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DREAM represses distinct targets by cooperating with different THAP domain proteins
Csenge Gal1, Francesco Nicola Carelli1, Alex Appert1
1Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Genetics, University of Cambridge, Cambridge, UK.
Cell Reports
|October 23, 2021
Summary
Two C. elegans THAP proteins, LIN-36 and LIN-15B, regulate the DREAM complex to control cell quiescence. They repress distinct gene sets through unique mechanisms, highlighting THAP proteins as key mediators of DREAM function.
Area of Science:
- Cellular biology
- Developmental biology
- Genetics
Background:
- The DREAM (dimerization partner [DP], retinoblastoma [Rb]-like, E2F, and MuvB) complex is crucial for controlling cellular quiescence.
- Its precise mechanism of gene repression remains incompletely understood.
- THAP domain proteins are implicated in cell-cycle regulation in humans, but their roles are poorly defined.
Purpose of the Study:
- To elucidate the mechanism by which THAP domain proteins LIN-36 and LIN-15B interact with and modulate the DREAM complex in C. elegans.
- To differentiate the roles and regulatory mechanisms of LIN-36 and LIN-15B in target gene repression.
- To explore the conserved function of THAP proteins in Rb/DREAM pathway regulation.
Main Methods:
- Co-localization studies to assess the interaction of LIN-15B and LIN-36 with the DREAM complex.
- Chromatin immunoprecipitation (ChIP) assays to analyze DREAM binding and histone modifications (H2A.Z, H3K9me2) at target genes.
- Identification of specific target genes repressed by LIN-36 and LIN-15B.
- Analysis of the DREAM subunit EFL-1/E2F specificity for LIN-36 targets.
Main Results:
- LIN-36 and LIN-15B co-localize with the DREAM complex and repress distinct sets of target genes via different mechanisms.
- LIN-36 promotes DREAM binding and H2A.Z enrichment at classical cell-cycle genes, with EFL-1/E2F being specific to these targets.
- LIN-15B facilitates H3K9me2 promoter marking to repress germline-specific genes in the soma.
- LIN-36 and LIN-15B differentially regulate DREAM binding to target loci.
Conclusions:
- THAP domain proteins LIN-36 and LIN-15B are key functional mediators of the DREAM complex in C. elegans.
- These proteins employ distinct mechanisms to achieve repression of specific target gene sets, contributing to cellular quiescence and developmental regulation.
- The findings suggest a conserved role for THAP proteins as critical components of the Rb/DREAM pathway across species.
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