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Dissecting the regulatory logic of poised enhancers

Project description

The role of enhancers in the control of transcriptional precision during development

Despite the stochastic nature of transcription, during embryogenesis gene expression are implemented with great spatio-temporal precision. Scientists of the EU-funded PoisedLogic project are working under the hypothesis that a set of conserved cis-regulatory elements known as poised enhancers (PEs) are essential to achieve transcriptional precision, particularly during the establishment of anterior neural identity. PEs display a unique genetic composition since, in addition to clusters of transcription factor binding sites, they also contain CpG islands. These CpG island might confer PE with privileged chromatin, topological and regulatory features that enable the precise induction of the PE target genes. To test these hypotheses, the scientists will use embryonic stem cells as a model system in order to dissect the contribution of the different PE elements in the establishment of gene expression programmes during vertebrate embryogenesis.

Objective

The mechanisms that, despite the noisy and stochastic nature of transcription, enable the specific, precise and robust deployment of developmental gene expression programs are poorly understood. We previously identified Poised Enhancers (PEs) as a conserved set of cis-regulatory elements essential for the induction of major anterior neural genes upon ESC differentiation. Importantly, before becoming active in anterior neural progenitors, PEs are already bookmarked in embryonic stem cells (ESC) with unique chromatin and topological features, including binding by polycomb-group protein complexes (PcG) and pre-formed contacts with their target genes. Here I hypothesize that the competence of pluripotent cells to faithfully execute an anterior neural gene expression program is genetically encoded and dependent on the unique modular composition of PEs, consisting of a cluster of highly conserved transcription factor binding sites (TFBS) and a nearby CpG island (CGI). This modular composition might endow PEs with privileged regulatory properties, whereby the TFBS confer cis-activation capacity, while the CGI bestow permissive chromatin and topological features that boost the PEs regulatory activity and increase transcriptional precision. Furthermore, I hypothesize that, together with architectural proteins, this modular composition dictates the specificity, compatibility and responsiveness between PEs and their target genes. Using ESC as a tractable system and genomic, single-cell/single-allele and genetic engineering methods, we will systematically dissect the contribution of each PE module (i.e. TFBS, CGI) and of different epigenetic (e.g. PcG, DNA methylation) and architectural factors (e.g. Cohesin, CTCF) to the regulatory logic of PEs. By systematically dissecting PEs, our work will illuminate novel and general mechanisms whereby enhancer pre-marking facilitates the precise and specific establishment of gene expression programs during vertebrate embryogenesis.

Host institution

UNIVERSIDAD DE CANTABRIA
Net EU contribution
€ 1 199 567,25
Address
AVENIDA DE LOS CASTROS S/N
39005 Santander
Spain

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Region
Noroeste Cantabria Cantabria
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 1 997 662,00

Beneficiaries (2)