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TALE transcription factors binding and transcriptional effect [RNA-Seq]

ABSTRACT: Meis, Prep and Pbx1 TALE homeoproteins interactions with Hox proteins are essential for development and disease. Although Meis and Prep behave similarly in vitro, their in vivo activities remain largely unexplored. We show that Prep and Meis interact with largely independent sets of genomic sites and select different DNA binding sequences, with Prep associating mostly with promoters and house-keeping genes and Meis with promoter-remote regions and developmental genes. Hox target sequences associate strongly with Meis but not with Prep binding sites, while Pbx1 cooperates with both Prep and Meis. Accordingly, Meis1 shows strong genetic interaction with Pbx1 but not with Prep1. Meis1 and Prep1 nonetheless co-regulate a subset of genes, predominantly through opposing effects. Notably, the TALE homeoprotein binding profile subdivides Hox clusters into two domains differentially regulated by Meis1 and Prep1. After duplication of the ancestral gene, Meis and Prep thus specialized their interactions but maintained significant regulatory coordination. RNA-seq of 2 Meis1 and Prep1 loss of function mutants in E11.5 C57BL/6 embryonic mice

ORGANISM(S): Mus musculus

SUBMITTER: Daniel Mateos San Martín

PROVIDER: E-GEOD-39605 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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TALE transcription factors binding and transcriptional effect [ChIP-Seq]

Project description:Meis, Prep and Pbx1 TALE homeoproteins interactions with Hox proteins are essential for development and disease. Although Meis and Prep behave similarly in vitro, their in vivo activities remain largely unexplored. We show that Prep and Meis interact with largely independent sets of genomic sites and select different DNA binding sequences, with Prep associating mostly with promoters and house-keeping genes and Meis with promoter-remote regions and developmental genes. Hox target sequences associate strongly with Meis but not with Prep binding sites, while Pbx1 cooperates with both Prep and Meis. Accordingly, Meis1 shows strong genetic interaction with Pbx1 but not with Prep1. Meis1 and Prep1 nonetheless co-regulate a subset of genes, predominantly through opposing effects. Notably, the TALE homeoprotein binding profile subdivides Hox clusters into two domains differentially regulated by Meis1 and Prep1. After duplication of the ancestral gene, Meis and Prep thus specialized their interactions but maintained significant regulatory coordination. ChIP-seq of 3 TALE proteins in E11.5 C57BL/6 embryonic mice

2013-03-31 | E-GEOD-39608 | biostudies-arrayexpress

TALE transcription factors binding and transcriptional effect [RNA-Seq]

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TALE transcription factors binding and transcriptional effect [ChIP-Seq]

2013-03-31 | GSE39608 | GEO

Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis [hP]

Project description:Prep1 is a tumor-suppressor, whereas Meis1 is an oncogene. We show that to perform these activities in MEFs both proteins competitively hetero-dimerize with Pbx1. Meis1 alone transforms Prep1-deficient fibroblasts while Prep1 overexpression inhibits Meis1 tumorigenicity. Pbx1 can therefore alternatively act as oncogene or tumor-suppressor. Prep1 post-translationally controls the level of Meis1 decreasing its stability by sequestering Pbx1. The different levels of Meis1 and the presence of Prep1 are followed at the transcriptional level by the induction of specific transcriptional signatures. The decrease of Meis1 prevents Meis1 interaction with Ddx3x and Ddx5, which are essential for Meis1 tumorigenesis, and modifies the growth promoting DNA binding landscape of Meis1 to the growth controlling landscape of Prep1. Hence the key feature of Prep1 tumor inhibiting activity is the control of Meis1 stability.

2016-06-01 | GSE58802 | GEO

Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis [hM, hMP]

2014-03-05 | GSE54221 | GEO

Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis.

