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.Chromatin state, as defined by chromosome topology, chromatin accessibility and epigenetic modifications, can act as a filter of genomic information influencing lineage commitment and epigenetic stability (Perino and Veenstra, 2016)
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.
Gene-regulatory networks of development
Based on the conceptually simple premise that transcription factors (TFs) bind their cognate motifs in regions with accessible chromatin, it is possible to construct gene-regulatory networks by integrating results from ATAC-seq, RNA-seq and underlying genomic sequence. We are using these networks to model gene regulatory dynamics, spatial gene regulation and developmental transitions.
TBP family-insensitive network during early development (Gazdag et al., 2016)
Developmental and comparative genomics
Studies of Xenopus embryos have contributed much to our understanding of early vertebrate embryogenesis. The genomes of both Xenopus tropicalis and Xenopus laevis have 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 genes and regulatory regions. The comparison of X. tropicalis and the two X. laevis genome duplicate can provide insight into mechanisms of genomic evolution.
Comparison of the gene-regulatory landscape of the two X.laevis hoxb4 homeologs at an early gastrula stage (Session et al., 2016)