Hdac6 regulates Tip60-p400 function in stem cells

Chen, Poshen B.; Hung, Jui-Hung; Hickman, Taylor; Coles, Andrew H.; Carey, James F.; Weng, Zhiping; Chu, Feixia; Fazzio, Thomas G.

doi:10.7554/elife.01557

Cited by 62 publications

(87 citation statements)

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“…Following up on the initial observation of early defects in GSCs and cyst differentiation upon loss of DOM (Yan et al, 2014), we now find that this phenotype is exclusively caused by loss of DOM-A. Interestingly, studies with human embryonic stem cells show that p400/TIP60 (KAT5) integrates pluripotency signals to regulate gene expression (Chen et al, 2013;Fazzio et al, 2008), suggesting similar roles for DOM-A in GSCs. This is in contrast to requirements for both isoforms for germline development outside of the germarium, highlighting a developmental specialization of the two DOM remodelers.…”

Section: Discussionmentioning

confidence: 86%

Splice variants of the SWR1-type nucleosome remodeling factor Domino have distinct functions during Drosophila melanogaster oogenesis

Börner

Becker

2016

Development

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SWR1-type nucleosome remodeling factors replace histone H2A by variants to endow chromatin locally with specialized functionality. In Drosophila melanogaster a single H2A variant, H2A.V, combines functions of mammalian H2A.Z and H2A.X in transcription regulation and the DNA damage response. A major role in H2A.V incorporation for the only SWR1-like enzyme in flies, Domino, is assumed but not well documented in vivo. It is also unclear whether the two alternatively spliced isoforms, DOM-A and DOM-B, have redundant or specialized functions. Loss of both DOM isoforms compromises oogenesis, causing female sterility. We systematically explored roles of the two DOM isoforms during oogenesis using a cell type-specific knockdown approach. Despite their ubiquitous expression, DOM-A and DOM-B have non-redundant functions in germline and soma for egg formation. We show that chromatin incorporation of H2A.V in germline and somatic cells depends on DOM-B, whereas global incorporation in endoreplicating germline nurse cells appears to be independent of DOM. By contrast, DOM-A promotes the removal of H2A.V from stage 5 nurse cells. Remarkably, therefore, the two DOM isoforms have distinct functions in cell type-specific development and H2A.V exchange.

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Section: Discussionmentioning

confidence: 86%

Splice variants of the SWR1-type nucleosome remodeling factor Domino have distinct functions during Drosophila melanogaster oogenesis

Börner

Becker

2016

Development

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“…NuA4 has been reported to engage many transcription factors, including Myc, p53, and E2F (McMahon et al 2000;Frank et al 2003;Legube et al 2004;Taubert et al 2004) to turn on target gene expression in proliferating cells. However, the NuA4 complex also acts as an essential repressor of gene expression in certain contexts, such as embryonic stem cells (Fazzio et al 2008;Chen et al 2013), and can promote closed chromatin formation in flies (Qi et al 2006). Furthermore, NuA4 components paradoxically act as both tumor suppressors and oncogenes, leaving their positive vs. negative roles in cell cycle control unresolved (Sapountzi et al 2006;Judes et al 2015).…”

Section: The Nua4 Complexmentioning

confidence: 99%

Roles for the Histone Modifying and Exchange Complex NuA4 in Cell Cycle Progression in Drosophila melanogaster

Flegel¹,

Grushko²,

Bolin³

et al. 2016

Genetics

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Robust and synchronous repression of E2F-dependent gene expression is critical to the proper timing of cell cycle exit when cells transition to a postmitotic state. Previously NuA4 was suggested to act as a barrier to proliferation in Drosophila by repressing E2F-dependent gene expression. Here we show that NuA4 activity is required for proper cell cycle exit and the repression of cell cycle genes during the transition to a postmitotic state in vivo. However, the delay of cell cycle exit caused by compromising NuA4 is not due to additional proliferation or effects on E2F activity. Instead NuA4 inhibition results in slowed cell cycle progression through late S and G2 phases due to aberrant activation of an intrinsic p53-independent DNA damage response. A reduction in NuA4 function ultimately produces a paradoxical cell cycle gene expression program, where certain cell cycle genes become derepressed in cells that are delayed during the G2 phase of the final cell cycle. Bypassing the G2 delay when NuA4 is inhibited leads to abnormal mitoses and results in severe tissue defects. NuA4 physically and genetically interacts with components of the E2F complex termed Drosophila, Rbf, E2F and Myb/Multi-vulva class B (DREAM/MMB), and modulates a DREAM/MMB-dependent ectopic neuron phenotype in the posterior wing margin. However, this effect is also likely due to the cell cycle delay, as simply reducing Cdk1 is sufficient to generate a similar phenotype. Our work reveals that the major requirement for NuA4 in the cell cycle in vivo is to suppress an endogenous DNA damage response, which is required to coordinate proper S and G2 cell cycle progression with differentiation and cell cycle gene expression.KEYWORDS DNA damage; proliferation; H2Av; cell cycle checkpoint; cell cycle exit A conserved eukaryotic transcriptional oscillator controls cell cycle gene expression in proliferating cells and underlies the well-studied Cyclin/Cdk cell cycle protein oscillator (Orlando et al. 2008;Oikonomou and Cross 2010). In metazoans, this oscillator depends upon transcriptional activation of several hundred cell cycle genes, initiated by E2F transcription factor complexes followed by E2F inhibition (or degradation) (Shibutani et al. 2008;Zielke et al. 2011;Sadasivam and Decaprio 2013). This generates an oscillation of chromatin opening and closing at cell cycle genes that is thought to properly coordinate G1/S and G2/M gene expression as well as the transition to a noncycling state (Litovchick et al. 2007(Litovchick et al. , 2011Forristal et al. 2014). Disruption of this coordination can affect cell cycle progression by causing inappropriate gene expression (Reis and Edgar 2004;Wen et al. 2008;Forristal et al. 2014). While the oscillation of E2F activity is required for robust cell cycle gene expression Korenjak et al. 2012), E2F complexes are not absolutely essential for cell cycle progression or timely cell cycle exit in Drosophila (Frolov et al. 2001(Frolov et al. , 2005. In the absence of E2F activity there must be E2F-independ...