2014-03-05 | E-GEOD-54221 | biostudies-arrayexpress

Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis [hP]

2016-06-01 | E-GEOD-58802 | biostudies-arrayexpress

The Epigenetic Regulator Landscape of HOX/MEIS Expression in AML [scRNA-seq]

Project description:Aberrant and constitutive activation of the clustered homeobox (HOX) genes and the three-amino-acid loop extension (TALE) domain-containing HOX co-factor MEIS1 (henceforth termed HOX/MEIS) is a recurrent feature in several types of myeloid and lymphoid leukemias. HOX/MEIS misexpression is linked to aberrant self-renewal and therapy resistance in leukemia, but the therapeutic targeting of this important pathway has remained elusive. Using AF10-rearranged leukemia as a prototypical example of HOX/MEIS dysregulation, we sought to comprehensively characterize chromatin regulators that sustain aberrant expression of these genes. We deployed a GFP-MEIS1 knock-in reporter cell line to conduct small-molecule inhibitor screens and a high-density domain-focused CRISPR-Cas9 screen targeting epigenetic regulators. We identified members of at least six distinct chromatin-modifying complexes as HOX/MEIS regulators, including previously characterized HOX/MEIS regulators such as DOT1L, AF10, ENL, and HBO1 as well as less well-characterized and completely novel HOX/MEIS regulators including AFF2, JADE3, casein kinase 2 and the chromatin reader SGF29. These HOX/MEIS regulators were important for the growth of AML cell lines representing diverse leukemia subtypes characterized by HOX/MEIS dysregulation including leukemias with AF10 rearrangements, MLL rearrangements, and NPM1 mutation. Determination of gene expression changes after perturbing each of these MEIS1 regulators in parallel using CROP-seq demonstrated that the deletion of DOT1L, ENL, AFF2, or SGF29 led to the downregulation of several genes associated with stem cell self-renewal and upregulation of differentiation-associated genes.

2023-11-10 | GSE217779 | GEO

Gene expression signatures of Meis1 conditional knockout hematopoietic stem cells

Project description:Meis1 encodes a TALE family homeodomain protein that was first identified as a common retroviral integration site in mouse BHX2 myeloid leukemia. It functions as a DNA binding co-factor of Hox proteins through interacting with Pbx, a member of another TALE family protein. Moreover, Meis1 homozygous knockout mice are embryonic lethal, showing significant defects in vasculogenesis, eye development and hematopoiesis. Severe defects were also observed in adult hematopoiesis by conditional inactivation of Meis1 in vivo. Meis1 is critical to maintain the balance between enter and exit from cell cycles of hematopoietic stem cells (HSCs), indicating that Meis1 regulates self-renewal and quiescence of HSCs.

2013-12-01 | GSE38336 | GEO

Meis1 induces and Prep1 suppresses tumors by exploiting low affinity AP1 binding sites.

Project description:We have defined the tumor and tumor suppressor signature for Meis1 and Prep1 (pKnox1), respectively, using ChIP-seq and RNA-seq in a cell system in which tumor suppressor Prep1 and oncogene Meis1 compete for tumorigenesis [GSE54221; GSE58802]. In this paper we report that the number of Meis1 or Prep1 DNA binding sites increases linearly with the level of expression of the two transcription factors. Overexpression of Meis1 induces tumors. At the molecular level it modifies the DNA target specificity by increasing the number of low-affinity binding sites, which results in a different choice of consensus sequences with predominance of sites normally bound by the AP1 transcription factor family. Upon concomitant overexpression of Prep1 and Meis1 tumorigenesis is inhibited. Prep1 dominates over Meis1 not only because it partially decreases Meis1 protein level but also because it prevents the binding to a substantial fraction of the low affinity binding sites. Overall, overexpression of Prep1 reverses the nature of the bound and regulated genes from stimulatory to inhibitory of signal transduction and transcription, which suppresses tumorigenesis. By identifying the Meis1 tumor signature, specific relevant signaling pathways are identified. In line with these results, tumorigenic Meis1-overexpressing cells are uniquely hypersensitive to inhibitors of the MAPK/Akt pathways. Examination of Prep1 and Meis1 in five cell type

2016-06-25 | E-GEOD-58818 | biostudies-arrayexpress

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