One of the most profound and intriguing questions in biology concerns the relationships
between genetic diversity, morphology and function. This complex biology arises during
embryonic development. The key to understanding early embryonic development will be
found in uncovering molecular mechanisms of gene regulation and deciphering the regulatory
circuitry underlying pluripotency, regional specification and patterning. These processes are essential for our understanding of congenital disease and cancer and for developing the
potential of regenerative medicine.
Epigenetics of pluripotency and differentiation
Model systems: Xenopus embryos and mammalian cells. To increase our understanding of the transcriptional regulation of the genome during early embryogenesis, we are using chromatin immunoprecipitation in combination with Next Generation deep sequencing to identify expressed and gene-regulatory sequences during the early stages of embryonic development, and to uncover the dynamics of transcription regulatory mechanisms during these stages. We probe the molecular mechanisms involved in establishing the pluripotent chromatin state and the remodeling events that occur during cell lineage commitment.
Developmental and comparative genomics
Studies of Xenopus embryos have contributed much to our understanding of early vertebrate embryogenesis. The Xenopus tropicalis genome has been sequenced and the next challenge will be to characterize the functionally relevant sequences in this genome, and to identify novel genes and their regulatory sequences in a comprehensive and unbiased way, which is a prerequisite for uncovering the gene-regulatory network of early vertebrate development. The genome of Xenopus laevis has been subject to a whole genome duplication event, followed by selective loss of only a fraction of the duplicated genes.
General transcription factors and promoter architecture
The general transcription machinery is not as universally used as once thought, as metazoans in general, and vertebrates in particular, contain general transcription factor paralogs not found in yeast. We have contributed to this change in paradigm by our studies of TATA binding protein (TBP, present in all eukaryotes), TBP-like factor (TLF, also known as TRF2, present in all multicellular organisms) and TBP2 (also known as TRF3, found in vertebrates only). We have observed gene-selective roles of TBP, TLF and TBP2 in gene expression, as well as developmental stage specificity in expression and promoter recruitment of TBP and TBP2, highlighting their specialized roles in development. Using expression profiling, chromatin immunoprecipitation (ChIP), promoter analysis and biochemical methods we are investigating the biological roles of general transcription factors and the molecular mechanisms by which these proteins exert their function during development.