lo 1 . PcG proteins in development and cell fate

What is the classical Polycomb phenotype in Drosophila?

Loss of HOX gene repression, resulting in ectopic expression of homeotic genes (like AbdB) in anterior body segments.

What happens to PcG when a cell changes fate or lineage?

PcG is evicted from target genes that become active and occupies new genes that become repressed.

What is Waddington's landscape in relation to PcG?

A model showing cell fate decisions where PcG helps maintain cells in their differentiated state by repressing alternative lineage genes.

How do PRC1 and PRC2 function at developmental genes?

They occupy promoters of developmentally repressed genes and maintain their repression.

What is the Drosophila homolog of mammalian CBX2/4/6/7/8?

Pc (Polycomb).

What is Sce the homolog of in mammals?

Mammalian RING1A and RING1B.

What happens in Drosophila Pc mutants?

Loss of PcG repressive activity results in ectopic expression of AbdB and other homeotic genes in anterior body segments.

Which subunits in Drosophila share the loss of homeotic gene repression phenotype when mutated?

Psc (PCGF homolog) and Phc (PHC1-3 homolog).

Why is the situation more complex in mammals compared to Drosophila?

PRC1 has expanded through gene duplication events, creating redundancy between subunits.

What is the advantage of gene duplication in the PcG system?

It allows sub-functionalization of some subunits (e.g., PCGF proteins in mouse/human have distinct functions).

How many paralogs of PRC1 subunits need to be mutated in mammals to observe Polycomb phenotypes?

Multiple paralogs need to be mutated/deleted to observe mis-expressed HOX genes in the developing embryo.

What does the double PCGF2 and PCGF4 mutant show in mouse embryos?

Homeotic transformations (mis-expressed HOX genes).

What does the double PHC1 and PHC2 mutant show in mouse embryos?

Homeotic transformations (mis-expressed HOX genes).

What is the phenotype of RING1B (Rnf2) knockout in mice?

Embryonic lethality around gastrulation stage.

What is the phenotype of EZH2 knockout in mice?

Embryonic lethality around gastrulation stage.

What is the phenotype of SUZ12 knockout in mice?

Embryonic lethality around gastrulation stage.

What is the phenotype of EED knockout in mice?

Embryonic lethality around gastrulation stage.

Why can't we detect homeotic transformations in RING1B, EZH2, SUZ12, or EED knockout embryos?

Because they die too early (at gastrulation stage) before Hox gene expression patterns can be observed.

What does the PR-DUB complex do?

It erases PRC1-mediated H2AK119ub1 through its catalytic subunit BAP1.

What is the paradox of PR-DUB catalytic activity?

PR-DUB mutants have homeotic transformations (Polycomb phenotype) but its catalytic activity opposes PRC1.

How does PR-DUB prevent accumulation of H2AK119ub1 and H3K27me3?

It prevents their accumulation across the genome, pulling PRC1 and PRC2 away from target sites.

What happens when PR-DUB is lost and H2AK119ub1 and H3K27me3 spread across the genome?

This causes global chromatin compaction and de-repression of PcG target gen