Chromatin, metabolism and cell fate
Epigenetic information is written in chromatin. But how exactly do epigenetic mechanisms operate on the molecular level? How do chromatin alterations contribute to cell fate transitions? How does the environment influence these processes? And how does the metabolic state of a cell impact on its chromatin structure and its epigenetic memory?
These are questions we address in the lab. Studying stem cells and cancer we focus on molecular aspects of epigenetic regulation and on the question whether we can translate this knowledge into diagnostic and therapeutic tools for the management of diseases such as leukemia and myelodysplastic syndrome.
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. As model system for cell differentiation we are using embryonic stem cells, myoblasts and hematopoietic cells. 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 fall in one or several of three main themes:
- The link between metabolism and epigenetic regulation.
- The regulation and molecular function of histone variants.
- Chromatin as drug target in myelodysplastic syndrome (MDS) and leukemia.
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). 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.
|Marcus Buschbeck||Group Leaderemail@example.com|
|David Corujo||PhD Studentfirstname.lastname@example.org|
|Jeannine Diesch||Postdoctoral Investigatoremail@example.com|
|Iva Guberovic||PhD Studentfirstname.lastname@example.org|
|Sarah Hurtado-Bagès||PhD Student||Shurtado@carrerasresearch.org|
|Michael Maher||PhD Studentemail@example.com|
|Roberto Malinverni||Postdoctoral Investigatorfirstname.lastname@example.org|
|Marguerite Marie Le Pannérer||PhD Studentemail@example.com|
MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD(+) consumption.Nat. Struct. Mol. Biol. 9 Oct 2017, . Epub 9 Oct 2017
MacroH2A histone variants maintain nuclear organization and heterochromatin architecture.J. Cell. Sci. 10 Mar 2017, . Epub 10 Mar 2017
Variants of core histones and their roles in cell fate decisions, development and cancer.Nat. Rev. Mol. Cell Biol. 1 Feb 2017, . Epub 1 Feb 2017
A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers.Clin Epigenetics 2016, 8 71. Epub 21 Jun 2016
Immunophenotypic, cytogenetic, and mutational characterization of cell lines derived from myelodysplastic syndrome patients after progression to acute myeloid leukemia.Genes Chromosomes Cancer Mar 2017, 56 (3) 243-252. Epub 21 Nov 2016
LAS VARIANTES DE HISTONAS MACROH2A VINCULAN LA ARQUITECTURA DEL GENOMA AL METABOLISMO
|Data de finalització:||31/12/2018|
Chromatin-metabolism interactions as targets for healthy living (ChroMe)
|Data de finalització:||29/02/2020|
|Data de finalització:||31/12/2019|
Drug repositioning as a fast and cost effective approach to personalized therapies. A pilot study on myelodysplastic syndrome and acute myeloid leukaemia
|Data de finalització:||31/03/2016|
Plan Nacional - Epigenetic Regulators of Stem Cell Function
|Data de finalització:||31/12/2015|
Dissecting the Role of Polycomb Complexes in the Pathogenesis of Myelodysplastic Syndromes (MDS) and the Evolution to Acute Myeloid Leukemia (DJCLS R 14/16)
|Codi:||DJCLS R 14/16|
|Data de finalització:||31/07/2017|
How does the histone variant macroH2A regulate muscle metabolism in health and disease?
|Data de finalització:||26/10/2017|