We perform both basic and applied research. In our basic research, we aim to understand the molecular mechanism by which histone variants link epigenetic regulation to metabolism. In our translational research, we mine the chromatin regulatory space for combinatorial drug targets that can improve the therapy of blood cancers. We currently focus on acute myeloid leukemias and related myelodysplastic syndromes
For an overview of our activities please watch the following presentation :
Fundamental Research: Understanding the function and regulation of histone variants.
We have a long-standing interest in the study of histone variants. These alternative histones can replace replication-coupled histones in the organizational unit of chromatin, the nucleosome, and provide targeted chromatin regions with unique properties.
During the last years we gained first insight in the functions of these domains. We were able to demonstrate that the linker is contributing to the three-dimensional organization of chromatin in the nuclear space (Douet et al., 2017; Kozlowski, Corujo, 2018, reviewed in Corujo and Buschbeck, 2018, Cancers). Our results showed that changes in 1-2% of nucleosomes (presence and absence of the histone variant) can lead to changes in higher-order nuclear organization and provokes exciting questions related to its relevance for gene regulation and in extension to cell fate.
Specifically, we are focusing on the family of macroH2A histone variants that are particular interesting from a biochemical point of view because they possess two additional domains of poorly understood function. These domains are the linker and the macrodomain.
Second, we have been able to demonstrate that one specific macroH2A variant called macroH2A1.1 can act as a metabolic regulator by directly binding NAD+ derived metabolites and post-translationally modified effector proteins through its macrodomain (Posavec Marjanovic, Hurtado-Bagès, 2017, reviewed in Hurtado-Bagès, 2020). Excitingly, we found that this function is ancient dating back to before the origins of multicellular life (Guberovic, 2021, reviewed in Guberovic, Farkas et al., 2022).
During the next years, our overall goal is to test the intriguing hypothesis that macroH2As are metabolic sensors on chromatin that modulate gene expression through changes in 3D chromatin architecture.
We are proud of having been able to establish ourselves as a reference lab for the research in histone variants. We were honored by invitations to author a review for Nature Reviews MCB (Buschbeck and Hake, 2017), to contribute to a special issue on histone variants (Sem Dev Cell Biol, 2022) and to organize the leading conference on the topic for EMBO (2017, 2021).
Translational Research: Improving current leukemia treatments.
Intrinsic and acquired resistances are the main reason for failure of current cancer treatments. Even for the best available treatments, initial responses are limited to less than 50% of patients and virtually all responders eventually relapse and progress. The best solution to avoid and overcome resistances is the combination of multiple drugs attacking the disease from different angles.
The main goal of our translational research line is to identify urgently needed new combinatorial drug targets and to accelerate preclinical development to increase rate and durability of response and patients’ quality of life. By leveraging the exceptional environment of the Josep Carreras Leukaemia Research Institute and my expertise in epigenetic regulation, we are in the unique position to identify new drug targets in the chromatin regulatory space. Recently, we focused on the current treatment scheme for a subset of acute myeloid leukemia patients consisting in treatment cycles with the hypomethylating drug azacitidine. We were able to show that CBP/p300 inhibitors synergize with azacitidine in a cancer cell-intrinsic manner (Diesch et al., 2021, Nat Commun).
Together with the MSCA Innovative Training, we are exploring the possibility to also target the tumor microenvironment making it less permissive for the expansion of cancer cells. In collaboration with Katharina Götze, we were able to contribute to the proof-of-concept showing that this can indeed be achieved by a drug treatment (Wenk et al., 2018, Blood Adv.). Our specific objectives for the next years are:
- To identify drug targets for novel combinatorial therapies improving current and emerging therapies for leukemia.
- To test novel therapeutic approaches targeting the cancer microenvironment such as the epigenetic reprogramming of bone marrow niche cells.
- To understand the underlying molecular mechanisms.