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Mechanisms of Chromatin-based Epigenetic Inheritance

Objective

Epigenetic mechanisms heritably maintain gene expression states and chromosome organization across cell division. These include chromatin-based factors that are propagated independent of local DNA sequence elements, and are critical for normal development and prevent reprogramming, e.g. during induction of pluripotency. We focus on the role of nucleosomes, the histone-DNA complexes that make up chromatin. While prominently implicated in epigenetic memory, how histones and their local modifications can actually be inherited is largely unknown. We take aim at three fundamental aspects that we argue are central to this problem: stability of the epigenetic mark, self-templated duplication, and cell cycle coupling.
We developed a unique pulse-labeling strategy to determine whether silent and active chromatin can be inherited and how this relates to transcription, both in cancer cells and in vitro differentiating stem cells. By coupling this strategy to an imaging-based RNAi screen we aim to identify components controlling nucleosome assembly and heritability. We achieve this by focusing on the human centromere, the chromosome locus essential for chromosome segregation which serves as an ideal model for epigenetic memory. This locus is specified by nucleosomes carrying the histone H3 variant, CENP-A that we have previously shown to be highly stable in cycling cells and to be replicated in a strict cell cycle coupled manner. We build on our previous successes to uncover the molecular mechanism and cellular consequences of the coupling between CENP-A propagation and the cell cycle which we postulate, ensures proper centromere size and mitotic fidelity. Furthermore, by genome engineering we developed a strategy to delete an endogenous centromere to determine how centromeres can form de novo and how CENP-A chromatin, once formed, can template its own duplication. With this multi-facetted approach we aim to uncover general mechanistic principles of chromatin-based memory.

Call for proposal

ERC-2013-CoG
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Funding Scheme

ERC-CG - ERC Consolidator Grants

Host institution

FUNDACAO CALOUSTE GULBENKIAN
Address
Avenida Berna 45
1000 Lisboa
Portugal
Activity type
Research Organisations
EU contribution
€ 1 621 400
Principal investigator
Lars Jansen (Dr.)
Administrative Contact
Jose Mario Leite (Mr.)

Beneficiaries (1)

FUNDACAO CALOUSTE GULBENKIAN
Portugal
EU contribution
€ 1 621 400
Address
Avenida Berna 45
1000 Lisboa
Activity type
Research Organisations
Principal investigator
Lars Jansen (Dr.)
Administrative Contact
Jose Mario Leite (Mr.)