Birth defects, including those of the neural tube, eye and limb, are caused by improper cellular specification during embryogenesis. One of the primary embryological events necessary for the formation of these specialized tissues is the induction of mesoderm.
Our aim i s to identify the genomic and biochemical processes that drive the formation of mesoderm with the long-term goal of being able to generate more complex tissue types. While the signaling pathways that mediate mesoderm induction and many other embryological processes are well understood, how downstream transcription factors interface and communicate with chromatin is still a mystery. This juxtaposition is central for normal cellular specification, and is emerging as a critical element of cellular reprogramming. Therefore, inroads into this problem are important for understanding errors during development and will enable the establishment of better protocols for regenerative medicine. With the advent of genomic sequencing technologies, we can now ask fundamental questions about how signaling pathways interface with chromatin, whether they are permissive or active players in generating open chromatin structures and how these signals are communicated between neighboring cells. In this grant, we use Xenopus laevis and Xenopus tropicalis to address the involvement of the chromatin state and its interface with the Nodal signaling factor, smad2/3, during in vivo mesoderm induction. The wealth of embryological resources present in these species, the deep knowledge of their fate maps, combined with newly available genomic tools, presents a prime opportunity to revisit mechanisms underlying classic cell fate and inductive interactions using emerging modern technologies. The central hypothesis of this grant is that the interplay between chromatin state and smad2/3 underlie mesoderm induction and patterning.
Birth defects, including those of the neural tube, eye and limb, are caused by improper cellular specification during embryogenesis. The molecular signals underlying many of these disorders are understood, but how they interact with the genome is largely unknown. In this grant, we use the frog embryo to examine how signaling between neighboring cells influences their genomes, both in terms of chromatin signatures and in transcription factor occupancy. Our central hypothesis is that chromatin and its associated transcriptional states underlie the competency of tissues to communicate for normal embryonic development.
|Wills, Andrea E; Baker, Julie C (2015) E2a is necessary for Smad2/3-dependent transcription and the direct repression of lefty during gastrulation. Dev Cell 32:345-57|
|Spies, Noah; Smith, Cheryl L; Rodriguez, Jesse M et al. (2015) Constraint and divergence of global gene expression in the mammalian embryo. Elife 4:e05538|
|Benayoun, BÃ©rÃ©nice A; Pollina, Elizabeth A; Ucar, Duygu et al. (2014) H3K4me3 breadth is linked to cell identity and transcriptional consistency. Cell 158:673-88|
|Gupta, Rakhi; Wills, Andrea; Ucar, Duygu et al. (2014) Developmental enhancers are marked independently of zygotic Nodal signals in Xenopus. Dev Biol 395:38-49|
|Wills, Andrea E; Gupta, Rakhi; Chuong, Edward et al. (2014) Chromatin immunoprecipitation and deep sequencing in Xenopus tropicalis and Xenopus laevis. Methods 66:410-21|
|Finn, Elizabeth H; Smith, Cheryl L; Rodriguez, Jesse et al. (2014) Maternal bias and escape from X chromosome imprinting in the midgestation mouse placenta. Dev Biol 390:80-92|