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Competition Between Histone and Transcription Factor Binding Regulates the Onset of Transcription in Zebrafish Embryos

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Competition Between Histone and Transcription Factor Binding Regulates the Onset of Transcription in Zebrafish Embryos 1 Competition between histone and transcription factor binding regulates the 2 onset of transcription in zebrafish embryos 3 4 Shai R. Joseph1, Máté Pálfy1, Lennart Hilbert1,2,3, Mukesh Kumar1, Jens Karschau3, 5 Vasily Zaburdaev2,3, Andrej Shevchenko1, and Nadine L. Vastenhouw1# 6 7 1Max Planck Institute of Molecular Cell Biology and Genetics, 2Center for Systems 8 Biology Dresden, Pfotenhauerstraße 108, D-01307 Dresden, Germany, 3Max Planck 9 Institute for the Physics of Complex Systems, Nöthnitzerstraße 38, D-01187 Dresden, 10 Germany #Corresponding author 11 12 Email: [email protected] 13 1 14 SUMMARY 15 Upon fertilization, the genome of animal embryos remains transcriptionally inactive until 16 the maternal-to-zygotic transition. At this time, the embryo takes control of its 17 development and transcription begins. How the onset of zygotic transcription is regulated 18 remains unclear. Here, we show that a dynamic competition for DNA binding between 19 nucleosome-forming histones and transcription factors regulates zebrafish genome 20 activation. Taking a quantitative approach, we found that the concentration of non-DNA 21 bound core histones sets the time for the onset of transcription. The reduction in nuclear 22 histone concentration that coincides with genome activation does not affect nucleosome 23 density on DNA, but allows transcription factors to compete successfully for DNA 24 binding. In agreement with this, transcription factor binding is sensitive to histone levels 25 and the concentration of transcription factors also affects the time of transcription. Our 26 results demonstrate that the relative levels of histones and transcription factors regulate 27 the onset of transcription in the embryo. 28 2 29 INTRODUCTION 30 In many organisms, early embryonic development is directed exclusively by maternal 31 products that are deposited into the female gamete during oogenesis. Following the 32 clearance of a subset of these products (Yartseva and Giraldez, 2015), transcription is 33 initiated and the zygotic genome acquires developmental control (Blythe and Wieschaus, 34 2015a; Harrison and Eisen, 2015; Lee et al., 2014; Tadros and Lipshitz, 2009). This 35 handover is referred to as the maternal-to-zygotic transition and the onset of transcription 36 is called zygotic genome activation (ZGA). The absolute time and number of cell cycles 37 required before the first transcripts can be detected is species specific (Tadros and 38 Lipshitz, 2009). Additionally, from one gene to another the timing of transcriptional 39 activation varies (Aanes et al., 2011; Collart et al., 2014; Harvey et al., 2013; Heyn et al., 40 2014; Lott et al., 2011; Owens et al., 2016; Pauli et al., 2012; Sandler and Stathopoulos, 41 2016; Tan et al., 2013). In fact, for some genes the first zygotic transcripts can be 42 detected several cell cycles before the stage that is traditionally defined as the time point 43 of ZGA (De Renzis et al., 2007; Heyn et al., 2014; Skirkanich et al., 2011; Yang, 2002). 44 In spite of the progress made, it remains unclear how the onset of transcription in 45 embryos is temporally regulated. 46 47 Several lines of evidence suggest that the absence of transcription during early embryonic 48 development could be due to limited levels of transcription factors (Almouzni and Wolffe, 49 1995; Veenstra et al., 1999). In this scenario, transcriptional activation would occur once 50 a threshold level of these factors is reached. For example, experiments that used the 51 transcriptional activity of injected plasmids as a read-out revealed that an increase in the 3 52 amount of the potent, heterologous, transcriptional activator GAL4-VP16 can overcome 53 transcriptional repression of its target gene in the early embryo (Almouzni and Wolffe, 54 1995). However, it remained unclear whether limited levels of transcription factors 55 contribute to the absence of endogenous transcription in early embryos. Additional 56 support for the limited machinery model came from work showing that an increase in the 57 concentration of the general transcription factor TBP can cause premature transcription 58 from an injected – and incompletely chromatinized – DNA template in Xenopus embryos. 