Systematically Mapping the Epigenetic Context-Dependence of Transcription Factor Binding
Event details
| Date | 01.11.2018 |
| Hour | 12:00 › 13:00 |
| Speaker | Dr. Judith Kribelbauer; Columbia University, New York City, NY (USA) |
| Location | |
| Category | Conferences - Seminars |
BIOENGINEERING SEMINAR
Abstract:
At the core of gene regulatory networks are transcription factors (TFs) that recognize specific DNA sequences and target distinct gene sets. In recent years, several high-throughput methods have been developed, providing measurements of in vitro TF binding specificity for a large number of TFs. Although the resulting motif models are now routinely used to inform or interpret in vivo studies, it still remains challenging to predict TF binding patterns genome-wide, or to distinguish between gene networks controlled by paralogous TFs or those within the same structural family. One, perhaps, evident reason for this shortcoming is that our current models do not account for epigenetic modulators of TF binding that are generally present in a cellular context, such as DNA modifications, cooperativity between TFs, DNA shape, or motif-flanking bases that might enhance or reduce a TF’s overall binding strength.
To close the gap between in vitro measured enrichment and in vivo detected TF occupancy, we have developed novel experimental and computational methods that elucidate the impact of epigenetic modulators on TF binding. Our results provide new insights into the array of mechanisms used by TFs to recognize DNA substrates with varying affinity, such as position- and paralog- specific readout of DNA modifications, or the use of distinct binding modes by multi-TF complexes. Using a D. melanogaster multi-homeodomain Hox complex as an example, we show that combinatorial logic in terms of complex composition and configuration is readily used to modulate multi-TF binding preferences.
We further demonstrate how the detailed shape of DNA aids in creating a substrate for adaptive TF binding and how the mechanistic insight into such shape readout can be exploited to design TFs with unique properties, such as the ability to differentiate between complex compositions and configurations. Reinserting such engineered proteins into the fly genome and comparing genome-wide binding patterns of “wild-type” and “designer” TF together with DNA sequence and binding site accessibility scores further allows the classification of in vivo bound sites in terms of complex composition.
By doing so, we obtain approximate “TF-complex-to-gene-set” mappings, which ultimately allow inference of Hox-dependent and -independent gene regulatory networks and their associated biological functions.
Abstract:
At the core of gene regulatory networks are transcription factors (TFs) that recognize specific DNA sequences and target distinct gene sets. In recent years, several high-throughput methods have been developed, providing measurements of in vitro TF binding specificity for a large number of TFs. Although the resulting motif models are now routinely used to inform or interpret in vivo studies, it still remains challenging to predict TF binding patterns genome-wide, or to distinguish between gene networks controlled by paralogous TFs or those within the same structural family. One, perhaps, evident reason for this shortcoming is that our current models do not account for epigenetic modulators of TF binding that are generally present in a cellular context, such as DNA modifications, cooperativity between TFs, DNA shape, or motif-flanking bases that might enhance or reduce a TF’s overall binding strength.
To close the gap between in vitro measured enrichment and in vivo detected TF occupancy, we have developed novel experimental and computational methods that elucidate the impact of epigenetic modulators on TF binding. Our results provide new insights into the array of mechanisms used by TFs to recognize DNA substrates with varying affinity, such as position- and paralog- specific readout of DNA modifications, or the use of distinct binding modes by multi-TF complexes. Using a D. melanogaster multi-homeodomain Hox complex as an example, we show that combinatorial logic in terms of complex composition and configuration is readily used to modulate multi-TF binding preferences.
We further demonstrate how the detailed shape of DNA aids in creating a substrate for adaptive TF binding and how the mechanistic insight into such shape readout can be exploited to design TFs with unique properties, such as the ability to differentiate between complex compositions and configurations. Reinserting such engineered proteins into the fly genome and comparing genome-wide binding patterns of “wild-type” and “designer” TF together with DNA sequence and binding site accessibility scores further allows the classification of in vivo bound sites in terms of complex composition.
By doing so, we obtain approximate “TF-complex-to-gene-set” mappings, which ultimately allow inference of Hox-dependent and -independent gene regulatory networks and their associated biological functions.
Practical information
- Informed public
- Free
Organizer
- UPDEPLA - Prof. Bart Deplancke
Contact
- Marie Künzle : 39505