Seminar Colour Guide:
External Faculty | External Postdoc | Company Representative Science and Society EMBL Distinguished Visitor Lecture Vision2020 Lecture Series Molecular Medicine Seminar | EIPOD Seminar | PSB Seminar | TAC Seminar Hamburg Speaker EMBL-La Sapienza Lecture
|External Faculty Speaker||Abstract: Broad filtering of irrelevant inputs is essential for extracting relevant sensory information from noisy environments. This filtering can involve input-dependent (bottom up) or internally guided (top down) operations, but the computational principles and circuit implementation of these processes are unclear. Here we find that the auditory thalamic reticular nucleus (audTRN) regulates sensory thalamic responses through divisive normalization, a process required for broad filtering within a given modality. Employing a combination of anatomical tracing and functional readouts, we identify a top down control signal from the PFC to the audTRN conveyed through basal ganglia. This control results in a subtractive effect on thalamic sensory responses that enhances signal to noise ratio and improves sensory discrimination behavior under noisy conditions. Using this insight, we develop a strategy to target attentional deficits in a model of human neurodevelopmental disease, Ptchd1 KO, where TRN function is impaired. Specifically, by combining a pharmacological method that enhances normalization with top down engagement of subtractive control, we restored behavioral performance nearly to WT level. Overall, the discovery that basal ganglia circuits convey the control signal from PFC allowed us to both determine how top down inputs interact with bottom up normalization, and to identify novel circuit nodes of intervention for disease correction.|
|Science and Society||Abstract: Collaboration is in. So are networks and sharing, open science and open access. Global student mobility is at unprecedented levels and so is globally distributed scientific work. Humanity faces enormous challenges that can only be tackled by large-scale, cross-national efforts of collaboration and coordination. Meanwhile, the unrelenting generation of ever more data, waiting to be curated and processed, made interoperable and translated into tangible benefits, continues to transform the organisation of scientific practice and how to manage scientific institutions.|
The younger generation of researchers finds itself caught in the ensuing turbulence. The geographical-spatial extension of research is accompanied by a tighter temporal grip exerted locally. Standardisation of career paths favours mainstream thinking while failure, creativity and diversity are celebrated as desirable ideals at the same time. Expectations of being adept at multi-tasking abound while the focus on the tasks ahead becomes more narrow. How to survive such contradictions? How to embrace the uncertainty that comes with it?
I will attempt to discuss how greater reflexive awareness of the enablement and constraints that come with the current transformation can help to better understand the different imaginaries of what working together might mean and entail.
Free shuttle bus available on first come, first serve basis.
Friday 29 Sept at 10:00 from Pzale Aldo Moro (near building CU036)
Proof of ID will be requested
(Return free shuttle bus to leave EMBL Rome at 12:30)
|EMBL Distinguished Visitor Lecture||Abstract: We have studied how transcriptional and epigenetic programmes are played out on chromatin spanning the terminal 500kb of human chromosome 16 (16p13.3), and the corresponding region in mice, as hematopoietic cells undergo lineage fate decisions and differentiation. This region includes the alpha globin cluster and its regulatory elements, which are silenced in early progenitors, poised for expression in later progenitors and fully expressed during terminal erythroid differentiation. Other genes in this region are also up-regulated in an erythroid specific manner. Using a variety of approaches we have established the order in which silencing factors are removed, activating transcription factors bind and epigenetic modifications occur. In addition we have shown how chromosomal conformation and nuclear sub-localisation change during haematopoiesis. Natural cis and trans acting mutations (involving transcription factors and chromatin associated proteins) that cause alpha thalassaemia provide additional insight into how the long range regulatory elements may interact with the promoters of the globin genes and other flanking genes to activate their expression. Together these observations establish some of the general principles by which genes within their natural chromosomal environment are switched on and off during haematopoiesis and how gene expression is perturbed in human genetic disease. |
|External Faculty Speaker|
|EMBL - Sapienza Lecture|
|External Faculty Speaker||Abstract: In mammals, gene dosage of X-chromosomal genes is equalized between the sexes by random inactivation of either one of the two X chromosomes in female cells. X chromosome inactivation (XCI) is regulated by the X-linked X inactivation centre (Xic). This Xic covers a region of ~800kb, and harbours a plethora of long non-coding RNA genes involved in XCI. Located within the Xic, Xist plays a crucial role in XCI. Xist RNA accumulates in cis, thereby recruiting silencing complexes that render the X inactive. One key intriguing question in XCI is how a cell determines the number of X chromosomes and initiates XCI. Our work and that of others has indicated that this process is directed by X-linked activators and autosomaly encoded inhibitors of XCI. In my seminar I will discuss studies performed in mouse providing new insights in the interplay of these activators and inhibitors in counting and feedback mechanisms required to direct a robust XCI process. |
