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
Functional studies have been severely limited by the inefficient ex vivo growth of primary MDS cultures. In order to circumvent this problem we have characterized MDS patient-derived AML cell lines and identified lines that retain MDS characteristics such as a limited differentiation capacity. Our current efforts aim at the development of methods that will allow us to screen both FDA-approved drugs as well as novel compounds as first step of the drug development process. Furthermore genetic engineering allows us to test drug-gene interactions.
As several chromatin modifiers were found mutated in MDS patients we use genetic engineering in MDS-AML cell cultures to test the functional relevance of known and novel chromatin modifiers and their alterations. In collaboration with Katharina Götze (TU Munich) we will validate promising results in co-cultures of primary cells isolated from MDS patient bone marrow.
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. MacroH2A is the only histone with a tripartite structure consisting of a N-terminal histone-fold, an intrinsically unstructured linker domain and a C-terminal macro domain. The incorporation of a macroH2A protein into the nucleosome places the macro domain in close proximity to the symmetrical axis and can be considered as the most extensive chromatin modification at the building block level.
From a large set of loss-of-function studies we could conclude that macroH2A is required for the establishment and maintenance of differentiated epigenomes. Want to know more? Please have a look at our recent reviews on macroH2A (Creppe, 2012; Posavec, 2013; Cantariño, 2013). In our current work we study context-dependent functions of macroH2A and the regulation of the locus-specific incorporation of macroH2A.
|Marcus Buschbeck||Principal Investigatorfirstname.lastname@example.org|
|David Corujo||PhD Studentemail@example.com|
|Jeannine Diesch||Postdoctoral Investigatorfirstname.lastname@example.org|
|Julien Douet||Postdoctoral Investigatoremail@example.com|
|Iva Guberovic||PhD Studentfirstname.lastname@example.org|
|Sarah Hurtado||PhD Student||Shurtado@carrerasresearch.org|
|Michael Maher||PhD Studentemail@example.com|
|Roberto Malinverni||Postdoctoral Investigatorfirstname.lastname@example.org|
|Anna Palau||PhD Studentemail@example.com|
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
A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers.Clin Epigenetics 2016, 8 71. Epub 21 Jun 2016
Downregulation of the Deiminase PADI2 is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis.Mol. Cancer Res. 8 Jun 2016, . Epub 8 Jun 2016
A Cbx8-Containing Polycomb Complex Facilitates the Transition to Gene Activation during ES Cell Differentiation.PLoS Genet. Des 2014, 10 (12) e1004851. Epub 11 Des 2014
LAS VARIANTES DE HISTONAS MACROH2A VINCULAN LA ARQUITECTURA DEL GENOMA AL METABOLISMO
|Data de finalització:||31/12/2018|
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|
Chromatin-metabolism interactions as targets for healthy living (ChroMe)
|Data de finalització:||29/02/2020|
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|