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evolSingleCellGRN — Constraint, adaptation, and heterogeneity

Genomic and single-cell approaches to understanding the evolution of developmental gene regulatory networks

Funding: ERC Starting Grants
Period: 2019 (cancelled by PI)
Project leader: David Garfield (IRI Life Sciences)

Cell types in development arise from precise patterns of gene expression driven by differential usage of DNA regulatory elements. Mutations affecting these elements, or proteins binding them, are major contributors to disease and underlie the evolution of new morphologies. To better understand these elements and how they evolve, that:
A) identify tissue-specific regulatory elements and expression profiles by interrogating individual cells,
B) allow for a precise read-out of developmental responses to mutation and perturbation, including cell-fate re-specification,
C) lead to the development of a regulatory-information based concept of homology that will be used to understand developmental evolution.

HantaHunt

Structure and function analyses of the Hantavirus envelope glycoproteins and their role in virus assembly, virus entry and immune recognition as novel targets for antiviral treatment

Funding: Bundesministerium für Bildung und Forschung (BMBF)
Period: 2016 - 2019
Project partner: Andreas Herrmann (HU, Coordinator), Detlev Krüger (Charité), Yechiel Shai (The Weizmann Institute of Science), Felix Rey (Institut Pasteur/ Structural Virology Unit)

Hantaviruses (HV), which belong to the Bunyaviridae family of RNA viruses, are emerging pathogens that cause life-threatening human zoonoses with case fatalities reaching 50% and is ranked among the top five reportable virus infections by the Robert Koch Institute in Berlin. In spite of its medical importance, our knowledge of HV biology is extremely fragmentary.

This project focuses on HV envelope glycoproteins Gn and Gc, which form a heterodimer exposed at the virus surface, carrying the main viral antigenic determinants. Both are responsible for entry into host cells by recognizing a receptor at the plasma membrane and by catalyzing membrane fusion in the endosomes after receptor-mediated endocytosis. The heterodimer also plays a crucial role in the morphogenesis of newly formed HV via interaction of the cytosolic domains with the viral genomic RNA and by driving virion assembly and budding.

This project is tackled by a consortium of four complementary groups, combining experts in molecular virology, cell and structural biology, biochemistry and biophysics to provide an in-depth analysis of the glycoproteins and their crucial interactions with other cellular and viral factors including the segmented HV RNA genome. In this context a multiude of state-of-the-art methods and techniques will be established and utilized. Our results will thereby characterize important potential interactions to be targeted for therapeutic intervention, e.g. the receptor site and the fusogenic conformational change of the Gn/Gc complex.

How to Shape Living Structures — Factors Controlling Spindle Geometry

HU-PU Profile Partnership

Funding: Humboldt-Universität zu Berlin / Princeton University
Period: 2017 - 2019
Project partner: Simone Reber (IRI Life Sciences), Sabine Petry (PU)

The goal of this research project is to understand the way in which cells engineer larger scale structures, in particular the mitotic spindle. In particular, we wish to understand (1) how the biochemical heterogeneity of tubulin effects spindle organization, how the correct (2) number and (3) length of microtubules is regulated to build a spindle of the correct size.

An important objective of our proposal continues to be graduate and postgraduate training including lab exchanges. Taken together, the proposed work will provide important insights into the physical principles that underlie the organization of the mitotic spindle as a molecular machine, which is likely to have important implications for its function in cell proliferation and molecular origins of diseases.

Patterning and Timing in Development and Evolution

HU-NUS Profil Partnership

Funding: Humboldt-Universität zu Berlin / National University of Singapore
Period: 2017 - 2018
Project partner: David Garfield (HU), Tim Saunders (NUS)

Embryonic development represents a balancing act between robustness and evolvability. For individual organisms, developmental processes must be robust to environmental fluctuations and the influence of segregating mutations. But at the same time, development must be able to evolve if populations are to adapt. Understanding this interplay requires the integration of genetic and evolutionary approaches, a physical understanding of how the embryo develops, and modern methods for assessing developmental phenotypes (from developmental rate to embryonic shape to developmental gene expression profiles).

