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Polycomb group proteins adjust the threshold for retinoic acid mediated signaling during early proximal-distal patterning in forelimb development

ABSTRACT: Polycomb group (PcG) proteins play a pivotal role in epigenetically silencing development-related genes, restricting their expression to appropriate tissues. However, in some instances PcG target genes must also be dynamically regulated in response to developmental signals encountered during morphogenesis. Here we examine the role of PcG factors in early forelimb bud patterning, a process that relies on various morphogenetic signals. Depletion of Ring1 proteins, which are essential components of Polycomb repressive complex-1 (PRC1), led to dramatic deficiencies in forelimb formation and proximal-distal regionalization. Gene expression analysis identified Meis2 and Meis1 as critical PRC1 targets genes in early distal specification, with PcG proteins counteracting retinoic acid (RA) signaling to control their expression. Importantly, in this system, PcG factors appear to function by adjusting the threshold for RA signaling, revealing an unexpected role of polycomb proteins in dynamic gene regulation during development.

ORGANISM(S): Mus musculus

PROVIDER: GSE57990 | GEO | 2015/05/27

SECONDARY ACCESSION(S): PRJNA248654

REPOSITORIES: GEO

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Polycomb group proteins adjust the threshold for retinoic acid mediated signaling during early proximal-distal patterning in forelimb development

Project description:Polycomb group (PcG) proteins play a pivotal role in epigenetically silencing development-related genes, restricting their expression to appropriate tissues. However, in some instances PcG target genes must also be dynamically regulated in response to developmental signals encountered during morphogenesis. Here we examine the role of PcG factors in early forelimb bud patterning, a process that relies on various morphogenetic signals. Depletion of Ring1 proteins, which are essential components of Polycomb repressive complex-1 (PRC1), led to dramatic deficiencies in forelimb formation and proximal-distal regionalization. Gene expression analysis identified Meis2 and Meis1 as critical PRC1 targets genes in early distal specification, with PcG proteins counteracting retinoic acid (RA) signaling to control their expression. Importantly, in this system, PcG factors appear to function by adjusting the threshold for RA signaling, revealing an unexpected role of polycomb proteins in dynamic gene regulation during development. [Affymetrix] Mouse E10.5 forelimb buds of Ring1A-KO, Ring1A/B-dKO and RA-treated wild type were used for RNA extraction and hybridization on Affymetrix microarrays. [Agilent] ChIP analysis of mouse E10.5 whole forelimb buds against anti-H3K27me3 antibody.

2015-05-27 | E-GEOD-57990 | biostudies-arrayexpress

Variant PRC1 competes with retinoic acid-related signals to repress Meis2 in distal forelimb bud

Project description:Suppression of Meis genes in the distal limb bud is required for Proximal-Distal (PD) specification of the forelimb. Polycomb group (PcG) factors play a role in downregulation of retinoic acid (RA)-related signals in the distal forelimb bud, causing Meis repression. It is, however, not known if downregulation of RA-related signals and PcG-mediated proximal genes repression are functionally linked. Here, we reveal that PcG factors and RA-related signals antagonize each other to polarize Meis2 expression along the PD axis. With mathematical modeling and simulation, we propose that PcG factors are required to adjust the threshold for RA-related signaling to regulate Meis2 expression. Finally, we show that a variant Polycomb repressive complex 1 (PRC1), incorporating PCGF3 and PCGF5, represses Meis2 expression in the distal limb bud. Taken together, we reveal a previously unknown link between PcG proteins and downregulation of RA-related signals to mediate the phase transition of Meis2 transcriptional status during forelimb patterning.

2018-09-07 | GSE105206 | GEO

RING1 links retinoic acid signaling to the early proximal-distal specification of forelimb bud via Meis2 repression (ChIP-Seq)

Project description:Polycomb group (PcG) proteins play a pivotal role in silencing of development-related genes and contribute to maintain various stem and precursor cells and regulate their differentiation. However, it is not well understood how PcG factors regulate dynamic and complex morphogenetic processes particularly in mammals. In this study, we focused on proximal-distal (PD) patterning of forelimb bud to elucidate how PcG factors contribute to regulation of morphogenetic processes that depends on developmental signals. Depletion of RING1 proteins, which are common components of both canonical and variant Polycomb repressive complex-1 (PRC1), led to dramatic deficiencies in forelimb formation. By using Ring1-deficient forelimb buds, we revealed the early defects in distal specification, which is due to the functional coupling of RING1 and retinoic acid (RA) signaling. RING1 activity is shown to antagonize with RA signals at Meis2 and likely Meis1, which are superior suppressors of distal formation program, in the prospective distal region of outgrowing forelimb bud. This study exhibits a first example showing how PcG factors interplay with developmental signals to mediate compartmentalization of elongating anlagen by regulating the expression of developmental genes.

