Perturbation of Polycomb components is involved in human cancer and leads to tumorigenesis in flies. Surprisingly, even upon a transient depletion followed by restoration of the full Polycomb compendium, epithelial cells lose their normal differentiated fate, continue proliferating and establish aggressive tumors, demonstrating that cancer can have a fully epigenetic origin. Similarly, transient perturbation of histone acetylation in mouse ES cells and gastruloids shows that they can record chromatin changes and that this results in cellular memory of the perturbation states. The implication of these data will be discussed.