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Distinct roles for CKM-Mediator in controlling Polycomb-dependent chromosomal interactions and priming genes for
Emilia Dimitrova1, Angelika Feldmann2,3, Robin H van der Weide4,5
1Department of Biochemistry, University of Oxford, Oxford, UK. emilia.dimitrova@bioch.ox.ac.uk.
Nature Structural & Molecular Biology
|October 11, 2022
Summary
The cyclin-dependent kinase module Mediator complex (CKM-Mediator) facilitates Polycomb repressive complex 1 (PRC1) binding to inactive gene regulatory elements. This interaction is crucial for gene regulation but not for priming genes during differentiation.
Area of Science:
- Epigenetics and Gene Regulation
- Molecular Biology
- Developmental Biology
Background:
- Precise gene expression control is vital for development, relying on interactions between promoters and regulatory elements.
- The cyclin-dependent kinase module Mediator complex (CKM-Mediator) was previously thought to link regulatory elements and prime genes for differentiation in embryonic stem cells (ESCs).
Purpose of the Study:
- To investigate the role of CKM-Mediator in three-dimensional genome organization and gene regulation in ESCs.
- To elucidate the specific function of CKM-Mediator in interactions involving Polycomb repressive complexes (PRCs).
- To determine the mechanism by which CKM-Mediator primes genes for induction during differentiation.
Main Methods:
- Three-dimensional genome organization analysis in ESCs.
- Investigation of CKM-Mediator and Polycomb repressive complex 1 (cPRC1) interactions.
- Separation-of-function experiments to dissect molecular mechanisms.
Main Results:
- CKM-Mediator plays a minimal role in the overall 3D genome organization of ESCs.
- CKM-Mediator is essential for controlling interactions between inactive gene regulatory elements bound by PRCs, specifically by facilitating cPRC1 binding.
- The collaboration between CKM-Mediator and cPRC1 in long-range interactions does not prime genes for differentiation.
- Gene priming for differentiation relies on an interaction-independent mechanism involving CKM support of core Mediator engagement with promoters.
Conclusions:
- CKM-Mediator's primary role in ESCs involves facilitating cPRC1 binding to regulatory elements, rather than organizing the 3D genome.
- The mechanism of gene priming during differentiation is distinct from the interaction-dependent role of CKM-Mediator with cPRC1.
- CKM-Mediator supports core Mediator function at promoters during differentiation for gene activation.
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