Pioneer factor Pax7 deploys a stable enhancer repertoire for specification of cell fate

Mayran, Alexandre; Khetchoumian, Konstantin; Hariri, Fadi; Pastinen, Tomi; Gauthier, Yves; Balsalobre, Aurélio; Drouin, Jacques

doi:10.1038/s41588-017-0035-2

Cited by 144 publications

(179 citation statements)

References 41 publications

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“…S2), we determined that promoter regions and 5' untranslated regions (5'UTR) were over-represented in the accessome ( P <0.01, binomial test; Fig. S1) , and we detected nucleosome footprints immediately upstream of TSSs , consistent with a tendency for constitutive accessibility [29][30][31] ( Fig. S2).…”

Section: A Reference Accessome For Cardiopharyngeal Developmentmentioning

confidence: 61%

Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices

Racioppi

Wiechecki

Christiaen

2019

Preprint

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In embryos, lineage-specific profiles of chromatin accessibility control gene expression by modulating transcription, and thus impact multipotent progenitor states and subsequent fate choices. Subsets of cardiac and pharyngeal/head muscles share a common origin in the cardiopharyngeal mesoderm, but the chromatin landscapes that govern multipotent progenitors’ competence and early fate choices remain largely elusive. Here, we leveraged the simplicity of the chordate model Ciona to profile chromatin accessibility through stereotyped transitions from naive Mesp+ mesoderm to distinct fate-restricted heart and pharyngeal muscle precursors. An FGF-Foxf pathway acts in multipotent progenitors to establish cardiopharyngeal-specific patterns of accessibility, which govern later heart vs. pharyngeal muscle-specific expression profiles, demonstrating extensive spatiotemporal decoupling between early cardiopharyngeal enhancer accessibility and late cell-type-specific activity. Combinations of cis-regulatory elements with distinct chromatin accessibility profiles are required to activate of Ebf and Tbx1/10, two key determinants of cardiopharyngeal fate choices. We propose that this higher order combinatorial logic increases the repertoire of regulatory inputs that control gene expression, through either accessibility and/or activity, thus fostering spatially and temporally accurate fate choices.

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Section: A Reference Accessome For Cardiopharyngeal Developmentmentioning

confidence: 61%

Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices

Racioppi

Wiechecki

Christiaen

2019

Preprint

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“…Dissection of proximal and distal of forelimb buds from wild type embryos and distal forelimb buds of Hox13 -/embryos 13 were performed at E11.5. All samples for ATAC-seq were processed as previously described 27…”

Section: Atac-seqmentioning

confidence: 99%

HOX13-dependent chromatin accessibility modulates the target repertoires of the HOX factors

Desanlis

Kherdjemil

Mayran

et al. 2019

Preprint

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Hox genes encode essential transcription factors that control patterning during embryonic development. Distinct combinations of nested Hox expression domains establish cell and tissue identities 1-3 . Consequently, spatial or temporal de-regulation of Hox genes can cause severe alterations of the body plan 3 . While HOX factors have very similar DNA binding motifs, their binding specificity is, in part, mediated by co-factors 4-6 . Yet, the interplay between HOX binding specificities and the cellular context remains largely elusive. To gain insight into this question, we took advantage of developing limbs for which the differential expression of Hox genes is well-characterized 7 . We show that the transcription factors HOXA13 and HOXD13 (hereafter referred as HOX13) allow another HOX factor, HOXA11, to bind loci initially assumed to be HOX13-specific. Importantly, HOXA11 is unable to bind these loci in distal limbs lacking HOX13 function indicating that HOX13 modulates HOXA11 target repertoire.In addition, we find that the HOX13 factors implement the distal limb developmental program by triggering chromatin opening, a defining property of pioneer factors 8,9 . Finally, single cell analysis of chromatin accessibility reveals that HOX13 factors pioneer chromatin opening in a lineage specific manner. Together, our data uncover a new mechanism underlying HOX binding specificity, whereby tissue-specific variations in the target repertoire of HOX factors rely, at least in part, on HOX13-dependent chromatin accessibility.

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“…39 PAX7 encodes a paired box transcription factor required for embryonal neural development 40 and renewal of skeletal muscle stem cells. 41 Translocations involving PAX7 and FKHR are found in the majority of alveolar rhabdomyosarcomas (ARMS), indicating a role of PAX7 in the pathogenesis of myogenic tumors.…”

Section: Discussionmentioning

confidence: 99%

Systematic identification of cancer-specific MHC-binding peptides with RAVEN

Baldauf¹,

Gerke²,

Kirschner

et al. 2018

OncoImmunology

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Immunotherapy can revolutionize anti-cancer therapy if specific targets are available. Immunogenic peptides encoded by cancer-specific genes (CSGs) may enable targeted immunotherapy, even of oligo-mutated cancers, which lack neo-antigens generated by protein-coding missense mutations. Here, we describe an algorithm and user-friendly software named RAVEN (Rich Analysis of Variable gene Expressions in Numerous tissues) that automatizes the systematic and fast identification of CSG-encoded peptides highly affine to Major Histocompatibility Complexes (MHC) starting from transcriptome data. We applied RAVEN to a dataset assembled from 2,678 simultaneously normalized gene expression microarrays comprising 50 tumor entities, with a focus on oligo-mutated pediatric cancers, and 71 normal tissue types. RAVEN performed a transcriptome-wide scan in each cancer entity for gender-specific CSGs, and identified several established CSGs, but also many novel candidates potentially suitable for targeting multiple cancer types. The specific expression of the most promising CSGs was validated in cancer cell lines and in a comprehensive tissue-microarray. Subsequently, RAVEN identified likely immunogenic CSG-encoded peptides by predicting their affinity to MHCs and excluded sequence identity to abundantly expressed proteins by interrogating the UniProt protein-database. The predicted affinity of selected peptides was validated in T2-cell peptide-binding assays in which many showed binding-kinetics like a very immunogenic influenza control peptide. Collectively, we provide an exquisitely curated catalogue of cancer-specific and highly MHC-affine peptides across 50 cancer types, and a freely available software (https://github.com/JSGerke/RAVENsoftware) to easily apply our algorithm to any gene expression dataset. We anticipate that our peptide libraries and software constitute a rich resource to advance anti-cancer immunotherapy.

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Pioneer factor Pax7 deploys a stable enhancer repertoire for specification of cell fate

Cited by 144 publications

References 41 publications

Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices

Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices

HOX13-dependent chromatin accessibility modulates the target repertoires of the HOX factors

Systematic identification of cancer-specific MHC-binding peptides with RAVEN

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