A Genetic Approach to the Recruitment of PRC2 at the HoxD Locus

Schorderet, Patrick; Lonfat, Nicolas; Darbellay, Fabrice; Tschopp, Patrick; Gitto, Sandra; Soshnikova, Natalia; Duboule, Denis

doi:10.1371/journal.pgen.1003951

Cited by 37 publications

(44 citation statements)

References 74 publications

(100 reference statements)

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“…As the Fgf8-and 5′-Hoxb1-repressive RAREs have sequences similar to activating RAREs (Balmer and Blomhoff, 2005), we suggest that the ability of some RAREs to function repressively depends upon differences in RARE half-site spacing or upon other nearby cis sequences that affect chromatin architecture. The mechanisms controlling recruitment of polycomb to vertebrate genes are more complex than those in lower animals and are still being explored (Schorderet et al, 2013). Further studies designed to understand how RA recruits PRC2 to the repressive Fgf8 and 5′-Hoxb1 RAREs might provide additional clues to the mechanism of PRC2 recruitment in general.…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid controls body axis extension by directly repressing Fgf8 transcription

2014

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Retinoic acid (RA) generated in the mesoderm of vertebrate embryos controls body axis extension by downregulating Fgf8 expression in cells exiting the caudal progenitor zone. RA activates transcription by binding to nuclear RA receptors (RARs) at RA response elements (RAREs), but it is unknown whether RA can directly repress transcription. Here, we analyzed a conserved RARE upstream of Fgf8 that binds RAR isoforms in mouse embryos. Transgenic embryos carrying Fgf8 fused to lacZ exhibited expression similar to caudal Fgf8, but deletion of the RARE resulted in ectopic trunk expression extending into somites and neuroectoderm. Epigenetic analysis using chromatin immunoprecipitation of trunk tissues from E8.25 wild-type and Raldh2 −/− embryos lacking RA synthesis revealed RAdependent recruitment of the repressive histone marker H3K27me3 and polycomb repressive complex 2 (PRC2) near the Fgf8 RARE. The co-regulator RERE, the loss of which results in ectopic Fgf8 expression and somite defects, was recruited near the RARb RARE by RA, but was released from the Fgf8 RARE by RA. Our findings demonstrate that RA directly represses Fgf8 through a RARE-mediated mechanism that promotes repressive chromatin, thus providing valuable insight into the mechanism of RA-FGF antagonism during progenitor cell differentiation.

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Section: Discussionmentioning

confidence: 99%

Retinoic acid controls body axis extension by directly repressing Fgf8 transcription

2014

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“…Previous studies of the regulation of Hox expression by chromatin state have focused on the molecules responsible for histone methylation/demethylation -mainly members of the Polycomb repressive complex 2 (PRC2) and the jumonji-domain containing demethylases -rather than on HDACs (Lan et al, 2007;Schorderet et al, 2013;Williamson et al, 2012). However, histone methylation and acetylation have been shown to be interdependent and to act as a single pathway in several tissues (Kleer et al, 2003;van der Vlag and Otte, 1999), justifying our approach.…”

Section: Chromatin Opening Not Signal Integration Controls the Timimentioning

confidence: 99%

Diffusible signals and epigenetic timing cooperate in late proximo-distal limb patterning

et al. 2014

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Developing vertebrate limbs initiate proximo-distal patterning by interpreting opposing gradients of diffusible signaling molecules. We report two thresholds of proximo-distal signals in the limb bud: a higher threshold that establishes the upper-arm to forearm transition; and a lower one that positions a later transition from forearm to hand. For this last transition to happen, however, the signal environment seems to be insufficient, and we show that a timing mechanism dependent on histone acetylation status is also necessary. Therefore, as a consequence of the time dependence, the lower signaling threshold remains cryptic until the timing mechanism reveals it. We propose that this timing mechanism prevents the distal transition from happening too early, so that the prospective forearm has enough time to expand and form a properly sized segment. Importantly, the gene expression changes provoked by the first transition further regulate proximo-distal signal distribution, thereby coordinating the positioning of the two thresholds, which ensures robustness. This model is compatible with the most recent genetic analyses and underscores the importance of growth during the time-dependent patterning phase, providing a new mechanistic framework for understanding congenital limb defects.

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“…small intrinsic sequences within the cluster itself 20,21 as well as long-range enhancers. 22,23 In particular, 3-dimensional folding of chromatin permits long-range interactions between distal enhancer regions, including a global control region (GCR) and gene promoters, resulting in gene activation.…”

Section: Normal Developmental Regulation Of the Posterior Hoxd Clustementioning

confidence: 99%

Overexpression of HOX genes is prevalent in Ewing sarcoma and is associated with altered epigenetic regulation of developmental transcription programs

et al. 2014

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(2014) Overexpression of HOX genes is prevalent in Ewing sarcoma and is associated with altered epigenetic regulation of developmental transcription programs, Epigenetics, 9:12, 1613-1625, DOI: 10.4161/15592294.2014 The polycomb proteins BMI-1 and EZH2 are highly overexpressed by Ewing sarcoma (ES), a tumor of stem cell origin that is driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. In the current study we analyzed expression of transcription programs that are controlled by polycomb proteins during embryonic development to determine if they are abnormal in ES. Our results show that polycomb target gene expression in ES deviates from normal tissues and stem cells and that, as expected, most targets are relatively repressed. However, we also discovered a paradoxical up regulation of numerous polycomb targets and these were highly enriched for homeobox (HOX) genes. Comparison of HOX profiles between malignant and non-malignant tissues revealed a distinctive HOX profile in ES, which was characterized by overexpression of posterior HOXD genes. In addition, ectopic expression of EWS-FLI1 during stem cell differentiation led to aberrant up regulation of posterior HOXD genes. Mechanistically, this up regulation was associated with altered epigenetic regulation. Specifically, ES and EWS-FLI1C stem cells displayed a relative loss of polycomb-dependent H3K27me3 and gain of trithorax-dependent H3K4me3 at the promoters of posterior HOXD genes and also at the HOXD11.12 polycomb response element. In addition, a striking correlation was evident between HOXD13 and other genes whose regulation is coordinately regulated during embryonic development by distal enhancer elements. Together, these studies demonstrate that epigenetic regulation of polycomb target genes, in particular HOXD genes, is altered in ES and that these changes are mediated downstream of EWS-FLI1.

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A Genetic Approach to the Recruitment of PRC2 at the HoxD Locus

Cited by 37 publications

References 74 publications

Retinoic acid controls body axis extension by directly repressing Fgf8 transcription

Retinoic acid controls body axis extension by directly repressing Fgf8 transcription

Diffusible signals and epigenetic timing cooperate in late proximo-distal limb patterning

Overexpression of HOX genes is prevalent in Ewing sarcoma and is associated with altered epigenetic regulation of developmental transcription programs

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