The PAX3 Paired Domain and Homeodomain Function as a Single Binding Module In Vivo to Regulate Subnuclear Localization and Mobility by a Mechanism That Requires Base-Specific Recognition

Corry, Gareth N.; Raghuram, Nikhil; Missiaen, Kristal; Hu, Ninghe; Hendzel, Michael J.; Underhill, D. Alan

doi:10.1016/j.jmb.2010.07.016

Cited by 12 publications

(11 citation statements)

References 89 publications

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“…1d), indicating that an intact homeodomain in Pax3 is required for major satellite binding. This result was in line with previous reports describing pericentric localization of the isolated Pax3 homeodomain 23 .…”

supporting

confidence: 94%

A transcription factor–based mechanism for mouse heterochromatin formation

Bulut-Karslıoğlu

Perrera

Scaranaro

et al. 2012

Nat Struct Mol Biol

160

139

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1 0 2 3 a r t i c l e s RESULTS Pax3 binds to major satellite repeatsTo examine transcription factors operating at heterochromatic regions, we first investigated transcription factors that had been shown to associate with heterochromatic core components 15 . Pax3 emerged as a particularly notable candidate because it has been reported to interact with both heterochromatin protein-1 (HP1) and the transcriptional regulator Kap1(Trim28) 16 . In addition, subrepeat Heterochromatin is important for genome integrity and stabilization of gene-expression programs. We have identified the transcription factors Pax3 and Pax9 as redundant regulators of mouse heterochromatin, as they repress RNA output from major satellite repeats by associating with DNA within pericentric heterochromatin. Simultaneous depletion of Pax3 and Pax9 resulted in dramatic derepression of major satellite transcripts, persistent impairment of heterochromatic marks and defects in chromosome segregation. Genome-wide analyses of methylated histone H3 at Lys9 showed enrichment at intergenic major satellite repeats only when these sequences retained intact binding sites for Pax and other transcription factors. Additionally, bioinformatic interrogation of all histone methyltransferase Suv39h-dependent heterochromatic repeat regions in the mouse genome revealed a high concordance with the presence of transcription factor binding sites. These data define a general model in which reiterated arrangement of transcription factor binding sites within repeat sequences is an intrinsic mechanism of the formation of heterochromatin.npg

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supporting

confidence: 94%

A transcription factor–based mechanism for mouse heterochromatin formation

Bulut-Karslıoğlu

Perrera

Scaranaro

et al. 2012

Nat Struct Mol Biol

160

139

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“…A subset of family members, including Pax3, contain an additional DNA8-binding domain known as a paired-type homeodomain (HD) (33, 41). The PD and HD are functionally interdependent and capable of modifying Pax binding to DNA (13). Although the Myf5 ES enhancer and promoter do not contain a consensus PD motif, multi-species sequence alignments revealed a highly conserved single HD motif (TAAT) at −79 relative to the transcription start site in mouse.…”

Section: Resultsmentioning

confidence: 99%

Pax3 synergizes with Gli2 and Zic1 in transactivating the Myf5 epaxial somite enhancer

Himeda

Barro

Emerson

2013

Developmental Biology

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Both Glis, the downstream effectors of hedgehog signaling, and Zic transcription factors are required for Myf5 expression in the epaxial somite. Here we demonstrate a novel synergistic interaction between members of both families and Pax3, a paired-domain transcription factor that is essential for both myogenesis and neural crest development. We show that Pax3 synergizes with both Gli2 and Zic1 in transactivating the Myf5 epaxial somite (ES) enhancer in concert with the Myf5 promoter. This synergy is dependent on conserved functional domains of the proteins, as well as on a novel homeodomain motif in the Myf5 promoter and the essential Gli motif in the ES enhancer. Importantly, overexpression of Zic1 and Pax3 in the 10T1/2 mesodermal cell model results in enrichment of these factors at the endogenous Myf5 locus and induction of Myf5 expression. In our previous work, we showed that by enhancing nuclear translocation of Gli factors, Zics provide spatiotemporal patterning for Gli family members in the epaxial induction of Myf5 expression. Our current study indicates a complementary mechanism in which association with DNA-bound Pax3 strengthens the ability of both Zic1 and Gli2 to transactivate Myf5 in the epaxial somite.

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“…The transcriptional activity of Pax3 depends on the presence of two independent DNA binding domains, the paired domain and the homeodomain, which are conserved across evolution [12, 13]. Pax3, its homologous Pax7, and other Pax‐family members also share a short sequence named the octapeptide, which has been proposed to bind the corepressor Groucho [14].…”

Section: Introductionmentioning

confidence: 99%

Functional Dissection of Pax3 in Paraxial Mesoderm Development and Myogenesis

et al. 2012

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The paired box transcription factor Pax3 is well-known as a major regulator of embryonic myogenesis. Before Pax3 expression becomes restricted to the dermomyotome, this transcription factor is also expressed in the developing somites. The role of Pax3 at this early stage is unclear, in particular because of the scarce frequency of Pax3-positive cells in the early mouse embryo. Inducible gene expression in embryonic stem (ES) cells represents an excellent tool to overcome this limitation, since it can provide large quantities of otherwise rare embryonic populations expressing a factor of interest. Here we used engineered mouse ES cells to perform a functional analysis of Pax3 with the aim to identify the molecular determinants involved in the early functions of this transcription factor. We find that Pax3 induction during embryoid body (EB) differentiation results in the up-regulation of genes expressed in the presomitic and somitic mesoderm. Moreover, we show that paraxial mesoderm induced by transient expression of Pax3 is not irreversibly committed to myogenesis, rather requires sustained Pax3 expression. Using a series of deletion mutants of Pax3, which differentially affect its transcriptional activity, we map protein domains necessary for induction of paraxial mesoderm and induction of the myogenic program. The paired, homeo- and transcriptional activation domains were each required for both processes, however the paired-c-terminal RED domain showed a paraxial mesoderm-specific activity that was dispensable for myogenesis. These findings demonstrate and provide mechanistic insight into an early role for Pax3 in the generation of paraxial mesoderm.

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The PAX3 Paired Domain and Homeodomain Function as a Single Binding Module In Vivo to Regulate Subnuclear Localization and Mobility by a Mechanism That Requires Base-Specific Recognition

Cited by 12 publications

References 89 publications

A transcription factor–based mechanism for mouse heterochromatin formation

A transcription factor–based mechanism for mouse heterochromatin formation

Pax3 synergizes with Gli2 and Zic1 in transactivating the Myf5 epaxial somite enhancer

Functional Dissection of Pax3 in Paraxial Mesoderm Development and Myogenesis

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