UNIVERSITY OF HAMBURG

Sequence information (the genome) determines phenotypic outcome, but depends on a proper chromatin environment (the epigenome) for both the transcriptional competence of genes, and the organization of the genome. The epigenome is thus of great interest for fundamental as well as translational research. Arabidopsis has thus far provided most of our understanding of epigenetic regulation in plants. It is, however, an unusual plant with a small genome and few repetitive elements, in sharp contrast to most crops, whose epigenomes differ from the Arabidopsis paradigm in both structural and mechanistic terms. Importantly, altering the epigenome in crops, particularly in maize, has strong developmental consequences, while Arabidopsis is highly resilient to epigenomic instability. Reproductive development is central to plant breeding, yield, and hence food security. Yet, the mechanisms controlling epigenome function and dynamics during plant reproduction remain understudied in food crops. Many laboratories have shown that chromatin-level regulations are important for reproductive success. We, and others, have hinted that heterochromatin in particular, which encompasses most of the repeated fraction of the genome, plays an important role in plant reproduction. This is especially clear in species with complex genomes, where the disruption of enzymes that control heterochromatin results in altered reproductive development, including abnormal meiosis, and tendencies apomixis, a widely recognized but unrealized goal in plant breeding that would greatly benefit farmers and breeders. In this proposal, we posit that heterochromatin acts as a stabilizer of reproductive outcome, and that altering heterochromatin results in more flexible reproductive outcomes, of potential value for breeding. We thus propose to elucidate the role and regulation of heterochromatin during reproduction, using maize as our model, and focusing on two aspects of reproduction: meiosis and early embryogenesis. We will then assess the consequences of altered heterochromatin on two traits: recombination rates, and the potential for clonal reproduction. Maize is a key crop worldwide, and an exceptional model to address the interplay between genetics and epigenetics, owing to a long history of epigenetic research, many mutants affecting epigenetic determinants, and an exceptional cytology. This project relies on a collection of maize mutants affecting heterochromatin, the strong experience of the participants in epigenomic and plant reproduction, novel methods to analyze epigenomic information in living cells, and a strong body of preliminary data showing that heterochromatin can be genetically and epigenetically manipulated through mutation and recombination. We will combine these elements to assess the functional importance of heterochromatic pathways in shaping maize reproductive outcomes, and derive novel tools for plant breeding.

The digital revolution, in particular big data and artificial intelligence (AI), offer new opportunities to transform healthcare. Big data analytics has the potential to combine molecular patient data with electronic health records to fulfil the promises of precision medicine. Systemic marker panels will identify personalized disease mechanisms to treat a disease efficiently. Big data and AI are inevitable technologies to find the needle in the haystack for identifying patients at risk of developing diseases. With FeMAI we want to establish gut microbiome-based machine learning models for the prediction of human health in terms of diagnostic and prognostic. The fundament for big data, however, is data access, which at such dimension raises valid ethical concerns regarding the privacy protection of patient data. They are expressed legally in policies like the General Data Protection Regulation (GDPR), which downscales data sizes from millions of patient data sets to only a few hundred available for AI model learning - reducing their predictive power. With FeMAI we want to address these obstacles by creating a totally privacy preserving federated database network containing decentralized microbiome and clinical data, processed by machine learning tools for human health prediction. The goal is to address the urgently unmet need to access big data in order to pave the road to successful long term collaboration in human health analysis across France, Germany and the EU. Thus FeMAI consortium consists of worldwide recognized experts from AI microbiome development to federated learning.

Heart automaticity is a fundamental physiological function in animals. In the adult heart of higher vertebrates, automaticity is generated in the sino-atrial node by specialized “pacemaker” cells having low contractility and generating a periodic electrical oscillation. The readout of cardiac automaticity is heart rate, which is a primary determinant of the capability of the organism to fulfill the physiological demand of the environment. Heart rate is also positively correlated with cardiovascular mortality and constitutes an important epidemiological parameter. However, despite of its importance, the signalling pathways involved in the genesis of pacemaking and heart rate regulation are not completely understood and some essential aspects of the cardiac pacemaker mechanism are still hotly debated. Development of therapeutically active molecules, able to control heart rate, is thus of outstanding interest. The clinical development of ivabradine (©Procoralan) for stable angina pectoris is a striking example of the potential importance of heart rate control in cardiac pathologies. However, the lack of knowledge on the importance of some mechanisms underlying pacemaking is a major obstacle in the development of heart rate controlling drugs and cellular therapy of heart diseases. The Beat-Genesis consortium proposes a cutting edge research program to reach two main objectives. First, we aim to define the role of critical ion channels and protein involved in intracellular Ca2+ signalling in cardiac automaticity and in the determination of heart rate and secondly, we will explore the potential cardioprotective effect of gene inactivation or pharmacological inhibition of critical ion channels (L-type Cav1.3, T-type Cav3.1 and HCN) against cardiac ischemia. The Beat-Genesis research program is based on recent advances in the understanding of heart rate regulation obtained by already established and fruitful collaborations between partners. The project is based on a unique collection of genetically-modified mouse strains which is the outcome of an eight years long strategic investment to target key points of the complex cellular pathway underlying cardiac automaticity. This mouse line collection will allow definition of the respective functional roles of Cav1.3 and HCN channels in cardiac automaticity and heart rate control of adult hearts. Furthermore, we propose to investigate the minimal or predominant mechanism required for generating viable automaticity during the adulthood and to study how the loss of Cav1.3 and HCN channels influences automaticity and cellular differentiation of pacemaker cells differentiated from skeletal muscle derived stem cells. Finally, we propose to investigate the potential cardioprotective role of genetic inactivation or pharmacological inhibition of Cav1.3 and Cav3.1 channels.