HU and NUS lead in aspects of this required synthesis. Through a workshop and funding for preliminary research collaborations, we propose to combine these strengths in pursuit of competitive research projects aimed at understanding the emergence of developmental robustness and evolvability.

Mesoscale self-organization of non-membrane bound cellular structures

Funding: Humboldt-Universität zu Berlin (HU)
Period: 2015 - 2016
Project partner: Simone Reber (HU), Clifford Brangwynne (Princeton University), Sabine Petry (Princeton University)

The goal of this research proposal is to understand the way in which cells engineer larger scale structures, in particular the mitotic spindle. The mitotic spindle’s function is to precisely partition the genetic material into two daughter cells. This makes the spindle an essential structure for cell proliferation and procreation. Errors during chromosome segregation can result in chromosome mis-segregation, aneuploidy, and cancer.

While the last decades were instrumental in putting together the parts lists of individual organelles, it is still unknown which principles organise these mesoscale structures. The international collaboration combines biochemical reconstitution, structural biology, biophysical measurements and modelling, and robust analysis of phenotypes at the cellular level. The work will provide important insights into the physical principles that underlie the organization of the mitotic spindle as a molecular machine, which is likely to have important implications for its function in cell proliferation and molecular origins of diseases.

Single molecule RNA biology — dynamics and function of RNA from transcription to degradation

Funding: Einstein Stiftung Berlin
Period: 2013 - 2016
Project partner: Andreas Herrmann (HU, Coordinator), Edda Klipp (HU), Oliver Seitz (HU), Christoph Arenz (HU), Nikolaus Rajewsky (BIMSB, MDC), Alexander Löwer (BIMSB, MDC), Markus Landthaler (BIMSB/MDC), Marina Chekulaeva (BIMSB, MDC), Markus Wahl (FU)

RNA plays a central role in every living cell, as it connects the genetic information with the phenotype. Specific species of RNA are involved in virtually every aspect of cellular function. At the same time, RNA molecules themselves are subject to dynamic regulation at all stages from their generation to degradation. During their life cycle, RNAs interact with numerous proteins and are embedded in the regulatory networks of the cells.

The integrity of these interactions is crucial for maintaining cellular homeostasis and function. Perturbations of RNA function can directly lead to human disease. Moreover, pathogens, such as viruses, can exploit the cellular RNA machinery and reprogram it to mediate their own proliferation. Therefore, a deeper understanding of RNA biology will not only provide insights into core cellular functions, but is also of medical relevance and may enable new therapeutic approaches to human diseases.

The collaborative network aims of expanding RNA biology to the single molecule level and connecting it across multiple scales to system-wide functions to gain a predictive understanding of the complex and dynamic regulation of RNA metabolism and function.

OncoPATH

Understanding oncogenic signaling and metabolic networks in solid cancer

Funding: Bundesministerium für Bildung und Forschung (BMBF)
Period: 2013 - 2016
Project partner: Christine Sers (Charité, Coordinator), Nils Blüthgen (Charité, Coordinator), Reinhold Schäfer (Charité), Stefan Legewie (IMB Mainz), Ulf Leser (HU), Tilman Brummer (Uni Freiburg), Markus Morkel (Charité), Edda Klipp (HU), Stefan Kempa (MDC), Iduna Fichtner (EPO Berlin)

The major objective of the OncoPATH consortium is to dissect and model the impact of driver genetic alterations on biological properties of tumorigenic epithelial cells and their clinical behaviour at the systems level. The ultimate goal is to bridge the gap in the current understanding of the mechanisms controlling the response of individual tumor cell populations to targeted therapies. Using an integrated and iterative approach combining genome, transcriptome, proteome and metabolome analysis, functional assays in vitro and in vivo as well as mathematical modelling, we will study colon cancer as a paradigmatic malignant disease.