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Zelda overcomes the high intrinsic nucleosome barrier at enhancers during Drosophila zygotic genome activation

ABSTRACT: A central question in biology is how enhancers are made accessible. The Drosophila embryo is a good model system to study this question as the gene regulatory networks regulating early developmental events have been well characterized. Zelda (Zld) is a uniformly distributed transcription factor (TF) integral to these networks, acting prior to and in collaboration with the patterning TFs to regulate target enhancers. Here we test the hypothesis that Zld directs TF binding, examplified by Dorsal (Dl) which patterns the dorsoventral axis, across the genome by displacing nucleosomes at enhancers. By performing ChIP-seq and MNase-seq experiments on early embryos with or without Zld, we demonstrated that early enhancers are characterized by an intrinsically high nucleosome barrier, which is overcome by Zld, and that without Zld, Dl binding decreases at enhancers and redistributes to open regions devoid of enhancer activity. We propose that enhancers are initially specified across the genome by the binding of Zld, which locally decreases nucleosome occupancy, thereby assisting TFs in accessing their binding motifs and promoting transcriptional activity.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE65441 | GEO | 2015/08/21

SECONDARY ACCESSION(S): PRJNA273997

REPOSITORIES: GEO

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Zelda overcomes the high intrinsic nucleosome barrier at enhancers during Drosophila zygotic genome activation

Project description:A central question in biology is how enhancers are made accessible. The Drosophila embryo is a good model system to study this question as the gene regulatory networks regulating early developmental events have been well characterized. Zelda (Zld) is a uniformly distributed transcription factor (TF) integral to these networks, acting prior to and in collaboration with the patterning TFs to regulate target enhancers. Here we test the hypothesis that Zld directs TF binding, examplified by Dorsal (Dl) which patterns the dorsoventral axis, across the genome by displacing nucleosomes at enhancers. By performing ChIP-seq and MNase-seq experiments on early embryos with or without Zld, we demonstrated that early enhancers are characterized by an intrinsically high nucleosome barrier, which is overcome by Zld, and that without Zld, Dl binding decreases at enhancers and redistributes to open regions devoid of enhancer activity. We propose that enhancers are initially specified across the genome by the binding of Zld, which locally decreases nucleosome occupancy, thereby assisting TFs in accessing their binding motifs and promoting transcriptional activity. Zld, Dl, Pol II ChIP-seq and MNase-seq profiles comparing 2-3h wild-type (wt) and zld- embryos, and MNase-seq profiles comparing 2-4h wt and gd7 embryos, all in 2 replicates

2015-08-21 | E-GEOD-65441 | biostudies-arrayexpress

CLAMP and Zelda function together as pioneer transcription factors to promote Drosophila zygotic genome activation [ChIP-Seq]

Project description:The pioneer transcription factor Zelda (ZLD) increases the accessibility of chromatin to promote the essential process of zygotic genome activation (ZGA) in the Drosophila early embryo. However, many genomic loci remain accessible in the absence of ZLD and are enriched for GA-rich DNA binding motifs. Therefore, we hypothesized that other pioneer TFs that function with ZLD have not yet been identified, especially those that bind to GA-rich motifs. CLAMP (Chromatin-linked adaptor for Male-specific lethal MSL proteins) is a GA-rich motif binding TF that is essential for early embryonic development. Here, we identify for the first time that CLAMP is a pioneer TF which interacts directly with nucleosomes, regulates zygotic genome activation, promotes chromatin accessibility, and facilitates the binding of ZLD to promoters. When ZLD is bound at a locus but does not regulate chromatin accessibility, CLAMP can often function redundantly to open the chromatin. Because ZGA is an essential process across metazoans, it is key to evolve redundant pioneer TFs to protect organisms from lethality that would be caused by loss of a single non-redundant factor.

2021-08-05 | GSE152598 | GEO

CLAMP and Zelda function together as pioneer transcription factors to promote Drosophila zygotic genome activation [ATAC-Seq]

2021-08-05 | GSE152596 | GEO

Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites [Validation Set]

Project description:During cell division, transcription factors (TFs) are removed from chromatin twice, during DNA synthesis, and during condensation of chromosomes. How TFs can efficiently find their sites following these stages has been unclear. Here, we have analyzed the binding pattern of expressed TFs in human colorectal cancer cells. We find that binding of TFs is highly clustered, and that the clusters are enriched in binding motifs for several major TF classes. Strikingly, almost all clusters are formed around cohesin, and loss of cohesin decreases both DNA accessibility and binding of TFs to clusters. We show that cohesin remains bound in S phase, holding the nascent sister chromatids together at the TF cluster sites. Furthermore, cohesin remains bound to the cluster sites when TFs are evicted in early M-phase. These results suggest that cohesin binding functions as a cellular memory that promotes re- stablishment of TF clusters after DNA replication and chromatin condensation. Examination of TF binding by ChIP-seq in a CRC cell-line.