2015-12-28 | GSE70076 | GEO

RING1 links retinoic acid signaling to the early proximal-distal specification of forelimb bud via Meis2 repression (mRNA)

2015-12-28 | GSE70075 | GEO

RING1 links retinoic acid signaling to the early proximal-distal specification of forelimb bud via Meis2 repression (ChIP-chip)

2015-12-28 | GSE70074 | GEO

RING1 proteins contribute to early proximal-distal specification of the forelimb bud by restricting Meis2 expression

Project description:Polycomb group (PcG) proteins play a pivotal role in silencing developmental genes and help to maintain various stem and precursor cells and regulate their differentiation. PcG factors also regulate dynamic and complex regional specification, particularly in mammals, but this activity is mechanistically not well understood. In this study, we focused on proximal-distal (PD) patterning of the mouse forelimb bud to elucidate how PcG factors contribute to a regional specification process that depends on developmental signals. Depletion of the RING1 proteins RING1A (RING1) and RING1B (RNF2), which are essential components of Polycomb repressive complex 1 (PRC1), led to severe defects in forelimb formation along the PD axis. We show that preferential defects in early distal specification in Ring1A/B-deficient forelimb buds accompany failures in the repression of proximal signal circuitry bound by RING1B, including Meis1/2, and the activation of distal signal circuitry in the prospective distal region. Additional deletion of Meis2 induced partial restoration of the distal gene expression and limb formation seen in the Ring1A/B-deficient mice, suggesting a crucial role for RING1-dependent repression of Meis2 and likely also Meis1 for distal specification. We suggest that the RING1-MEIS1/2 axis is regulated by early PD signals and contributes to the initiation or maintenance of the distal signal circuitry. This SuperSeries is composed of the SubSeries listed below.

2015-12-28 | GSE70077 | GEO

A Polycomb Repressive Complex 1 proteome from Drosophila cells

Project description:Polycomb Group (PcG) proteins regulate gene expression through changes to chromatin structure and are essential for development. PcG proteins function together with the Trithorax Group (TrxG) proteins, which affect diverse steps in transcription activation. The PcG and TrxG are genetically and functionally antagonistic, and current understanding suggests a balance of their activities can maintain a wide range of transcription states. PcG and TrxG proteins assemble into a series of complexes. How these complexes work together, how PcG complexes are recruited to target genes, and whether other proteins are involved in their regulation of gene expression remain open questions. We carried out tandem affinity purification followed by mass spectrometry (TAP-MS) on two core components of Drosophila Polycomb Repressive Complex 1 (PRC1). Our data reveal a network of interactions among PcG complexes, and extensive co-purification of TrxG complexes with PRC1. We co-purified >50 transcription factors with PRC1 that were not previously linked to the PcG. Finally, we identify novel co-purifying complexes, including HP1c and PCNA handling complexes. Our resource of candidate PRC1 interacting proteins generate new hypotheses for PRC1 function.

2023-04-20 | MSV000091759 | MassIVE

Decoupling of H2Aub and H3K27me3 in early mammalian development

Project description:Polycomb group (PcG) proteins play critical roles during development. H2Aub and H3K27me3 are deposited by Polycomb-repressive Complex 1 and 2 (PRC1/2) respectively, and largely overlap in the genome due to mutual recruitment of the two complexes. However, whether PRC1/H2Aub and PRC2/H3K27me3 also function independently remains elusive. Here we uncovered a large-scale decoupling of H2Aub and H3K27me3 in preimplantation mouse embryos, at both canonical PcG targets and broad distal domains. H2Aub represses future bivalent genes without H3K27me3 but does not contribute to maintenance of H3K27me3-dependent non-canonical imprinting. Our study thus revealed their distinct and independent functions in early mammalian development.

2021-11-17 | GSE169199 | GEO

Chromatin immunoprecipitation of mouse polycomb group (PcG) proteins in embryonic stem cells

Project description:Polycomb group (PcG) proteins are highly conserved from flies to mammals and many of these factors have essential roles in early embryonic development. PcG proteins comprise two multimeric complexes, the Polycomb Repressive complexes 1 and 2 (PRC1 and 2), which have been shown to repress transcription through epigenetic modification of chromatin structure. To gain insight into the role of Polycomb in early development, we have identified PRC1 and PRC2 target genes in mouse embryonic stem (ES) cells using genome-scale location analysis. We found that PRC2 occupies many genes that encode key regulators of development including those encoding transcription factors and components of signaling pathways. These genes are repressed and contain nucleosomes methylated at lysine 27 on histone H3. The majority of PRC2 bound and methylated target genes are co-occupied by PRC1 indicating that these complexes function at a similar set of genes in ES cells. Lack of PRC1 or PRC2 subunits in ES cells results in derepression of target genes and loss of pluripotency. These results provide insight into how PcG proteins contribute to the maintenance of stem cell identity.

2006-05-09 | E-WMIT-12 | biostudies-arrayexpress

Transcriptome analysis of bone marrow in Phc2 knock out mice

Project description:This study investigated the biological function of Phc2 by Phc2 knock out mice. Polycomb group (PcG) proteins function as transcriptional repressors of target genes by mainly modulating histone methylation. The canonical Polycomb repressor complex 1 (PRC1), type of PcG proteins, recognizes and binds to H3K27me3 to sustain the transcriptional repression of a target gene. To investigate the function of canonical PRC1, We identified potential function of Phc2 that is component of the canonical PRC1 by Phc2 knock out mice.

2019-07-10 | GSE128705 | GEO

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