Defining the essential function of FBP/KSRP proteins:<i>Drosophila</i>Psi interacts with the mediator complex to modulate<i>MYC</i>transcription and tissue growth

Guo, Linna; Zaysteva, Olga; Nie, Zhongzhen; Mitchell, Naomi C; Lee, Jue Er Amanda; Ware, Thomas; Parsons, Linda M.; Luwor, Rodney B; Poortinga, Gretchen; Hannan, Ross D.; Levens, David; Quinn, Leonie M.

doi:10.1093/nar/gkw461

Cited by 17 publications

(47 citation statements)

References 55 publications

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“…In wild‐type, Pros nuclear entry triggers pupal NB differentiation (Maurange et al , ), which is regulated by the mediator complex in response to the pupal ecdysone pulse (Homem et al , ). Interestingly, the mediator complex also regulates myc expression (Guo et al , ). It is thus tempting to speculate that a developmentally regulated reduction of myc expression triggers pupal NB differentiation.…”

Section: Discussionmentioning

confidence: 99%

Myc and the Tip60 chromatin remodeling complex control neuroblast maintenance and polarity in Drosophila

et al. 2018

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Stem cells establish cortical polarity and divide asymmetrically to simultaneously maintain themselves and generate differentiating offspring cells. Several chromatin modifiers have been identified as stemness factors in mammalian pluripotent stem cells, but whether these factors control stem cell polarity and asymmetric division has not been investigated so far. We addressed this question in neural stem cells called neuroblasts. We identified the Tip60 chromatin remodeling complex and its interaction partner Myc as regulators of genes required for neuroblast maintenance. Knockdown of Tip60 complex members results in loss of cortical polarity, symmetric neuroblast division, and premature differentiation through nuclear entry of the transcription factor Prospero. We found that aPKC is the key target gene of Myc and the Tip60 complex subunit Domino in regulating neuroblast polarity. Our transcriptome analysis further showed that Domino regulates the expression of mitotic spindle genes previously identified as direct Myc targets. Our findings reveal an evolutionarily conserved functional link between Myc, the Tip60 complex, and the molecular network controlling cell polarity and asymmetric cell division.

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Section: Discussionmentioning

confidence: 99%

Myc and the Tip60 chromatin remodeling complex control neuroblast maintenance and polarity in Drosophila

et al. 2018

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“…The Drosophila ortholog of FUBP1, called Psi, is required for transcriptional initiation and elongation of RNA Pol II across the MYC gene. Additionally, Psi interacts with the Mediator transcriptional complex, likely playing a role to integrate multiple signaling inputs on the MYC promoter . The ortholog of FIR, encoded by the Half pint ( Hfp ) gene in Drosophila , is required for repression of Drosophila MYC .…”

Section: Single‐stranded Nucleic Acid Binding Proteins Regulate Confomentioning

confidence: 99%

DNA Conformation Regulates Gene Expression: The MYC Promoter and Beyond

Zaytseva

Quinn

2018

BioEssays

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Emerging evidence suggests that DNA topology plays an instructive role in cell fate control through regulation of gene expression. Transcription produces torsional stress, and the resultant supercoiling of the DNA molecule generates an array of secondary structures. In turn, local DNA architecture is harnessed by the cell, acting within sensory feedback mechanisms to mediate transcriptional output. MYC is a potent oncogene, which is upregulated in the majority of cancers; thus numerous studies have focused on detailed understanding of its regulation. Dissection of regulatory regions within the MYC promoter provided the first hint that intimate feedback between DNA topology and associated DNA remodeling proteins is critical for moderating transcription. As evidence of such regulation is also found in the context of many other genes, here we expand on the prototypical example of the MYC promoter, and also explore DNA architecture in a genome-wide context as a global mechanism of transcriptional control.

