BRACHYURY directs histone acetylation to target loci during mesoderm development

Beisaw, Arica; Tsaytler, Pavel; Koch, Frank‐Thomas; Schmitz, Sandra U.; Melissari, Maria-Theodora; Senft, Anna D.; Wittler, Lars; Pennimpede, Tracie; Macura, Karol; Herrmann, Bernhard G.; Grote, Phillip

doi:10.15252/embr.201744201

Cited by 29 publications

(34 citation statements)

References 63 publications

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“…Eomes and Brachyury, the exact molecular mechanisms are just starting to be explored [58][59][60][61][62] . Previous reports have suggested that pluripotent cells have globally open chromatin that becomes progressively restricted during differentiation 63 .…”

Section: Despite the Wealth Of Knowledge On Transcriptional Regulatiomentioning

confidence: 99%

EomesandBrachyurycontrol pluripotency exit and germ layer segregation by changes of chromatin state

Tošić

Kim

Pavlovic

et al. 2019

Preprint

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The first lineage specification of pluripotent mouse epiblast segregates neuroectoderm (NE) from mesoderm and endoderm (ME) by currently poorly understood mechanisms.Here we demonstrate that the induction of any ME-gene programs critically relies on the T-box (Tbx) transcription factors Eomes and Brachyury that concomitantly repress pluripotency and NE gene programs. Tbx-deficient cells retain pluripotency and differentiate to NE lineages despite the presence of ME-inducing signals TGFb/Nodal and WNT. Pluripotency and NE gene networks are additionally repressed by Tbx-induced ME factors, demonstrating a remarkable redundancy in program regulation to safeguard mutually exclusive lineage specification. Chromatin analyses revealed that accessibility of ME-gene enhancers depends on Tbx-binding, while NE-gene enhancers are accessible and activation-primed already at pluripotency state. This asymmetry of chromatin landscape thus explains the default differentiation of pluripotent cells to NE in the absence of MEinduction mediated through the activating and repressive functions of early Tbx factors Eomes and Brachyury.

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Section: Despite the Wealth Of Knowledge On Transcriptional Regulatiomentioning

confidence: 99%

EomesandBrachyurycontrol pluripotency exit and germ layer segregation by changes of chromatin state

Tošić

Kim

Pavlovic

et al. 2019

Preprint

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“…For example, Yamanaka factors ( OCT4 , SOX2 , KLF4 , and cMYC ), which are highly expressed in ESCs, have been shown to participate in the regulation of developmental pathways and the pluripotency of ESCs. 3 During ESCDCD, MES specification is controlled by the T-box TFs ( T and EOMES ), 4 , 5 which could active another TF ( MESP1 ), in turn driving the expression of cardiac TFs along with repressing these genes related to pluripotency, 6 , 7 , 8 Moreover, the BMP signaling pathway is triggered to induce TFs such as Tbx5 , Mef2c , and Nkx2.5 for promoting the differentiation of CP. 9 , 10 In addition, UPS-mediated ASB2 proteolysis can play a role in the maturation of CM by targeting TF3 ( TCF3 ).…”

Section: Introductionmentioning

confidence: 99%

Molecular Signatures and Networks of Cardiomyocyte Differentiation in Humans and Mice

Wang

et al. 2020

Molecular Therapy - Nucleic Acids

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Cardiomyocyte differentiation derived from embryonic stem cells (ESCs) is a complex process involving molecular regulation of multiple levels. In this study, we first identify and compare differentially expressed gene (DEG) signatures of ESC-derived cardiomyocyte differentiation (ESCDCD) in humans and mice. Then, the multiscale embedded gene co-expression network analysis (MEGENA) of the human ESCDCD dataset is performed to identify 212 significantly co-expressed gene modules, which capture well the regulatory information of cardiomyocyte differentiation. Three modules respectively involved in the regulation of stem cell pluripotency, Wnt, and calcium pathways are enriched in the DEG signatures of the differentiation phase transition in the two species. Three human-specific cardiomyocyte differentiation phase transition modules are identified. Moreover, the potential regulation mechanisms of transcription factors during cardiomyocyte differentiation are also illustrated. Finally, several novel key drivers of ESCDCD are identified with the evidence of their expression during mouse embryonic cardiomyocyte differentiation. Using an integrative network analysis, the core molecular signatures and gene subnetworks (modules) underlying cardiomyocyte lineage commitment are identified in both humans and mice. Our findings provide a global picture of gene-gene co-regulation and identify key regulators during ESCDCD.

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“…However, T-box factors may differ in how they regulate transcription once they bind to DNA; acting as transcriptional activators, repressors or as both. Interestingly, in addition to facilitating DNA binding, the T-domain can also interact with chromatin remodelers ( Beisaw et al, 2018 ; Istaces et al, 2019 ; Lewis et al, 2007 ; Miller et al, 2008 , 2010 ), including histone methyltransferases, demethylases, acetyltransferases and deacetyltransferases, and these interactions regulate the permissiveness of the chromatin environment. Outside of the T-domain, the proteins share little similarity.…”

Section: Introductionmentioning

confidence: 99%

Functionally distinct roles for T and Tbx6 during mouse development

et al. 2020

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The mouse T-box transcription factors T and Tbx6 are co-expressed in the primitive streak and have unique domains of expression; T is expressed in the notochord, while Tbx6 is expressed in the presomitic mesoderm. T-box factors are related through a shared DNA binding domain, the T-domain, and can therefore bind to similar DNA sequences at least in vitro. We investigated the functional similarities and differences of T and Tbx6 DNA binding and transcriptional activity in vitro and their interaction genetically in vivo. We show that at one target, Dll1, the T-domains of T and Tbx6 have different affinities for the binding sites present in the mesoderm enhancer. We further show using in vitro assays that T and Tbx6 differentially affect transcription with Tbx6 activating expression tenfold higher than T, that T and Tbx6 can compete at target gene enhancers, and that this competition requires a functional DNA binding domain. Next, we addressed whether T and Tbx6 can compete in vivo. First, we generated embryos that express Tbx6 at greater than wild-type levels embryos and show that these embryos have short tails, resembling the T heterozygous phenotype. Next, using the dominant-negative TWis allele, we show that Tbx6+/− TWis/+ embryos share similarities with embryos homozygous for the Tbx6 hypomorphic allele rib-vertebrae, specifically fusions of several ribs and malformation of some vertebrae. Finally, we tested whether Tbx6 can functionally replace T using a knockin approach, which resulted in severe T null-like phenotypes in chimeric embryos generated with ES cells heterozygous for a Tbx6 knockin at the T locus. Altogether, our results of differences in affinity for DNA binding sites and transcriptional activity for T and Tbx6 provide a potential mechanism for the failure of Tbx6 to functionally replace T and possible competition phenotypes in vivo.

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BRACHYURY directs histone acetylation to target loci during mesoderm development

Cited by 29 publications

References 63 publications

EomesandBrachyurycontrol pluripotency exit and germ layer segregation by changes of chromatin state

EomesandBrachyurycontrol pluripotency exit and germ layer segregation by changes of chromatin state

Molecular Signatures and Networks of Cardiomyocyte Differentiation in Humans and Mice

Functionally distinct roles for T and Tbx6 during mouse development

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