2013-09-25 | E-GEOD-51142 | biostudies-arrayexpress

Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites

2013-08-15 | E-GEOD-49402 | biostudies-arrayexpress

Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites [GP5d/siRAD21 ChIP-Seq experiments]

2013-09-28 | E-GEOD-51234 | biostudies-arrayexpress

Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites [S-phase/M-phase synchronized cells]

2013-10-01 | E-GEOD-51290 | biostudies-arrayexpress

Pioneer factor-nucleosome binding events during differentiation are motif-encoded

Project description:Though the in vitro structural and in vivo spatial characteristics of transcription factor (TF) binding are well defined, TF interactions with chromatin and other companion TFs during development are poorly understood. To analyze such interactions in vivo, we profiled several TFs across a time course of human embryonic stem cell differentiation via CUT&RUN epigenome profiling, and studied their interactions with nucleosomes and co-occurring TFs by Enhanced Chromatin Occupancy (EChO), a computational strategy for classifying TF binding characteristics across time and space. EChO shows that at different enhancer targets, the same TF can employ either direct DNA binding, or “pioneer” nucleosome binding to access them. Pioneer binding is correlated with local binding of other TFs and enhancer motif character, including degeneracy at key bases in the pioneer factor target motif. Our strategy reveals a dynamic exchange of TFs at enhancers across developmental time that is aided by pioneer nucleosome binding.

2019-06-25 | GSE128499 | GEO

Impacts of the Ubiquitous Factor Zelda on Bicoid-dependent DNA-binding and Transcription in Drosophila

Project description:In vivo crosslinking studies suggest that the Drosophila transcription factor Bicoid (Bcd) binds to several thousand sites during early embryogenesis, but it is not clear how many of these binding events are functionally important. In contrast, reporter gene studies have identified more than 60 Bcd-dependent enhancers, all of which contain clusters of the consensus binding sequence TAATCC. These studies also identified clusters of TAATCC motifs (inactive fragments) that failed to drive Bcd-dependent activation. In general, active fragments showed higher levels of Bcd-binding in vivo, and were enriched in predicted binding sites for the ubiquitous maternal protein Zelda (Zld). Here we test the role of Zld in Bcd-mediated binding and transcription. Removal of Zld function and mutations in Zld sites caused significant reductions in Bcd-binding to known enhancers, and variable effects on the activation and spatial positioning of Bcd-dependent expression patterns. Genome-wide binding experiments in Zld mutants showed variable effects on Bcd-binding peaks, ranging from strong reductions to significantly enhanced levels of binding. Increases in Bcd binding caused the precocious Bcd-dependent activation of genes that are normally not expressed in early embryos, suggesting that Zld controls the genome-wide binding profile of Bcd at the qualitative level, and is critical for selecting target genes for activation in the early embryo. These results underscore the importance of combinatorial binding in enhancer function, and provide data that will help predict regulatory activities based on DNA sequence. 1-3 hour wild type and zelda mutant embryos were examined for Bicoid binding using Illumina HiSeq 2000. The Bcd antibody is a rabbit polyclonal antiserum raised against full length Drosophila Bcd protein (Ochoa-Espinosa et al. 2009 PNAS). The antiserum was further purified using the Protein A Antibody Purification Kit (Sigma) for ChIP-seq.

2014-05-02 | E-GEOD-55256 | biostudies-arrayexpress

Genome-wide maps of NME2 in A549 lung adenocarcinoma cells.

Project description:It is widely believed that reorganization of nucleosomes result in availability of transcription factor (TF) binding sites for eukaryotic gene regulation. Recent findings also show TFs induced during physiological perturbations can alter nucleosome occupancy to facilitate DNA binding. Although, these suggest a close relationship between TF binding and nucleosomes, the nature of this interaction, or to what extent it influences transcription is not clear. Moreover, since physiological perturbations induced multiple TFs, relatively direct effect of any TF on nucleosome occupancy remains poorly addressed. With these in mind, we used a single TF to induce physiological changes and following characterization of the two states (before and after induction of the TF) we determined: (a) genome wide binding sites of the TF, (b) promoter nucleosome occupancy and (c) transcriptome profiles, independently in both conditions. We find only ~20% of TF binding results from nucleosome repositioning - interestingly, almost all corresponding genes were transcriptionally altered. Whereas, when TF-occupancy was independent of nucleosome repositioning only a small fraction of corresponding genes were expressed/repressed. These observations suggest a model where TF occupancy leads to transcriptional change only when coupled with nucleosome repositioning in close proximity. This, to our knowledge, for the first time also helps explain why genome wide TF occupancy (e.g., from ChIP-sequencing) typically overlaps with only a small fraction of genes that change expression. The nature of interaction between TF binding and nucleosomes and what extent it influences transcription

2014-08-04 | E-GEOD-40300 | biostudies-arrayexpress

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