Differentiation of cells during normal development and disease is governed by changes to chromatin structure that manifest at several levels to determine gene activity. At a more local level, genes are embedded in active or repressive chromatin structures. Changes between these states are modulated by DNA binding transcription factors recruiting histone modifying and nucleosome remodelling enzymes to chromatin. At a more global level, structural proteins drive chromatin folding and loop formation and establish chromosomal contacts to regulate larger genomic regions. Local and global chromatin regulation are tightly interconnected.The TRR81 has made substantial progress in our understanding of how pathways transmitting developmental signals interface with histone modifying enzymes to change chromatin structure during muscle and neuronal differentiation. We unraveled molecular functions of chromatin remodellers in diverse developmental contexts, including heart development and spermatogenesis. In addition, factors and mechanisms driving chromosome conformation, topologically associated domains and enhancer-promoter-interactions, were uncovered in different cell systems. Finally, our understanding of the molecular mechanisms underlying global chromatin compaction during X-chromosome inactivation and spermatogenesis has been significantly advanced.The focus of this extension application is the utilization of new and refined methods allowing “Chromatin Changes in Differentiation and Malignancies” to be addressed at unprecedented levels of detail. Among these are the development of small molecules to modulate chromatin regulators, improved CRISPR methods to precisely change genomic DNA and targeting of chromatin regulators to specific genomic loci. Novel sequencing approaches have been introduced, some of which invented by TRR81 members, to probe chromatin contacts over large distances. Sensitivity and resolution of key techniques have been dramatically improved such that analyses of the epigenomes of small numbers or even single cells have become possible. Finally, super resolution microscopy is continuously being refined by the TRR81.One of the strengths of the TRR81 is to apply these techniques to multiple, complementary models to investigate normal and pathological mechanisms that lead to chromatin changes. The differentiation models include spermatogenesis, immune cells and their activation by signalling, hematopoietic stem cells and their differentiation, ES cells and cell lines that allow differentiation towards neural and muscle lineages, cerebral organoid cultures and cancer cells. Disease models include tumor formation, neurodevelopmental syndromes, inflammation, muscle dystrophy and hemoglobinopathies. The TRR81 projects proposed will advance our understanding of epigenetic mechanisms underlying differentiation in healthy and in diseased cells and will provide the basis for the future development of novel therapeutic approaches.
DFG Programme
CRC/Transregios
International Connection
Netherlands
Completed projects
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A01 - Epigenome regulation by ATP-dependent nucleosome remodelers
(Project Head
Brehm, Alexander
)
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A02 - Delineating the interplay of epigenetic modifiers and transcription factors in the control of muscle stem cell homeostasis and higher-order chromatin organization
(Project Heads
Braun, Thomas
;
Yuan, Xuejun
;
Zhou, Ph.D., Yonggang
)
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A03 - Functional analysis of the histone arginine methyltransferase PRMT6
(Project Head
Bauer, Uta-Maria
)
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A06 - Recruitment and mechanisms of action of the L3MBTL2-containing non-canonical PRC1 complex
(Project Head
Suske, Guntram
)
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A07 - Functional characterization of novel histone phosphorylations
(Project Head
Schmitz, M. Lienhard
)
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A10 - Role of p73-directed chromatin alterations for neuroendocrine differentiation in small cell lung cancer
(Project Head
Stiewe, Thorsten
)
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A12 - Chromatin regulation mediated by the RBP-J/SHARP corepressor complex
(Project Head
Borggrefe, Tilman
)
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A15 - Role of mammalian histone variants H3.3 and H2A.Z in differentiation and disease
(Project Head
Hake, Sandra Brigitte
)
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A17 - Molecular mechanisms and (patho)physiological consequences of PRC2.1-mediated gene regulation
(Project Head
Liefke, Robert
)
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B02 - Characterization of nuclear IL-1-regulated protein complexes that mediate chemokine gene expression
(Project Head
Kracht, Michael
)
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B03 - Molecular mechanisms of CTCF mediated gene regulation in Drosophila
(Project Head
Renkawitz, Rainer
)
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B06 - Mechanisms of epigenetic regulation of tumor suppressor genes
(Project Head
Dammann, Reinhard
)
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B07 - Lamins and Rnf20 at the interface of cancer metabolism and epigenetics
(Project Head
Dobreva, Gergana
)
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B08 - Unravelling the mechanism of the histone-to-protamine transition during spermatogenesis in Drosophila
(Project Head
Renkawitz-Pohl, Renate
)
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B12 - Chromatin regulation in the mammalian nucleus mediated by ATP-dependent chromatin remodeling complexes
(Project Head
Mermoud, Ph.D., Jacqueline
)
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B13 - Chromatin dynamics in Drosophila spermatids
(Project Head
Pütz-Rathke, Christina
)
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B14 - High mobility group B factors as regulators of genomic architecture via CTCF clustering
Argyris Papantonis
(Project Head
Papantonis, Argyris
)
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MGK - Integrated Research Training Group "Epigenetics and Chromatin"
(Project Heads
Borggrefe, Tilman
;
Philipsen, Sjaak
;
Suske, Guntram
)
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Z01 - Bioinformatics analysis of genome-wide data sets
(Project Heads
Bartkuhn, Marek
;
Chung, Ho-Ryun
;
Goesmann, Alexander
)
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Z03 - Central Tasks of the Collaborative Research Centre
(Project Head
Brehm, Alexander
)
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Z04 - Chemoinformatics, Medicinal Chemistry & Peptidomimetics
(Project Heads
Diederich, Wibke Elisabeth
;
Kolb, Peter
;
Vazquez, Olalla
)
