Research

In our scientific approach we combine biochemical techniques, genetic manipulation of cell cultures and ultrasequencing of enriched chromatin fractions to address mechanistic and functional aspects of epigenetics. Key findings are validated in vivo. For the study of cancer we combine established cell lines, primary cultures and other patient samples.

Ongoing projects in the lab are related to the several of the following themes:

•    The link between metabolism and epigenetic regulation.
•    The regulation and molecular function of histone variants.
•    Nuclear organization and 3D chromatin architecture
•    Chromatin regulators as drug targets in myeloid diseases.

These are two examples of ongoing projects:

Chromatin modifiers as drug targets in MDS and cancer

Intrinsic and acquired resistances are the main reason for failure of current cancer treatments. For best treatments initial responses are limited to less than 50% of patients and virtually all responders eventually relapse and progress. The main goal of this study is to identify urgently needed response-predicting biomarkers and new combinatorial drug targets to increase rate and durability of response.

We coordinate the RESPONSE network (PIE16/00011) that brings together clinical and experimental groups. Together we we focus on three major cancers and their current treatments: advanced colorectal and lung cancer treated with chemotherapy and high-risk myelodysplastic syndrome treated with azacitidine.

To achieve our goals we combine the power of genetic screening technology with the analysis of highly informative clinical sample collections. We focus on transcriptional and chromatin regulators as a promising yet underexplored group of drug effectors. We examine drug-sensitizing genes and pathways with the aim to determine new drug targets for combinational therapy. Our long-term goal is to maximally advance the preclinical studies enabling the design of well-informed clinical trials. Using transcriptomic and epigenomic techniques we will further dissect the molecular function of most relevant effector genes.

The regulation and function of the macroH2A histone variants

Histones form the protein core of the nucleosome, which is the modular building block of chromatin structure. Histone variants endow chromatin with unique properties and show a specific genomic distribution. The histone variants macroH2A are unique in having a tripartite structure consisting of a N-terminal histone-fold, an intrinsically unstructured linker domain and a C-terminal macro domain. Recently, we have made two major discoveries. First, macroH2A proteins have a major role in the nuclear organization (Douet et al., 2017, JCS; Kozlowski, Corujo et al., 2018, EMBO Rep). This has the potential to explain how these proteins can act as tumor suppressors, promoters of differentiation and barriers to somatic ecll reprogramming (discussed in Buschbeck and Hake, 2017, Nature Reviews).

Second, we have identified the macroH2A1.1 isoform to be part of amolecular mechanism allowing cells to couple the metabolic requirements between distant organelles such as nucleus and mitochondria. Specifically, we found that macroH2A1.1 binds nuclear PARP1 and dampens its NAD+ consumption thereby creating a buffer of NAD+ precursors facilitating NAD+ dependent reactions in other organelles, such as respiration in mitochondria (Posavec Marjanovic, Hurtado-Bagès et al., 2017, NSMB). As co-coordinators of the MSCA ITN 'ChroMe', we are further pursuing additional research lines at the intersection of the chromatin and metabolism fields.