RT Journal
A1 Riley, Daniela M.
A1 Elsayed, Randa
A1 Walsh, Mark D.
A1 Johal, Simaran
A1 Lin, Ying
A1 Walton, Harry
A1 Bretschneider, Till
A1 Ott, Sascha
A1 Nelson, Andrew C.
T1 Functional genomics analysis of developing zebrafish and human endoderm reveals highly conserved cis-regulatory modules acting during vertebrate organogenesis
JF Genome Research 
JO Genome Research 
YR 2026 
FD March 04 
DO 10.1101/gr.280838.125 
UL http://genome.cshlp.org/content/early/2026/03/19/gr.280838.125.abstract 
AB Although vertebrate species are superficially diverse, they share key commonalities in terms of overall morphology, as well as organ configuration and function. Maintenance of these traits during evolution is partially explained by the conservation of critical genes governing embryonic development. However, for conserved genes to deliver consistent developmental outcomes between species, similar gene regulatory programs and gene expression patterns must also be maintained. The endoderm germ layer makes major contributions to the respiratory and gastrointestinal tracts and to associated organs including the liver and pancreas. We used functional genomic approaches to identify highly conserved endodermal cis-regulatory modules (CRMs) functioning across the 400 million years of evolution separating zebrafish and humans. Our analyses suggest that there are few endoderm-specific CRMs, with many CRMs governing pancreas development also likely acting within the nervous system. Furthermore, these highly conserved CRMs are strongly enriched for binding sites of “neuro-pancreatic” transcription factors governing both pancreas and nervous system development, potentially suggesting function across these distinct organ systems. Additionally, we identify highly conserved CRMs potentially participating in endodermal patterning of adjacent craniofacial structures and sensory tissues. The highly conserved CRMs we identify are characterized by conserved patterns of transcription factor binding site co-occurrence. However, rigid arrangement of binding sites is not a common characteristic of the identified CRMs, suggesting more complex or individual grammatical rules. Overall, our analyses provide key insights into critical gene regulatory control during vertebrate endoderm organogenesis and define a compendium of highly conserved CRMs that should be prioritized for analysis of neuro-pancreatic gene transcriptional control and of anterior embryonic patterning.