In higher organisms, the co-ordinated secretion of pituitary hormones is essential for regulating basic body functions such as growth, reproduction and lactation. Pituitary secretions are primarily under the control of hypothalamic hypophysiotropic neurons, which release their signalling factors into the portal blood vessels at the level of the median eminence. Defaults in hormone levels and their rhythms are signatures of many hormonal disorders which are major and economically costly health care problems (dwarfism, infertility, metabolic disorders…). However, little is known about the in vivo rhythms of hypophysiotropic neuron activity that drive pituitary hormone responses. Similarly, the pituitary gland is still an enigma regarding how endocrine cells receive and respond to blood-borne hypothalamic stimuli, as well as how hormone outputs are finally delivered to the complex network of pituitary capillaries. During the former Pit-Net grant, we (Mtp and London groups) have changed the view of how both GH- and PRL-secreting cells are functionally organized within the pituitary. In the past, this gland was considered to be a mosaic of distinct endocrine cell types so that functional assessment of these apparently dispersed cells was traditionally based on cell numbers and activities. Using pituitary-scale 2-photon imaging and functional in situ assays (Mtp groups) on tractable transgenic mice tagged with fluorescent proteins (GH-eGFP, PRL-DsRed…) (London group and other collaborators), we pioneered integrative developmental, morphological and functional studies showing that the pituitary gland is composed of interacting cell networks (PNAS 2005, J. Endoc. 2009, Endocrinology 2010). Another fascinating outcome of the Pit-Net project has been our recent development of in vivo approaches to measure local blood flow, oxygen partial pressure and cell activity at single-cell resolution in mouse pituitary glands in situ. These methods involved modifying a fluorescent stereomicroscope with long working distance objectives to image an exposed pituitary gland deep in its in vivo environment at both wide field and single cell resolution (Lafont et al. PNAS, final revision; see also http://ipam.igf.cnrs.fr/). Cellular in vivo imaging and other functional assays will now be used to fill the critical gaps in our understanding of how the pituitary cell networks receive and decode their native hypothalamic inputs. Two systems will be studied: 1) GH-cells which respond to GHRH by forming pulses of hormone; and 2) lactotrophs which are negatively regulated by dopamine (released by TIDA neurons) due to their high basal activity. Mollard’s group proposes to continue collaborating with Paul Le Tissier's group as well as beginning a new collaboration with Ulrich Boehm (Center for Molecular Neurobiology, Hamburg). Boehm’s group has recently generated ROSA26-driven mice floxed for light-activatable opsin-based tools, either the depolarizing blue light-gated cation channel channelrhodopsin-2 [ChR2] or the hyperpolarizing yellow light-driven chloride pump halorhodopsin [NpHR]. The ChR2 and NpHR are tagged with the fluorescent proteins YFP and mCherry, respectively, to allow identification of their specific cellular location. Boehm’s group has already validated the R26-NpHR-mCherry mice which were successfully crossed with neurohormone-Cre animals, allowing the hormonal manipulation. R26-ChR2-YFP mice are currently under testing. Based on the synergistic and complementary expertises of the three groups forming the proposed ANR team, we are confident that we can achieve the following goals: 1) to determine how the pattern of hypothalamic stimulation influences pituitary gland output; 2) precisely identify how the different topological arrangements of endocrine cell networks in the pituitary gland determines specific functions; and 3) to characterize the role of the relationship between the microcirculation and endocrine cell networks.

The research of the last three decades has fundamentally modified our image of the cities of Spain and North Africa: From the perspective of classical studies, the cities’ strength and significance as ruling entities remained unbroken between 300 and 800 A.D. Military-political events such as the “crisis of the 3rd century” or the invasion of the Vandals seem to have barely touched the urban worlds. It is not downfall but transformation that characterises their urbanism, not change but continuity that describes the functions their social elites fulfilled. This communis opinio is grounded in an astonishingly slim material basis. The aim of the ATLAS project is therefore to create an atlas (WebGIS in Open Access) that records selected cities in the former Roman provinces Baetica (Andalusia) and Africa Proconsularis (Tunisia) – two economically flourishing regions, who thanks to their high levels of urbanism may be taken as paradigmatic for questions of urban studies. This atlas will be the first to encompass all transmitted records necessary for research into Late Antique urban histories within the context of “micro-regions” – not just material remains, but also epigraphic monuments and the entire spectrum of literary evidence. Here, we concentrate our research on the period between 3rd and 8th century. The selection of case studies from two historical landscapes offers a methodological first: A comparison on the basis of these structurally designed case studies enables insight into conformities or discrepancies, leading to productive conclusions for the evaluation of the regional situation as a whole. This comparative urban research is only possible because ATLAS combines German research’s focus on the subjects of ancient history and epigraphy on the Iberian Peninsula with the French focus on the subject of archaeology in both Spain and North Africa. The compilation and analysis of the transmitted records is to serve as the basis of a new narrative of Late Antiquity, which does not – as in previous works on urbanism in this period – rest on analogical conclusions and therefore skew towards generalisations. Moreover, the detailed examination of all types of sources and a methodically clear comparison is aimed at differentiating within the six centuries under investigation. This is aided by visualization of the historical developments in form of thematic maps. ATLAS therefore offers a contribution to urban research and so to the social history of power in the context of the developmentally open and dynamic research field between Late Antiquity and the Early Middle Ages. To make this work available to a broader public as well, the project will also be virtualized with the most modern technology, which enables users to individually experience urban history in the context of a travelling exhibition.