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“…Recent Drosophila genetic studies revealed a major developmental function of the sole FUBP ortholog (Psi); interaction with the RNA Polymerase II (Pol II) Mediator complex, regulation of MYC expression and control of cell and tissue growth. 5 …”

Section: Prefacementioning

confidence: 99%

“…43 Further to these RNA processing functions, and in accordance with Psi behaving in a functionally analogous manner to FUBP1, recent studies revealed a key role for Psi in sustaining developmentally regulated MYC transcription and, thus, cell and tissue growth. 5 Moreover, like FUBP1, 44 Psi has potent transcriptional activator capacity in vitro, mediated by conserved tyrosine-rich domains (YM1 and YM2 repeats). 5 The Psi interactome is predominantly comprised of Pol II transcriptional machinery (63% of the top 65 Psi-interactors).…”

Section: Drosophila Fubp1/psi Interacts With Mediator To Control Tissmentioning

confidence: 99%

“…5 Moreover, like FUBP1, 44 Psi has potent transcriptional activator capacity in vitro, mediated by conserved tyrosine-rich domains (YM1 and YM2 repeats). 5 The Psi interactome is predominantly comprised of Pol II transcriptional machinery (63% of the top 65 Psi-interactors). This included chromatin-remodeling factors (32%) and gene specific transcriptional regulators (12%), however, most Pol II interactors (56%) comprised subunits of the Mediator (MED) complex.…”

Section: Drosophila Fubp1/psi Interacts With Mediator To Control Tissmentioning

confidence: 99%

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FUBP/KH domain proteins in transcription: Back to the future

Quinn

2017

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Drosophila genetic studies demonstrate that cell and tissue growth regulation is a primary developmental function of P-element somatic inhibitor (Psi), the sole ortholog of FUBP family RNA/ DNA-binding proteins. Psi achieves growth control through interaction with Mediator, observations that should put to rest controversy surrounding Pol II transcriptional functions for these KH domain proteins. KEYWORDSDrosophila; FUBP1; Growth control; MYC; Psi PrefaceHere I provide an historical perspective on the FUBP family of KH domain proteins in transcription, starting »25 years ago with discovery of FUBP1s single stranded DNA (ssDNA) binding function, and implication in activating transcription of the MYC oncogene.1-3 Despite the decades that have passed, the transcriptional function of the FUBP family remains somewhat controversial; most literature attributes RNA-binding functions, both as negative and positive regulators of mRNA splicing, mRNA stability, mRNA export and mRNA translation (reviewed in Ref. 4 ). The dogma remains: RNA processing constitutes the primary role of FUBP proteins, while interaction with ssDNA to elicit transcriptional control is a lesser function. Moreover, as evidence toward understanding FUBP1 function has been gathered primarily using mammalian systems, where function can be obscured by redundancy between multiple family members, key physiologic roles have remained unclear. Recent Drosophila genetic studies revealed a major developmental function of the sole FUBP ortholog (Psi); interaction with the RNA Polymerase II (Pol II) Mediator complex, regulation of MYC expression and control of cell and tissue growth. FUSE-a nuclease-sensitive site in the MYC promoter modulates transcriptionEven small changes in abundance of the MYC oncoprotein can significantly alter cell growth and proliferation, 6 hallmarks of cancer. The interest in MYC promoter regulation was fuelled by the observation that translocated MYC alleles in Burkitt's Lymphoma that contain either truncated or mutated exon 1.7,8 Analysis of the endogenous MYC promoter in human leukemia cell lines revealed that induction of differentiation, and transcriptional downregulation of MYC, was associated with a block to Pol II elongation. 9 The exon 1 mutation prevents the Pol II block and leads to constitutive Pol II read-through and elevated MYC. 8,[10][11][12] The complexity of the MYC promoter and regulation by post-initiation release of paused Pol II reflects the multitude of signaling inputs converging on MYC transcription. As early studies found a correlation between MYC promoter sensitivity to nuclease cleavage and expression levels, 9,10,13 analysis of nucleasesensitive elements was used as a means to understand integration of signaling inputs. Interestingly, of the multiple regions containing sequence-specific binding sites predicted for MYC regulators, only the region 1.5kb upstream of the P1 promoter lost binding activity, following induced differentiation and downregulation of MYC expression.

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Defining the essential function of FBP/KSRP proteins:DrosophilaPsi interacts with the mediator complex to modulateMYCtranscription and tissue growth

Cited by 17 publications

References 55 publications

Myc and the Tip60 chromatin remodeling complex control neuroblast maintenance and polarity in Drosophila

Myc and the Tip60 chromatin remodeling complex control neuroblast maintenance and polarity in Drosophila

DNA Conformation Regulates Gene Expression: The MYC Promoter and Beyond

FUBP/KH domain proteins in transcription: Back to the future

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