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We focus on systems level “big picture” approaches to understand gene regulation and build gene regulatory networks during development and disease in zebrafish, chick, lamprey and human models.

Sauka spengler group gene regulatory networks in development and disease 19

Gene regulatory networks underlying neural crest development

The neural crest is a unique multipotent stem cell-like population that differentiates into diverse cell types, giving rise to structures such as neurons and glia of peripheral nervous system, bone, cartilage and connective tissue elements of craniofacial skeleton and body’s pigmentation. Defects in neural crest patterning are one of the most common causes of birth anomalies, accounting for up to one-third of all congenital birth defects. Due to their unique multipotency and developmental plasticity, there is a broad interest in using the regenerative capacity of neural crest cells in stem cell-based treatments. We aim to understand and decipher multiple levels of regulatory circuitry in neural crest cells, in order to ultimately reconstitute such programmes in stem cells and develop a means to achieve directed differentiation into specific neural crest derivatives using embryonic programmes.

A major focus of our research constitutes the analysis of the cis-regulatory network underlying neural crest development using genome-wide approaches such as (sc)RNA-, ChIP-, ATAC-seq and Capture-C. Over the past few years, we have catalogued an extensive cohort of non-coding cis-regulatory elements, known as “enhancers”, which serve as molecular switches that control specific  gene expression during neural crest ontogeny. Using genome-wide regulatory datasets we have built putative neural crest gene regulatory networks in chick, zebrafish and lamprey embryo, and are currently testing specific gene regulatory circuits, and investigating the contribution of TF binding dynamics and affinity in the development and evolution of the neural crest. 

Technology and tools for developmental genetics

Our lab develops genetic, molecular and –omics tools to probe GRNs in vivo, including a fully optimised CRISPR/Cas9 toolkit developed for the chick embryo to knockout genes or knockdown specific enhancers. We robustly use the methods developed for the chick model to screen non-coding mutations in ovarian cancer, validating data gathered from human patient samples in a reliable and efficient manner. In zebrafish, we developed a versatile, genetically encoded, binary in vivo biotinylation approach called biotagging which allows for tissue-specific biotinylation of defined targets. This is achieved by co-expression of proteins tagged with biotin acceptor peptide (Avi-tag) and bacterial biotin ligase, BirA in the same cells, allowing to isolate specific proteins or cell populations, using single step affinity purification procedure.  Isolated genetically defined cell populations are profiled using genome-wide assays, adapted to small cell numbers. We use this technology to analyse cellular circuitry at as many levels as possible and to address transcriptional and epigenomic mechanisms at play during neural crest development  and during cardiac regeneration in zebrafish.

Lab Alumni

Dorit Hockman

Amy Kenyon

Daria Gavriouchkina

Lucy Wheatley

Gunes Taylor

Upeka Senanayake