Molecular Studies of Transcription and Regulation
of Developmental Genes
We study the molecular basis of the fascinating process by which our different body parts are formed during development.
The regulation of gene transcription is critical for the proper development and growth of an organism. The function of these genes is also crucial for us as adults; in the unfortunate event of malfunction, the end result might be cancer, such as leukemia.
Schematic model depicting the pivotal role of the core promoter module in diverse molecular events and stages of gene expression. The core promoter is important for (clockwise): basal transcription initiation and PIC- core promoter compatibility; enhancer-promoter compatibility; promoter-proximal Pol II pausing; termination/polyadenylation and Pol II recycling; and translation. Please see Danino et al. (2015) for detailed explanations.
Control elements that are embedded in the DNA sequences of genes are responsible for proper development. We study these DNA sequence elements and how they control different genes. Our analysis is important for understanding the regulation of development and complex systems.
Core promoter composition. Schematic illustration of the most common core promoter elements found in focused promoters. The diagram is roughly to scale. For more information, please refer to Danino et al. (2015).
We focus on the core promoter,which is generally defined as the DNA region that directs the accurate initiation of transcription by RNA polymerase II. In the past, the core promoter has often been presumed to be a generic entity that functions by a single universal mechanism. Recent findings reveal that there is widespread diversity in core promoter structure and function.We have embarked on the identification of biological functions of core promoter motifs and the identification of core promoter-specific activators.
Our goal is to understand the complex regulation of eukaryotic gene expression. We focus on the uniquecontribution of the core promoter to transcriptional regulation of gene networks.
Drosophila Hox genes preferentially contain DPE and not TATA elements. For complete discussion, see Juven-Gershon, T. and Kadonaga, J.T. (2010) Developmental Biology
We have recently discovered that the dorsal-ventral developmental GRN is dependent on the presence of the DPE motif. We demonstrated that over two-thirds of Dorsal target genes contain DPE sequence motifs, which is significantly higher than the proportion of DPE-containing promoters in Drosophila genes. Furthermore, we showed that multiple Dorsal target genes are evolutionarily conserved and functionally dependent on the DPE. We envision the core promoter composition as an additional component of the dorsal-ventral gene regulatory network, which contributes to the combinatorial transcriptional output.
The core promoter composition establishes an additional dimension in the dorsal-ventral gene regulatory network. Dorsal target genes are classified according to their embryonic tissues: the mesoderm, neurogenic ectoderm, and dorsal ectoderm. The Dorsal nuclear gradient is represented by the depth of the blue color. The upper side of the cube displays the color coding of the possible combinations of the discussed core promoter elements. The front depicts selected Dorsal target genes with the corresponding color-coded core promoter composition. The relative frequency of each core promoter combination among all Dorsal target genes in each of the three tissue (using the same color code) is shown on the right. The complete discussion is available here.
It is clear today that there is no universal transcription machinery and the term general transcription machinery should be replaced by basal transcription machinery. Since its discovery in 1999, it has been known that TRF2 (TATA-box-binding protein-related factor 2), despite its homology to the TBP (TATA-box-binding protein) core domain, does not bind TATA-containing promoters. Microfluidic affinity analysis has demonstrated DNA binding of TRF2-containing complexes to DPE-containing promoters. It is likely that there are TRF2-associated factors (like TBP-associated factors), which assist TRF2 in binding to its target promoters.
Recent findings have highlighted the involvement of TRF2 in the regulation of diverse biological processes and specialized transcription programs. Hence, specific core promoter composition serves to recruit a specialized basal transcription factor, demonstrating the diversity of transcriptional regulation.
Schematic model depicting the regulation of diverse biological processes and transcriptional programs by TRF2. For more information see here.
In our research, we use the fruit fly (scientifically known as Drosophila melanogaster), as our model organism. The fruit fly has been used as an excellent model for genetics and developmental biology for many years. Strikingly, at the molecular level, there is remarkable similarity between humans and flies. Practically, this means that studying the regulation of development in the fly can teach us a lot about the regulation in humans.
In our lab we combine methodologies of molecular biology, biochemistry, cell biology, bioinformatics and developmental biology.