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“…KD of most subunits results in a partial defect in self-renewal, whereby expression of some markers of pluripotency, such as alkaline phosphatase, are reduced, while other markers (Oct4, Nanog) are maintained. 38,39 Perhaps not surprisingly, given this altered ESC state, Tip60-p400 KD ESCs also have defects in normal differentiation. 20,38,39 Partial loss of Tip60-p400 function, as observed in the case of KD or mutation of the gene encoding the Tip60-p400 interacting protein Hdac6, result in differentiation defects without any significant effect on self-renewal.…”

Section: Role Of R-loops In Regulation Of the Esc Statementioning

confidence: 99%

“…38,39 Perhaps not surprisingly, given this altered ESC state, Tip60-p400 KD ESCs also have defects in normal differentiation. 20,38,39 Partial loss of Tip60-p400 function, as observed in the case of KD or mutation of the gene encoding the Tip60-p400 interacting protein Hdac6, result in differentiation defects without any significant effect on self-renewal. 39 Since R-loops were found to be necessary to restrict PRC2 targets and activity while simultaneously promoting Tip60-p400 binding, one might expect reduction of R-loops to result in defects in self-renewal or differentiation.…”

Section: Role Of R-loops In Regulation Of the Esc Statementioning

confidence: 99%

“…20,38,39 Partial loss of Tip60-p400 function, as observed in the case of KD or mutation of the gene encoding the Tip60-p400 interacting protein Hdac6, result in differentiation defects without any significant effect on self-renewal. 39 Since R-loops were found to be necessary to restrict PRC2 targets and activity while simultaneously promoting Tip60-p400 binding, one might expect reduction of R-loops to result in defects in self-renewal or differentiation. While self-renewal was not affected in Rnaseh1 over-expressing cells (in which R-loops were reduced, but not completely eliminated), differentiation was significantly impaired.…”

Section: Role Of R-loops In Regulation Of the Esc Statementioning

confidence: 99%

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Regulation of chromatin structure and cell fate by R-loops

Fazzio

2016

Transcription

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Hybridization of RNA to its template DNA strand during transcription induces formation of R-loops-RNA:DNA hybrids with unpaired non-template DNA strands. Although unresolved R-loops can be detrimental, some R-loops contribute to regulation of chromatin structure. Consequently, R-loops help regulate gene expression and play important roles in numerous cellular processes. 1 Studies have shown that R-loop accumulation in vivo is favored by G-rich transcripts.2,3 At least two structural features of R-loops may contribute to this observation. First, purine-rich RNAs hybridized to pyrimidine-rich DNA strands (rR:dY) adopt a conformation close to the highly stable A-form structure of RNA:RNA hybrids and are much more thermodynamically stable than rY:dR hybrids or DNA duplexes of the same sequence.4,5 Second, G-rich sequences on the displaced non-template DNA strand may be stabilized by formation of G-quadruplex structures.6 Therefore, given the access of nascent transcripts to their unwound, complementary templates during transcription, and the favorable energetics of RNA:DNA hybrid formation, it is perhaps not surprising that transcription-associated R-loops can be observed in eukaryotes from yeast to humans, as well as prokaryotes. 7Unresolved R-loops induce DNA single-and double-strand breaks, higher mutation rates, and genomic instability. 7-10Consequently, cells have evolved multiple mechanisms for regulating the accumulation of R-loops that help prevent mutations, DNA damage, and genomic instability. With the exception of the CRISPR/Cas system, 11 all regulators of R-loops that have been identified appear to act negatively-removing R-loops that have formed or preventing R-loop formation.7 One prominent example includes the DNA:RNA helicase SETX (Sen1 in yeast). SETX melts the RNA:DNA duplex of R-loops, 12 which can be accompanied by degradation of the transcript by the RNA exonuclease, Xrn2.13 A second method of Rloop removal is through the actions of RNase H enzymes (RNase H1 and RNase H2 in eukaryotes), which degrade the RNA strand of the duplex through their endonuclease activities.14 It is not known whether additional proteins exist that specifically promote R-loop stability, either directly or by counteracting the functions of proteins that destabilize R-loops.Despite these mechanisms of R-loop removal, Rloops accumulate at multiple regions of the genome, particularly near the transcription start sites (TSSs) and transcription termination sites (TTSs) of transcribed genes.2,3,13,15 Steady-state R-loop levels are therefore likely a function of the combined effects of biophysical properties of the particular RNA:DNA hybrid, the level of transcription of the RNA component of the R-loop, and the presence or absence of proteins that inhibit R-loop formation or disrupt R-loops CONTACT Thomas G. Fazzio

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Hdac6 regulates Tip60-p400 function in stem cells

Cited by 62 publications

References 62 publications

Splice variants of the SWR1-type nucleosome remodeling factor Domino have distinct functions during Drosophila melanogaster oogenesis

Splice variants of the SWR1-type nucleosome remodeling factor Domino have distinct functions during Drosophila melanogaster oogenesis

Roles for the Histone Modifying and Exchange Complex NuA4 in Cell Cycle Progression in Drosophila melanogaster

Regulation of chromatin structure and cell fate by R-loops

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