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GEN-AU III Project: Epigenetic Regulation of Cell Fate Decisions
The elucidation of epigenetic control mechanisms provides new potential for understanding important developmental processes. This GEN-AU cluster project will thus provide novel important insight into the molecular mechanisms underlying epigenetic plasticity and cell fate decisions in normal development and disease.


The mammalian genome with its ~25,000 genes contains the genetic information for directing the development of a totipotent zygote into a multicellular organism. The primary DNA sequence does, however, not provide sufficient information for correct interpretation of the genetic program. A second layer of information, referred to as epigenetic control, acts beyond the DNA sequence. Epigenetic information is stored as chemical modifications of cytosines in DNA and of amino acid residues in histone proteins that package the genome into chromatin. In addition to DNA methylation and histone modifications, epigenetic control mechanisms also rely on non-coding RNA-mediated gene silencing, chromosomal domain organization and DNA-binding transcription factors controlling these processes.
    
The elucidation of epigenetic control mechanisms provides new potential for understanding important developmental processes such as stem cell plasticity, cell fate decisions, inheritance of differentiated cell states and their deregulation in disease and cancer. Moreover, cellular senescence, chromosome organization, X-chromosome inactivation, imprinting and the repression of repetitive elements are other important aspects of epigenetic control. At the molecular level, epigenetic regulation contributes to the repression of inappropriate developmental programs, while ensuring the heritability of existing or newly acquired phenotypic states. Epigenetic control of cell identity has recently been investigated by large-scale chromatin profiling in a variety of cell types including embryonic stem (ES) cells. While these first-generation epigenetic maps have provided valuable information, the underlying molecular mechanism remains unclear, as histone modification patterns could be the cause or consequence of transcriptional activity. The regulation of cell fate decisions also critically depends on transcription factors. This is exemplified by the loss of B cell identity upon conditional removal of a single factor, Pax5, and by forced expression of several transcription factors (Oct4, Myc, Klf4 and Sox2), which are sufficient to reprogram differentiated fibroblasts into germline-competent induced pluriptent stem (iPS) cells.
    
In this GEN-AU cluster project, six research teams (Barlow, Busslinger, Jenuwein, Peters, Ringrose and Seiser) have come together to use their synergistic expertise to study different aspects of epigenetic control by genome-wide mapping of epigenetic states in ES cells, neural cells, erythroblasts, B-lymphocytes and fibroblasts. The availability of several mouse mutants lacking essential epigenetic regulators is a particular strength of this consortium, as epigenetic states will be investigated not only in wild-type, but also mutant cell types by state-of-the-art mapping techniques. This GEN-AU cluster project will thus provide novel important insight into the molecular mechanisms underlying epigenetic plasticity and cell fate decisions in normal development and disease.

Dynamic transitions in Polycomb and Trithorax regulation upon differentiation

Management:  Prof. Dr. Leonie Ringrose
Institutions:  IMBA - Institute for Molecular Biotechnology; Austrian Academy of Sciences
e-mail: leonie.ringrose@imba.oeaw.ac.at
WWW: http://www.imba.oeaw.ac.at/

Epigenetic and transciptional control of B cell development

Management:  Univ.-Prof. Dr. Meinrad Busslinger
Institutions:  IMP - Research Institute of Molecular Pathology
e-mail: busslinger@imp.univie.ac.at
WWW: http://www.imp.ac.at

Epigenetic control by histone lysine methylation

Management:  Prof. Dr. Thomas Jenuwein
Institutions: 
e-mail: jenuwein@immunbio.mpg.de
WWW: http://www.immunbio.mpg.de/

Epigenetic control of cellular proliferation

Management:  Ao Univ.-Prof. Dr. Christian Seiser
Institutions: 
Dept. of Medical Biochemistry; Med. Univ. of Vienna
e-mail: christian.seiser@univie.ac.at
WWW: http://www.mfpl.ac.at

Epigenetic gene regulation by imprinted macro non-coding RNAs

Management:  Dr. Denise P. Barlow
Institutions:  CeMM - Research Centre for Molecular Medicine; Austrian Academy of Sciences
e-mail: denise.barlow@univie.ac.at
WWW: http://www.cemm.oeaw.ac.at

Regulation of chromatin structure by cohesin complexes

Management:  Dr. Jan-Michael Peters
Institutions:  IMP - Research Institute of Molecular Pathology
e-mail: peters@imp.univie.ac.at
WWW: http://www.imp.ac.at


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