Decoding the Mammalian transcriptional Regulatory code in development and stimulatory responses

Objectif

Transcription factors (TF) regulate genome function by controlling gene expression. Comprehensive characterization of the in vivo binding of TF to the DNA in relevant primary models is a critical step towards a global understanding of the human genome. Recent advances in high-throughput genomic technologies provide an extraordinary opportunity to develop and apply systematic approaches to learn the underline principles and mechanisms of mammalian transcriptional networks. The premise of this proposal is that a tractable set of rules govern how cells commit to a specific cell type or respond to the environment, and that these rules are coded in regulatory elements in the genome. Currently our understanding of the mammalian regulatory code is hampered by the difficulty of directly measuring in vivo binding of large numbers of TFs to DNA across multiple primary cell types and their natural response to physiological stimuli.

Here, we overcome this bottleneck by systematically exploring the genomic binding network of 1. All relevant TFs of key hematopoietic cells in both steady state and under relevant stimuli. 2. Follow the changes in TF networks as cells differentiate 3. Use these models to engineer cell states and responses. To achieve these goals, we developed a new method for automated high throughput ChIP coupled to sequencing (HT-ChIP-Seq). We used this method to measure binding of 40 TFs in 4 time points following stimulation of dendritic cells with pathogen components. We find that TFs vary substantially in their binding dynamics, genomic localization, number of binding events, and degree of interaction with other TFs. The analysis of this data suggests that the TF network is hierarchically organized, and composed of different types of TFs, cell differentiation factors, factors that prime for gene induction, and factors that bind more specifically and dynamically. This proposal revisits and challenges the current understanding of the mammalian regulatory code.

Champ scientifique

Régime de financement

ERC-SG - ERC Starting Grant

Institution d’accueil

WEIZMANN INSTITUTE OF SCIENCE

Contribution de l’UE

€ 1 500 000,00

Adresse

HERZL STREET 234
7610001 Rehovot
Israël

Type d’activité

Higher or Secondary Education Establishments

Chercheur principal

Ido Amit (Dr.)

Contact administratif

Gabi Bernstein (Ms.)

Liens

Contacter l’organisation Site web

Coût total

Aucune donnée

Bénéficiaires (1)