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Initiation of Diverse Epigenetic States During Nuclear Programming of the Drosophila Body Plan

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Initiation of Diverse Epigenetic States During Nuclear Programming of the Drosophila Body Plan Initiation of diverse epigenetic states during nuclear programming of the Drosophila body plan Ann Boijaa and Mattias Mannervika,1 aDepartment of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691 Stockholm, Sweden Edited by Ruth Lehmann, New York University Medical Center, New York, NY, and approved June 17, 2016 (received for review August 18, 2015) Epigenetic patterns of histone modifications contribute to the main- and B). Comparing these embryos with naïve cells, we found that tenance of tissue-specific gene expression. Here, we show that such the pioneer factor, Zelda, establishes poised RNA polymerase modifications also accompany the specification of cell identities by at Dorsal target genes before zygotic activation. Upon Dorsal- the NF-κB transcription factor Dorsal in the precellular Drosophila mediated cell specification, three distinct histone signatures are embryo. We provide evidence that the maternal pioneer factor, produced, including two modes of transcriptional repression. Our Zelda, is responsible for establishing poised RNA polymerase at Dor- results show how transcription factors coordinate gene activity sal target genes before Dorsal-mediated zygotic activation. At the with initial establishment of distinct epigenetic patterns of histone onset of cell specification, Dorsal recruits the CBP/p300 coactivator modifications. to the regulatory regions of defined target genes in the presump- tive neuroectoderm, resulting in their histone acetylation and tran- Results and Discussion scriptional activation. These genes are inactive in the mesoderm due To investigate the mechanisms by which the Dorsal gradient to transcriptional quenching by the Snail repressor, which precludes generates tissue-specific gene expression and what chromatin recruitment of CBP and prevents histone acetylation. By contrast, states that follow, we examined the Dorsal-target genes brinker inactivation of the same enhancers in the dorsal ectoderm is asso- (brk)andshort-gastrulation (sog) whose expression is restricted to ciated with Polycomb-repressed H3K27me3 chromatin. Thus, the the presumptive neuroectoderm (Tollrm9/rm10)instage5embryos Dorsal morphogen gradient produces three distinct histone signa- (Fig. 1 B and C). Expression of brk and sog is repressed in the tures including two modes of transcriptional repression, active re- dorsal ectoderm (gd7) and mesoderm (Toll10B), and transcription BIOLOGY pression (hypoacetylation), and inactivity (H3K27me3). Whereas of brk and sog has not yet initiated in naïve cells obtained from DEVELOPMENTAL histone hypoacetylation is associated with a poised polymerase, 1- to 1.5-h-old wild-type (WT) stage 3 embryos (Fig. 1 B and C and H3K27me3 displaces polymerase from chromatin. Our results link Fig. S1). We designed primers across the brk and sog loci, in- different modes of RNA polymerase regulation to separate epige- cluding key features such as the embryonic and shadow enhancers, netic patterns and demonstrate that developmental determinants intergenic regions, several primers in the promoter region, as well orchestrate differential chromatin states, providing new insights in- as primers in the gene body. Occupancy of factors and histone to the link between epigenetics and developmental patterning. modifications were examined by ChIP followed by quantitative PCR (qPCR). We plotted occupancy in all graphs as fold enrich- epigenetics | cell specification | Drosophila embryo | Dorsal morphogen | ment over two intergenic loci devoid of known factors and Zelda histone modifications. We began by examining the occupancy of RNA polymerase II eneration of many specialized cell types from an identical DNA (pol II) using an antibody against the Rpb3 subunit and found Gsequence is a remarkable property of genomes in multicellular high levels at the promoters of brk and sog in the neuroectoderm organisms. Cell fate is specified by transcription factors through the (Fig. 1D), the tissue where these genes are expressed (Fig. 1 B initiation of differential gene expression patterns, but maintenance and C). Much lower levels of pol II are found over the gene of cell-type–specific gene expression programs often relies on epi- genetic mechanisms (reviewd in ref. 1). Epigenetic events such as Significance Polycomb-mediated repression are therefore important for main- tenance of specific cell identities and have been implicated in hu- Cellular memory is used to transmit information about gene man disease (reviewed in refs. 2 and 3), but how differences in activity to daughter cells and relies on epigenetic mechanisms epigenetic information between cell