| 1. |
- Bahr, Carsten, et al.
(författare)
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A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies
- 2018
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 553:7689, s. 515-520
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies1. Here we show that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that has previously been labelled as a ‘super-enhancer’2 is essential for the regulation of Myc expression levels in both normal haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in haematopoietic stem cells and progenitors. This caused an accumulation of differentiation-arrested multipotent progenitors and loss of myeloid and B cells, mimicking the phenotype caused by Mx1-Cre-mediated conditional deletion of the Myc gene in haematopoietic stem cells3. This super-enhancer comprises multiple enhancer modules with selective activity that recruits a compendium of transcription factors, including GFI1b, RUNX1 and MYB. Analysis of mice carrying deletions of individual enhancer modules suggests that specific Myc expression levels throughout most of the haematopoietic hierarchy are controlled by the combinatorial and additive activity of individual enhancer modules, which collectively function as a ‘blood enhancer cluster’ (BENC). We show that BENC is also essential for the maintenance of MLL–AF9-driven leukaemia in mice. Furthermore, a BENC module, which controls Myc expression in mouse haematopoietic stem cells and progenitors, shows increased chromatin accessibility in human acute myeloid leukaemia stem cells compared to blasts. This difference correlates with MYC expression and patient outcome. We propose that clusters of enhancers, such as BENC, form highly combinatorial systems that allow precise control of gene expression across normal cellular hierarchies and which also can be hijacked in malignancies.
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| 2. |
- Comai, Glenda Evangelina, et al.
(författare)
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Local retinoic acid signaling directs emergence of the extraocular muscle functional unit
- 2020
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Ingår i: PLoS biology. - : Public Library Science. - 1544-9173 .- 1545-7885. ; 18:11
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Tidskriftsartikel (refereegranskat)abstract
- Coordinated development of muscles, tendons, and their attachment sites ensures emergence of functional musculoskeletal units that are adapted to diverse anatomical demands among different species. How these different tissues are patterned and functionally assembled during embryogenesis is poorly understood. Here, we investigated the morphogenesis of extraocular muscles (EOMs), an evolutionary conserved cranial muscle group that is crucial for the coordinated movement of the eyeballs and for visual acuity. By means of lineage analysis, we redefined the cellular origins of periocular connective tissues interacting with the EOMs, which do not arise exclusively from neural crest mesenchyme as previously thought. Using 3D imaging approaches, we established an integrative blueprint for the EOM functional unit. By doing so, we identified a developmental time window in which individual EOMs emerge from a unique muscle anlage and establish insertions in the sclera, which sets these muscles apart from classical muscle-to-bone type of insertions. Further, we demonstrate that the eyeballs are a source of diffusible all-trans retinoic acid (ATRA) that allow their targeting by the EOMs in a temporal and dose-dependent manner. Using genetically modified mice and inhibitor treatments, we find that endogenous local variations in the concentration of retinoids contribute to the establishment of tendon condensations and attachment sites that precede the initiation of muscle patterning. Collectively, our results highlight how global and site-specific programs are deployed for the assembly of muscle functional units with precise definition of muscle shapes and topographical wiring of their tendon attachments.
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| 3. |
- Remeseiro, Silvia, et al.
(författare)
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Gene regulation during development in the light of topologically associating domains
- 2016
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Ingår i: Wiley Interdisciplinary Reviews. - : Wiley. - 1759-7684 .- 1759-7692. ; 5:2, s. 169-185
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Tidskriftsartikel (refereegranskat)abstract
- During embryonic development, complex transcriptional programs govern the precision of gene expression. Many key developmental genes are regulated via cis-regulatory elements that are located far away in the linear genome. How sequences located hundreds of kilobases away from a promoter can influence its activity has been the subject of numerous speculations, which all underline the importance of the 3D-organization of the genome. The recent advent of chromosome conformation capture techniques has put into focus the subdivision of the genome into topologically associating domains (TADs). TADs may influence regulatory activities on multiple levels. The relative invariance of TAD limits across cell types suggests that they may form fixed structural domains that could facilitate and/or confine long-range regulatory interactions. However, most recent studies suggest that interactions within TADs are more variable and dynamic than initially described. Hence, different models are emerging regarding how TADs shape the complex 3D conformations, and thereafter influence the networks of cis-interactions that govern gene expression during development. For further resources related to this article, please visit the WIREs website.
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| 4. |
- Rowe, Helen M., et al.
(författare)
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KAP1 controls endogenous retroviruses in embryonic stem cells
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 463, s. 40-237
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Tidskriftsartikel (refereegranskat)abstract
- More than forty per cent of the mammalian genome is derived from retroelements, of which about one-quarter are endogenous retroviruses (ERVs). Some are still active, notably in mice the highly polymorphic early transposon (ETn)/MusD and intracisternal A-type particles (IAP). ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation (and reviewed in ref. 7), although the initiators of this process, which is essential to protect genome integrity, remain largely unknown. KAP1 (KRAB-associated protein 1, also known as tripartite motif-containing protein 28, TRIM28) represses genes by recruiting the histone methyltransferase SETDB1, heterochromatin protein 1 (HP1) and the NuRD histone deacetylase complex, but few of its physiological targets are known. Two lines of evidence suggest that KAP1-mediated repression could contribute to the control of ERVs: first, KAP1 can trigger permanent gene silencing during early embryogenesis, and second, a KAP1 complex silences the retrovirus murine leukaemia virus in embryonic cells. Consistent with this hypothesis, here we show that KAP1 deletion leads to a marked upregulation of a range of ERVs, in particular IAP elements, in mouse embryonic stem (ES) cells and in early embryos. We further demonstrate that KAP1 acts synergistically with DNA methylation to silence IAP elements, and that it is enriched at the 5' untranslated region (5'UTR) of IAP genomes, where KAP1 deletion leads to the loss of histone 3 lysine 9 trimethylation (H3K9me3), a hallmark of KAP1-mediated repression. Correspondingly, IAP 5'UTR sequences can impose in cis KAP1-dependent repression on a heterologous promoter in ES cells. Our results establish that KAP1 controls endogenous retroelements during early embryonic development.
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