NUCLEAR aims at educating future experts that can drive the emerging field of Metabolic Regulation of Genome Function and Cell Identity relevant for stem cell biology and cancer. It is a Doctoral Training Network composed of 14 beneficiaries and 12 partner organisations including three industrial partners, a training-oriented foundation, a patient support association from 8 EU member states, 1 associated country and a non-EU member state self-funding itself to the level of beneficiary. Given the highly interdisciplinary nature of this emerging field, no single institution can provide all suitable infrastructures and the know-how required for high-quality PhD-level training. To address this shortfall in training capacity, NUCLEAR brings together European leaders in metabolomics, functional genomics, chromatin regulation, stem cell biology and cancer with innovators in precision nutrition, mass spectrometry technologies and drug development. Together we are committed to the following: 1. To train 16 doctoral candidates (DCs) through an innovative program structured in four capacity axes and occurring on three complementary levels to deliver enabling scientific and transferable skills. 2. To guide DCs in collaborative research bridging boundaries of countries, sectors, and disciplines. 3. To address three key challenges that limit the advancement and exploitation of the field and that are the lack of tools to measure nuclear metabolism, the lack of understanding of underlying molecular mechanisms and the lack of targets for novel cancer therapies. 4. To build lasting infrastructures for dissemination, communication and exploitation promoting an entrepreneurial culture and maximizing and extending the impact of this proposal beyond its lifetime. 5. To increase the international visibility of European research by taking leadership in the emerging field of Metabolic Regulation of Genome Functions and Cell Identity.

The CarrerasPathfinder program is new a world-wide unique doctoral program that covers the entire spectrum of research and innovation in blood cancers from understanding disease biology to the implementation of novel processes in the clinical practice. The program will fund 14 excellent Doctoral Candidates (DCs) for a period of 48 months. DCs will perform collaborative PhD projects involving associated partners from different sectors, countries, and disciplines through secondments. DCs will improve their research capacity and transferable skills through high-quality supervision arrangements and a tailored training program. The program has been designed and will be hosted by the Josep Carreras Leukaemia Research Institute (IJC) which is the first European non-profit institute exclusively devoted to blood cancers. By answering the European needs for human resources, it is fully aligned with the 13 recommendations of the EU Cancer Board’s Draft Mission and the Europe’s Beating Cancer Plan (2021). The CarrerasPathfinder program has a strong triple-I dimension of internationality, inter-sectorality and interdisciplinarity in training, networking, co-supervision and research. Its specific objectives are: • To develop an excellent doctoral program in blood cancer research conceived as a pilot for a permanent international doctoral program • To equip DCs with a unique skill set boosting effectiveness and innovation capacity. • To promote DCs’ career development and increase their employability in different sectors. • To establish the IJC as a European reference for research and training in blood cancers. • To provide Europe with a new generation of researchers able to address unmet needs and societal challenges of blood cancers. • To contribute to structuring the European research area by collaborating and synergizing with other European key opinion leaders.

The initiation and maintenance of leukaemia are often regulated through the interaction of epigenetic mechanisms and metabolism, but how these affect each other, is not always fully understood. One of the epigenetic mechanisms that alter cell fate is the replacement of replication-coupled histones with non-canonical variants. MacroH2A (mH2A) variants (mH2A1.1, mH2A1.2 and mH2A2) have a large, metabolite-binding macrodomain and differ from each other solely in the structure of their ligand-binding pocket. Of those three, only mH2A1.1 has known ligands, while the binding partner and corresponding biological functions of mH2A1.2, are still unknown. The preliminary data suggest phospholipid molecules as unique ligands of mH2A1.2. At the same time, they show that the MACROH2A1 is required for the maintenance of the stemness of leukaemia stem cells and leukaemia itself. During the ChroMet project, by using cutting-edge techniques in cell and molecular biology, computational biology and biochemistry, I aim i) to confirm the identity of putative ligands of mH2A1.2 and to biophysically characterize the binding interaction, and ii) to test the contribution of the newly identified metabolite-binding capacity of mH2A1.2 on the leukemia cell differentiation and tumorigenicity. The findings of the project will allow me to describe the mH2A1.2 as an entirely novel metabolic sensor on chromatin, which, through the binding of phospholipid ligands, regulates cell metabolism and impacts leukaemia cell fate. The complementary knowledge and expertise of the hosting group (in epigenetics and metabolism), the hosting institute and long-standing collaborators (in leukemia research), and my own (in biochemical analyses of protein-ligand interactions) will ensure the successful realization of the proposed project and contribute to the development of my career as an independent researcher, committed to exploring an interplay between epigenetics, metabolism and cancer.