59 This effect was maintained only when non-specific DNA was added to titrate chromatin 60 assembly (Almouzni and Wolffe, 1995; Veenstra et al., 1999). These results suggested 61 that low TBP levels may play a role in the absence of transcription during the early stages 62 of Xenopus development, but that increasing TBP alone is not sufficient to cause 63 sustained premature transcription. During the cleavage stages of Xenopus development, 64 TBP levels increase due to translation, which suggests that TBP levels might contribute 65 to the timely activation of transcription during ZGA (Veenstra et al., 1999). Transcription 66 factors have recently been identified that are required for the activation of the first 67 zygotically expressed genes in Drosophila (Zelda) and zebrafish (Pou5f3, Sox19b, 68 Nanog) (Harrison et al., 2011; Lee et al., 2013; Leichsenring et al., 2013; Liang et al., 69 2008; Nien et al., 2011). RNA for these factors is maternally provided and their levels 70 increase due to translation during the early cell cycles. This suggests the possibility that 71 an increase in the concentration of these transcription factors might contribute to the shift 72 from transcriptional repression to transcriptional activity. Although transcription factors 73 levels clearly influence transcriptional activity during early embryogenesis, there is 74 evidence to show that the transcriptional machinery is operational prior to ZGA (Dekens 4 75 et al., 2003; Lu et al., 2009; Newport and Kirschner, 1982b; 1982a; Prioleau et al., 1994) 76 (see below). Thus, the timing of ZGA cannot be solely explained by a requirement to 77 reach a threshold level of transcriptional activators. 78 79 The finding that a premature increase in the number of nuclei or the amount of DNA 80 resulted in premature transcription of injected plasmids in Xenopus embryos suggested 81 that the transcriptional machinery is fully functional prior to genome activation and led to 82 the excess repressor model (Newport and Kirschner, 1982). This model postulates that a 83 transcriptional repressor is titrated by binding to the exponentially increasing amount of 84 genomic DNA, until it is depleted first from the soluble fraction, and then from DNA, to 85 allow for the onset of transcription. Related studies in zebrafish and Drosophila have 86 provided further evidence for this model. Endogenous transcription is initiated earlier in 87 zebrafish embryos that accumulate DNA due to a defect in chromosome segregation 88 (Dekens et al., 2003), and transcription is delayed in haploid Drosophila embryos 89 compared to diploid embryos, albeit not for all genes (Lu et al., 2009). The excess 90 repressor model predicts that the repressor is present in large excess, at relatively stable 91 levels while the genome is inactive, and can bind DNA with high affinity. Core histones 92 fulfill these criteria (Adamson and Woodland, 1974; Woodland and Adamson, 1977). 93 Moreover, when bound to DNA in the form of nucleosomes, histones can affect DNA 94 accessibility for DNA binding proteins. To date, two key studies have investigated the 95 role of core histones in the temporal regulation of zygotic transcription in Xenopus 96 embryos (Almouzni and Wolffe, 1995; Amodeo et al., 2015). Experiments that used the 97 transcriptional activity of injected plasmids as a read-out revealed that premature 5 98 transcription caused by an excess of non-specific DNA can be negated by the addition of 99 histones (Almouzni and Wolffe, 1995). More recently, the level of histones H3/H4 was 100 shown to regulate the level of transcription in Xenopus egg extract and H3 was suggested 101 to play a similar role in the embryo (Amodeo et al., 2015). Taken together, these results 102 support the idea that histones play a role in regulating the timing of zygotic transcription. 103 104 If histones function as repressors according to the original excess repressor model, it 105 would be predicted that a substantial reduction of the histone-density on DNA would 106 cause the onset of transcription (Amodeo et al., 2015; Newport and Kirschner, 1982a). 107 However, while such a scenario might be possible for typical sequence-specific 108 repressors of transcription, it is unlikely for histones. Histones assemble into histone 109 octamers on DNA to form nucleosomes, the basic building blocks of chromatin. Thus, 110 random depletion of nucleosomes from DNA would severely compromise the integrity of 111 chromatin structure. Taken together, there is support for the idea that histone levels play a 112 role in regulating the timing of zygotic transcription, but it remains unclear how this 113 would mechanistically work. Furthermore, the observation that both activator and histone 114 levels play a role in shifting the balance between repression and activation at genome 115 activation remains to be clarified. 116 117 Here, we analyze the onset of zygotic transcription in zebrafish embryos. With a 118 quantitative approach, we show that the concentration of non-DNA bound histones 119 determines the timing of zygotic transcription and that all four core histones are required 120 for this effect. The reduction in nuclear histone concentration that coincides with genome 6 121 activation does not result in a significant change in nucleosome density, but rather allows 122 transcription factors to successfully compete for DNA binding. In agreement with this, 123 the association of transcription factors with the genome is sensitive to histone levels, and 124 changing the concentration of transcription factors also affects the time of transcription. 125 Our results show that transcription is regulated by a dynamic competition for DNA 126 binding between histones and transcription factors. Transcription begins when the 127 concentration of non-DNA bound histones in the nucleus has sufficiently dropped so that 128 the transcriptional machinery can outcompete histones for binding to DNA.
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