Poster Presentation ANZSCDB National Scientific Meeting 2019

Transcription factor kernel size and developmental timing contribute to variability in evolutionary conservation of tissue-specific enhancers (#Poster 21)

Markus Tondl 1 2 , Henry Chieu 1 , Michael Eichenlaub 1 , Louis Dang 1 , Mark Drvodelic 1 , Julian Stolper 1 , Mirana Ramialison 1
  1. ARMI, Monash University, Clayton, VIC, Australia
  2. Centre for Cancer Biology , University of South Australia, Adelaide, SA, Australia

The precise spatio-temporal activity of gene expression is controlled by genomic regulatory sequences, called cis-regulatory modules (CRMs) or enhancers. In comparison to genes, CRMs are less conserved between species and their precise DNA sequences evolve more rapidly. However, genomic studies have highlighted deep conservation of CRMs regulating genes controlling developmental processes and indicated a variable degree of evolutionary conservation among organs and cell-types. The reasons underlying this variable organ-specific evolutionary constraint on genomic CRMs is unknown. To assess the conservation differences in developmental enhancers among organs, we defined tissue-specific CRMs based on indicative histone modifications from the mouse ENCODE datasets. CRMs in brain and limb tissue show a higher degree of conservation among mammals, while CRMs from heart and liver appear to be less evolutionary constrained. In order to explain the differences in enhancer sequence conservation observed between organs, we investigated the contribution of transcription factors required for the development of a specific organ. We demonstrated that CRMs controlling genes coding for transcription factors, which are essential for the regulatory function of CRMs, are associated to higher degree of sequence conservation. In addition, we revealed that developmental timing of organ development is associated with the conservation degree of CRMs among mammals. At a given timepoint, organs close to maturation recruit enhancers with lower degree of sequence conservation. In summary, by bioinformatic mining of developmental enhancers accross 4 different organs, we shed light into the discrepancy observed in organ-specific enhancer conservation.