|External Faculty Speaker||Abstract: Hematopoietic stem cells (HSCs) harbor the capacity to generate a series of multipotent progenitors (MPPs) that differentiate into lineage-committed progenitors and subsequently mature cells. To explore essential HSC features, we recently integrated quantitative proteome, transcriptome, and methylome analyses of five FACS-sorted HSCs and MPP populations (MPP1-4) and combined these OMICs analyses to their functional potential (Cabezas-Wallscheid et al., Cell Stem Cell 2014; Klimmeck et al., Stem Cell Reports 2014; Lipka et al., Cell Cycle 2014). From the characterization of more than 6,000 proteins, 27,000 transcripts, and 15,000 differentially methylated regions (DMRs), we identified coordinated changes associated with early differentiation steps. DMRs show continuous gain or loss of methylation during differentiation, and the overall change in DNA methylation correlates inversely with gene expression at key loci. Our data reveal the differential expression landscape of 493 TFs and 682 lncRNAs and highlight specific expression clusters including Wnt and Lin28-Hmga signaling, the imprinted-gene-network, Hox genes, retinoic acid metabolism. We also found an unexpectedly dynamic pattern of transcript isoform regulation, suggesting a critical regulatory role during HSC differentiation, and a cell cycle/DNA repair signature associated with multipotency in MPP2 cells. To address differentiation potential of MPP2-4 we linked our OMICs data with functional reconstitution experiments. |
Recently, we have expanded this analysis to dormant HSCs (dHSCs) identified by label-retaining assays (Wilson et al., Cell 2008). Rare dHSCs reside at the top of the blood hierarchy harboring the highest long-term reconstitution capacity. However, till the date the molecular identity of dHSCs, as well as the mechanism regulating maintenance and the transition out of dormancy remain unknown. We now show by single-cell RNA-seq analysis that the transition from dormancy towards cell cycle entry is achieved by a continuous and coordinated up-regulation of all major biosynthetic processes rather than a switch on/off mechanism (Cabezas-Wallscheid et al. Cell 2007). We employed a novel transgenic reporter mouse model that reversibly marks dHSCs avoiding label retention assays. Finally, we show that dietary vitamin A/ retinoic acid signaling is a key pathway for in vivo retaining HSC dormancy.
|EMBL Distinguished Visitor Lecture||Abstract:|
|External Faculty Speaker||Abstract: |
|Science and Society|
|EMBL - Sapienza Lecture|
|External Faculty Speaker||Abstract: All sensory systems are specialised to efficiently provide information critical within an animal's sensory-ecological niche. In vertebrate vision, the retina of all visual species follows a common set anatomical and functional motifs, yet each species has tweaked details in this network to tune its vision for its natural visual environment. Accordingly, comparing functional processing strategies employed in different species that live in different visual envioronments provides a window into how neuronal networks evolve to better suit novel computational demands. In reference to our existing functional database on the retina of mice, we now study the retina of zebrafish in the context of their natural habitat to address these questions with a particular emphasis on colour vision.|
|EMBL Distinguished Visitor Lecture|
|EMBL Distinguished Visitor Lecture||Abstract: DNA methylation is a chemical modification that occurs predominantly on CG dinucleotides in mammalian genomes. However, recent studies from our laboratory have revealed that non-CG methylation (mCH) is more abundant than CG methylation and non-randomly distributed in the genomes of brain cells. mCH accumulates during the establishment of neural circuits and is associated with Rett syndrome. A comprehensive understanding of how neural circuits spanning the entire brain generate the full repertoire of perception and behaviors requires a list of brain cell types, as well the means to target each cell type in order to interrogate the functional interactions that give rise to the emergent properties of the whole system. Neuronal diversity is essential for mammalian brain function but poses a challenge to molecular profiling. To facilitate cell-type-specific epigenomic studies, we have developed approaches to isolate nuclei from subtypes of neocortical neurons, revealing highly distinctive epigenomic landscapes. Hundreds of thousands of regions differ in chromatin accessibility and DNA methylation signatures characteristic of gene regulatory regions which are predicted to bind distinct cohorts of neuron subtype-specific transcription factors. Surprisingly, neuronal epigenomes reflect both past and present gene expression, with DNA hyper-methylation at developmentally critical genes appearing as a novel epigenomic signature in mature neurons. More recently, we have developed single cell methylome profiling methods that now allow an unbiased census of the diversity of neuronal cell types in the mammalian brain. Taken together, these approaches are beginning to link the functional and transcriptional complexity of neurons to their underlying epigenomic diversity.|
|EMBL Distinguished Visitor Lecture|
|EMBL Distinguished Visitor Lecture||Abstract: Our lab is studying the chromatin and epigenetic mechanisms regulated by histone acetylation using evolutionary conserved complexes associated with MOF, a MYST family of histone acetyl transferase. In files and mammals MOF is associated with the MSL and NSL complexes, which are important regulators of gene expression. In flies the MSL complex is well known for regulation of the X chromosome by the process of dosage compensation, while the NSL complex regulates expression of house keeping genes. In mammals, both complexes appear to be involved in regulating diverse cellular processes. The recent progress of our work will be presented.|