Transient RUNX1 Expression during Early Mesendodermal Differentiation of hESCs Promotes Epithelial to Mesenchymal Transition through TGFB2 Signaling

VanOudenhove, Jennifer; Medina, Ricardo; Ghule, Prachi N.; Lian, Jane B.; Stein, Janet L.; Zaidi, Sayyed K.

doi:10.1016/j.stemcr.2016.09.006

Cited by 23 publications

(28 citation statements)

References 61 publications

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“…For deformable crawlers, a candidate is the Runx family of transcription factors (Coffman 2003), which were likely present as a single copy in urmetazoan and urholozoan progenitors (Rennert et al 2003; Sullivan et al 2008; de Mendoza et al 2013). Runx transcription factors specify circulating cells in animals that move by actin-mediated crawling (Pancer et al 1999; Otto et al 2003; Waltzer et al 2003; Burns et al 2005) and directly promote cell motility (Leong et al 2010; Zusso et al 2012; Lie-A-Ling et al 2014; VanOudenhove et al 2016). High levels of Runx transcription have been detected by RNA-seq in the archaeocytes of the sponge Ephydatia fluviatilis (Alié et al 2015), suggesting that the link between this transcription factor family and the crawling cell phenotype might be ancient in animals.…”

Section: Introductionmentioning

confidence: 99%

The Origin of Animal Multicellularity and Cell Differentiation

2017

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Over 600 million years ago, animals evolved from a unicellular or colonial organism whose cell(s) captured bacteria with a collar complex, a flagellum surrounded by a microvillar collar. Using principles from evolutionary cell biology, we reason that the transition to multicellularity required modification of pre-existing mechanisms for extracellular matrix synthesis and cytokinesis. We discuss two hypotheses for the origin of animal cell types: division of labor from ancient plurifunctional cells and conversion of temporally alternating phenotypes into spatially juxtaposed cell types. Mechanistic studies in diverse animals and their relatives promise to deepen our understanding of animal origins and cell biology.

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Section: Introductionmentioning

confidence: 99%

The Origin of Animal Multicellularity and Cell Differentiation

2017

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“…TGFβ2 knockout mice have cardiac, lung, craniofacial, limb, spinal column, eye, inner ear, and urogenital defects [Sanford et al, 1997], whereas the TGFβ1 knockout mice exhibit an autoimmune-like inflammatory disease or embryonic lethality due to defective yolk sac hematopoiesis and vasculogenesis, depending on the genetic background [Dickson et al, 1995; Kulkarni et al, 1993; Shull et al, 1992]. Consistent with the results from these mouse models, there is a specific requirement for TGFβ2, but not TGFβ1, to rescue the phenotype of RUNX1 depletion in hESCs [VanOudenhove et al, In Press, 2016]. …”

Section: Transient Preemptive Expression Of a Phenotypic Transcriptimentioning

confidence: 89%

“…The recent report that, prior to their established functions in specifying lineage and cell type-specific identity, phenotype-associated transcription factors play a role in initial stages of differentiation is counterintuitive but significant [VanOudenhove et al, In Press, 2016]. This “preemptive” expression of RUNX1 as early as eight hours after initiation of differentiation, during mesenchymal differentiation, illustrates the contribution of a phenotypic transcription factor in initial parameters of developmental control (see overview in Fig.…”

Section: Transient Preemptive Expression Of a Phenotypic Transcriptimentioning

confidence: 99%

“…The inhibition of motility and de-repression of epithelial genes observed upon RUNX1 depletion indicates that RUNX1 is upstream of the TGFβ pathway [VanOudenhove et al, In Press, 2016]. Moreover, RUNX1 specifically occupies the TGFβ2 promoter and regulates the expression of the TGFβ2 gene, which encodes one of the three TGFβ ligands.…”

Section: Transient Preemptive Expression Of a Phenotypic Transcriptimentioning

confidence: 99%

“…In addition to a decrease in TGFβ2 ligand expression upon RUNX1 depletion, there is a decrease in phosphorylation of the downstream effector SMAD Family Member 2 (SMAD2) [VanOudenhove et al, In Press, 2016]. SMAD2 is required for competency to initiate gastrulation, as well as primitive streak/mesendoderm and mesoderm formation, with SMAD2 knockout being embryonic lethal before E8.5 [Nomura and Li, 1998; Weinstein et al, 1998].…”

Section: Transient Preemptive Expression Of a Phenotypic Transcriptimentioning

confidence: 99%

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Precocious Phenotypic Transcription‐Factor Expression During Early Development

VanOudenhove

Medina

Ghule

et al. 2017

J of Cellular Biochemistry

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A novel role for phenotypic transcription factors in very early differentiation was recently observed and merits further study to elucidate what role this precocious expression may have in development. The RUNX1 transcription factor exhibits selective and transient upregulation during early mesenchymal differentiation. In contrast to phenotype-associated transcriptional control of gene expression to establish and sustain hematopoietic/myeloid lineage identity, precocious expression of RUNX1 is functionally linked to control of an epithelial to mesenchymal transition that is obligatory for development. This early RUNX1 expression spike provides a paradigm for precocious expression of a phenotypic transcription factor that invites detailed mechanistic study to fully understand its biological importance.

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RUNX1‐dependent mechanisms in biological control and dysregulation in cancer

Hong

Fritz

Gordon

et al. 2018

Journal Cellular Physiology

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The RUNX1 transcription factor has recently been shown to be obligatory for normal development. RUNX1 controls the expression of genes essential for proper development in many cell lineages and tissues including blood, bone, cartilage, hair follicles, and mammary glands. Compromised RUNX1 regulation is associated with many cancers. In this review, we highlight evidence for RUNX1 control in both invertebrate and mammalian development and recent novel findings of perturbed RUNX1 control in breast cancer that has implications for other solid tumors. As RUNX1 is essential for definitive hematopoiesis, RUNX1 mutations in hematopoietic lineage cells have been implicated in the etiology of several leukemias. Studies of solid tumors have revealed a context‐dependent function for RUNX1 either as an oncogene or a tumor suppressor. These RUNX1 functions have been reported for breast, prostate, lung, and skin cancers that are related to cancer subtypes and different stages of tumor development. Growing evidence suggests that RUNX1 suppresses aggressiveness in most breast cancer subtypes particularly in the early stage of tumorigenesis. Several studies have identified RUNX1 suppression of the breast cancer epithelial‐to‐mesenchymal transition. Most recently, RUNX1 repression of cancer stem cells and tumorsphere formation was reported for breast cancer. It is anticipated that these new discoveries of the context‐dependent diversity of RUNX1 functions will lead to innovative therapeutic strategies for the intervention of cancer and other abnormalities of normal tissues.

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Transient RUNX1 Expression during Early Mesendodermal Differentiation of hESCs Promotes Epithelial to Mesenchymal Transition through TGFB2 Signaling

Cited by 23 publications

References 61 publications

The Origin of Animal Multicellularity and Cell Differentiation

The Origin of Animal Multicellularity and Cell Differentiation

Precocious Phenotypic Transcription‐Factor Expression During Early Development

RUNX1‐dependent mechanisms in biological control and dysregulation in cancer

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