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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE70074 | GEO | 2015/12/28

SECONDARY ACCESSION(S): PRJNA287569

REPOSITORIES: GEO

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Project description:In mammals, totipotent pre-implantation embryos are formed by fusion of highly differentiated oocytes and spermatozoa. Acquisition of totipotency concurs with remodeling of chromatin states of parental genomes (M-bM-^@M-^\epigenetic reprogrammingM-bM-^@M-^]), changes in maternally contributed transcriptome and proteome, and zygotic genome activation. Genomes of mature germ cells are more proficient in supporting embryonic development than those of somatic cells. It is currently unknown whether transgenerational inheritance of chromatin states present in mature gametes underlies the efficacy of early embryonic development after natural conception. Here, we show that Ring1 and Rnf2, two core components of the Polycomb Repressive Complex 1 (PRC1), serve redundant gene regulatory functions during oogenesis that are required to support embryonic development beyond the two-cell stage. Numerous developmental regulatory genes that are established Polycomb targets in various somatic cell types are de-repressed in Ring1/Rnf2 double mutant (dm) fully grown germinal vesicle (GV) oocytes. Translation of tested aberrant maternal transcripts is, however, delayed until after fertilization. Exchange of maternal pro-nuclei between control and Ring1/Rnf2 maternally dm early zygotes demonstrates an essential role for Ring1 and Rnf2 during oogenesis in defining cytoplasmic and nuclear maternal contributions that are both essential for proper initiation of embryonic development. A large number of genes up-regulated in Ring1/Rnf2 dm GV oocytes harbor PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) in spermatozoa and in embryonic stem cells (ESCs), and are repressed during normal oogenesis and early embryogenesis. These data strongly support the model that Polycomb acts in the female and male germline to silence differentiation inducing genes and to program chromatin states, thereby sustaining developmental potential across generations. Expression profiling of fully grown mouse GV oocytes was performed with the following genotypes: Ring1+/+Rnf2F/F (control), Ring1-/-Rnf2F/F (Ring1 mutant), Ring1+/+Rnf2F/FZp3-cre (Rnf2 mutant) and Ring1-/-Rnf2F/FZp3-cre (Ring1/Rnf2 double mutant). 12 samples were analyzed: 3 biological replicates of each of the 4 genotypes (Ring1+/+Rnf2F/F (control), Ring1-/-Rnf2F/F (Ring1 mutant), Ring1+/+Rnf2F/FZp3-cre (Rnf2 mutant) and Ring1-/-Rnf2F/FZp3-cre (Ring1/Rnf2 double mutant)). Each sample contains 50 GV oocytes.

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

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