types arise is poorly understood. such as feedback loops and chemical modifications to DNA and The repressive nature of chromatin limits access of proteins to chromatin. Although epigenetic modifications have been sam- DNA. Pioneer factors facilitate chromatin opening, allowing ad- pled in many cell types, how epigenetic differences between ditional proteins to bind DNA (reviewed in ref. 4). In the Dro- cells arise is poorly understood. We show that a gene regulatory sophila embryo, zygotic genome activation occurs with the help of network controlling Drosophila embryogenesis is responsible for Zelda (5), a transcription factor with many features of a pioneer orchestrating differences in epigenetic patterns between cell factor. Zelda associates with target genes before their activation (6, types. We further discovered that different modes of RNA po- – 7) and increases chromatin accessibility (8 11). Zelda facilitates lymerase regulation, including poising and displacement, are DNA binding of other transcription factors, including Dorsal, a linked to these distinct chromatin states. Our results provide κ Rel-family transcription factor related to mammalian NF- B(9). novel insights into how transcription regulation and epigenetics Formation of the three germ layers, mesoderm, neuroectoderm, are coordinated during cell specification and explain how gene and dorsal ectoderm, in Drosophila embryos involves establish- regulatory networks can shape the epigenetic landscape. ment of differential gene expression patterns by the Dorsal mor- phogen (reviewed in refs. 12 and 13) (Fig. 1A). Dorsal forms an Author contributions: A.B. and M.M. designed research; A.B. performed research; A.B. intranuclear concentration gradient in response to signaling by the and M.M. analyzed data; and A.B. and M.M. wrote the paper. transmembrane receptor Toll (reviewed in ref. 14). Because many The authors declare no conflict of interest. components of the Toll pathway are strictly maternal, it is possible This article is a PNAS Direct Submission. to obtain mothers that generate a homogeneous population of 1To whom correspondence should be addressed. Email: [email protected]. 10B embryos that consist entirely of presumptive mesoderm (Toll ), This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. rm9/rm10 7 neuroectoderm (Toll ), or dorsal ectoderm (gd ) (Fig. 1 A 1073/pnas.1516450113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1516450113 PNAS Early Edition | 1of6 Downloaded by guest on September 25, 2021 OFF A dpp x gd7 dorsal ectoderm brk, sog ON Dl Tollrm9/rm10 sog sog neurogenic brk, sog brk brk ectoderm OFF mesoderm Dl x Toll10B Dorsal nuclear gradient sna Sna brk, sog Dorsal gradient BC 4 brk 3 sog 2 brk 1 sog sna Relative expression 0 evïan dorsal neuroectoderm mredosem wild-type ectoderm (Toll rm9/rm10) (Toll10B) (gd7) Naïve cells Mesoderm Dorsal ectodermNeuroectoderm D Pol II (Rpb3) ChIP 35 35 Naïve cells Dorsal ectoderm (gd7) 30 30 Neuroectoderm (Tollrm9/rm10) 10B 25 25 Mesoderm (Toll ) 20 20 15 15 10 10 Fold over background 5 5 0 0 E Pol II (8WG16) ChIP 16 16 14 14 Dorsal ectoderm (gd7) 12 12 Mesoderm (Toll10B) 10 10 8 8 6 6 4 4 2 Fold over background 2 0 0 F Pol II (Rpb3) ChIP on hand-sorted naïve embryos 6 7 6 wt naïve 5 zld RNAi naïve 5 4 4 3 3 2 2 1 1 Fold over background 0 0 -11kb -6kb -74bp 215bp““ 2kb 3kb 8kb 13kb -20kb -9k -7kb -93bp 103bp““ 2kb 15kb 20kb Enhancer Intergenic Promoter Exon 3’UTR Intergenic Shadow Shadow Intergenic Promoter Enhancer Intron Exon Enhancer Enhancer brk sog Fig. 1. Zelda establishes a poised polymerase in naïve cells that becomes evicted in dorsal ectoderm, repressed in mesoderm, and transcriptionally engaged in neuroectoderm. (A) Schematic drawings of gene regulation in early Drosophila embryos. Cross-section showing Dorsal gradient and differential gene ex- pression (Left), and regulation of brinker (brk) and short-gastrulation (sog) expression by Dorsal (Dl) and Snail (Sna) in mesoderm, neuroectoderm, and dorsal ectoderm (Right). (B) Wild-type (WT) 1- to 1.5-h (naïve) embryos, 2- to 4-h embryos derived from gd7 (dorsal ectoderm), Tollrm9/rm10 (neuroectoderm), or Toll10B (mesoderm) mutant mothers, and 2- to 4-h WT embryos were hybridized with digoxigenin-labeled brk, sog, and sna probes. Embryos are oriented with anterior to the left and dorsal up. (C) RT-qPCR showing brk and sog expression in embryos consisting of naïve cells, entirely dorsal ectoderm (gd7), neuro- ectoderm (Tollrm9/rm10), or mesoderm (Toll10B) normalized to β-tubulin and plotted relative WT expression, n = 3–4. Error bars represents SEM. (D) ChIP-qPCR of pol II using an Rpb3 antibody in extracts from 2- to 4-h embryos derived from gd7 (dorsal ectoderm), Tollrm9/rm10 (neuroectoderm), or Toll10B (mesoderm) mutant mothers. Values from amplicons located in enhancer, intergenic, promoter-proximal, exon, intron,
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