Cis-regulatory elements: learning the language of gene regulation

At the heart of cellular decision-making lies a complex network of transcriptional regulatory interactions, determined by cis-regulatory elements (CREs). These genomic regions play a pivotal role in controlling gene expression and, consequently, cell fate allocation during development. Despite their critical importance, our understanding of how CREs function within gene regulatory networks (GRNs) remains surprisingly limited.

We use cutting-edge genomic and computational techniques to identify functional sites bound by specific transcription factors (TFs) within the network. These regulatory regions are then investigated and tested using transgenic and gene editing approaches. We have identified genomic elements in neural progenitors regulated by the key developmental signals and our aim is to understand the mechanisms by which these elements function. By integrating this information with transcriptomic data, we aim to reconstruct the transcriptional logic of the system. Our ultimate goal is to find the fundamental mechanisms underlying gene regulation and the function of GRNs.

Our research has uncovered two distinct ways in which CREs interpret patterning cues to produce differential gene expression. The first mechanism, which we term “differential binding,” uses a common set of CREs to control spatial gene activity. The specific genes activated in a cell are determined by integrating cell-type-specific inputs. The second mechanism, “differential accessibility,” involves specific chromatin remodelling that increase accessibility of a unique set of CREs, allowing binding of specific transcription factors. These findings have significant implications for our understanding of cellular reprogramming and the plasticity of cell types.

We’ve found that the precision of gene expression is influenced not only by individual CREs but also by the overall design of the GRN. Our research has shown that different levels of TF expression can result in distinct gene expression programs. Moreover, we’ve found that spatial heterogeneity caused by stochastic gene expression can be mitigated by the dynamics resulting from the GRN structure. We’ve termed this phenomenon “precision by design,” demonstrating that certain GRNs can effectively manage the inherent stochasticity of gene expression to ensure robust tissue patterning.

While our findings shed light on several aspects of CRE function within GRNs, they also highlight how much remains unknown. The complexity of these regulatory elements and their context-dependent behaviour present significant challenges. Future research will focus on developing more sophisticated tools to predict and validate CRE function, investigating the three-dimensional organization of CREs and its impact on gene regulation, and exploring the evolutionary conservation and divergence of CREs across species.

By continuing to dissect the mechanisms of CRE operation, we aim to gain a deeper understanding of the fundamental processes that shape cellular identity and tissue development.

SELECTED PUBLICATIONS

  • Isabel Zhang, Giulia LM Boezio, Jake Cornwall-Scoones, Thomas Frith, Ming Jiang, Michael Howell, Robin Lovell-Badge, Andreas Sagner, James Briscoe, M Joaquina Delás (2024)
    The cis-regulatory logic integrating spatial and temporal patterning in the vertebrate neural tube
    bioRxiv 2024.04.17.589864
  • Delás MJ, Kalaitzis CM, Fawzi T, Demuth M, Zhang I, Stuart HT, Costantini E, Ivanovitch K, Tanaka EM, Briscoe J. (2023)
    Developmental cell fate choice in neural tube progenitors employs two distinct cis-regulatory strategies.
    Developmental Cell. 58:3-17
  • Blassberg R, Patel H, Watson T, Gouti M, Metzis V, Delás MJ, Briscoe J. (2022)
    Sox2 levels regulate the chromatin occupancy of WNT mediators in epiblast progenitors responsible for vertebrate body formation.
    Nature Cell Biol. 24:633-644
  • Exelby K, Herrera-Delgado E, Perez LG, Perez-Carrasco R, Sagner A, Metzis V, Sollich P, Briscoe J. (2021)
    Precision of tissue patterning is controlled by dynamical properties of gene regulatory networks.
    Development 148:dev197566.
  • Metzis V, Steinhauser S, Pakanavicius E, Gouti M, Stamataki D, Ivanovitch K, Watson T, Rayon T, Mousavy Gharavy SN, Lovell-Badge R, Luscombe NM, Briscoe J. (2018)
    Nervous System Regionalization Entails Axial Allocation before Neural Differentiation.
    Cell 175: 1105-1118