Nucleosome conformation dictates the histone code
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA632919 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11791775_1.fastq.gz | Fastqsanger.gz | |||
| SRR11791775_2.fastq.gz | Fastqsanger.gz | |||
| SRR11791776_1.fastq.gz | Fastqsanger.gz | |||
| SRR11791776_2.fastq.gz | Fastqsanger.gz | |||
| SRR11791778_1.fastq.gz | Fastqsanger.gz |
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Project description:Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized “codes” that are read by specialized domains (reader domains) in chromatin associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP - histone PTM] specificity, and in doing so to decipher the histone code. However, this has largely been done using a reductive approach of isolated reader domains and histone peptides, with the assumption that PTM readout is unaffected by any higher order considerations. Here we show that histone PTM specificity is in fact dependent on nucleosomal context, necessitating we re-define the ‘histone code’ concept and further interrogate it at the nucleosomal level.
2021-05-06 | GSE150617 | GEO
Project description:Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized 'codes' that are read by specialized regions (reader domains) in chromatin-associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP: histone PTM] specificities, and thus decipher the histone code and guide epigenetic therapies. However, this has largely been done using the reductive approach of isolated reader domains and histone peptides, which cannot account for any higher-order factors. Here, we show that the [BPTF PHD finger and bromodomain: histone PTM] interaction is dependent on nucleosome context. The tandem reader selectively associates with nucleosomal H3K4me3 and H3K14ac or H3K18ac, a combinatorial engagement that despite being in cis is not predicted by peptides. This in vitro specificity of the BPTF tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. We propose that regulatable histone tail accessibility and its impact on the binding potential of reader domains necessitates we refine the 'histone code' concept and interrogate it at the nucleosome level.
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Project description:We have used a high-resolution tiled microarray, with single-nucleosome resolution, to investigate the in vivo occurrence of combinations of 12 histone modifications on thousands of nucleosomes in actively growing S. cerevisiae. We found that histone modifications do not occur independently; there are roughly two groups of co-occurring modifications. We find no evidence for a deterministic code of many discrete states, but instead see blended, continuous patterns that distinguish nucleosomes at one location (promoter nucleosomes, for example) from those at another location (over the 3’ ends of coding regions, for example). These results are consistent with the idea of a simple, redundant histone code, in which multiple modifications share the same role. Keywords: ChIP-chip
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Project description:Histone code dynamics during nitrogen response in tomato
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Project description:Recent studies indicate that thousands of genes are expressed from bidirectional promoters (BDPs). Gene regulation at BDPs is poorly understood, in particular how the cell is able to regulate them differently. Here we investigate the effect of histone Modifications in BDP regulation. In this study, we model the gene activity using different gene expression assays, such as RNA-Seq, GRO-cap, and CAGE around the BDP transcription start sites (TSSs) using different histone modifications in various cell types. We develop a new statistical approach that links histone modifications to gene expression at BDPs. It improves over previous methods, because it is able to capture spatial dependencies of histone modifications along a promoter and leads to more interpretable results. We predict a general histone code that is independent of transcript orientation, cell type, and promoter configuration. The histone code at BDPs reveals that promoters are regulated unidirectionally, such that the majority of histone marks associated with gene expression occur downstream of the gene's TSS. By contrasting associations of histone marks with steady-state levels of capped RNAs in CAGE and nascent capped RNAs in GRO-cap, we show which histone marks have a preference for initiating polymerases and actively elongating polymerases. Using single-cell data we show that the bidirectional histone signal of activating marks is often due averaging of a heterogeneous cell population. Our results have implications for other experiments where the relationship between histone modification and gene initiation or gene elongation is investigated on a genome-wide scale.
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Project description:We assess the role of intrinsic histone-DNA interactions by mapping nucleosomes assembled in vitro on genomic DNA. Nucleosomes strongly prefer yeast DNA over E. coli DNA, indicating that the yeast genome evolved to favor nucleosome formation. Many yeast promoter and terminator regions intrinsically disfavor nucleosome formation, and nucleosomes assembled in vitro display strong rotational positioning. Nucleosome arrays generated by the ACF assembly factor display fewer nucleosome-free regions, reduced rotational positioning, and less translational positioning than obtained by intrinsic histone-DNA interactions. Importantly, in vitro assembled nucleosomes display only a limited preference for specific translational positions and do not show the pattern observed in vivo. Our results argue against a genomic code for nucleosome positioning, and they suggest that the nucleosomal pattern in coding regions arises primarily from statistical positioning from a barrier near the promoter that involves some aspect of transcriptional initiation by RNA polymerase II.
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Project description:Sequence-to-function neural networks learn cis-regulatory sequence rules driving many types of genomic data. Interpreting these models to relate the sequence rules to underlying biological processes remains challenging, especially for complex genomic readouts such as MNase-seq, which maps nucleosome occupancy but is confounded by experimental bias. We introduce pairwise influence by sequence attribution (PISA), an interpretation tool that combinatorially decodes which bases contributed to the readout at a specific genomic coordinate. PISA visualizes the effects of transcription factor motifs, detects undiscovered motifs with complex contribution patterns, and reveals experimental biases. By learning the bias for MNase-seq, PISA enables unprecedented nucleosome prediction models, allowing the \emph{de novo} discovery of nucleosome-positioning motifs and their long-range chromatin effects, as well as the design of sequences with altered nucleosome configurations. These results show that PISA is a versatile tool that expands our ability to train and interpret sequence-to-function neural networks on genomics data and understand the underlying cis-regulatory code.
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Project description:Linker histones are involved in the formation of higher-order chromatin structure. Although linker histones have been implicated in the regulation of specific genes, it still remains unclear what their principal binding determinants are and how their repressive function in vitro can be reconciled with presumed broad binding in vivo. We generated a full genome, high resolution binding map of linker histone H1 in Drosophila Kc cells, using DamID. H1 binds at similar levels across much of the genome, both in classical euchromatin and heterochromatin. Strikingly, there are pronounced dips of low H1 occupancy around transcription start sites of active genes and at many distant cis-regulatory sites. H1 dips are not due to lack of nucleosomes. Rather, all regions with low binding of H1 show enrichment of the histone variant H3.3 which itself has been linked to high nucleosome turnover. Upon knockdown of H3.3, we find that H1 levels increase at sites previously not covered with H1 with a concomitant increase in nucleosome repeat length. These changes are independent of transcriptional changes. Our results show that the H3.3 protein counteracts association of H1 at genomic sites with high rates of histone turnover. This antagonism provides a mechanism to keep diverse genomic sites in an open chromatin conformation. For this study, we generated DamID profiles of histone H1 and RpII18 in Drosophila Kc167 cells. Additionally, we generated H1 profiles in cells treated with RNAi against white, H3.3B, or H3.3A and H3.3B. Nucleosome occupancy profiles were generated in untreated cells and cells treated with RNAi against white or H3.3A and H3.3B. Profiles of expression changes were generated for H3.3B RNAi and H3.3A and H3.3B RNAi. DamID experiments for H1 and RpII18 were performed in Drosophila cell cultures. Samples were hybridized to 380k NimbleGen arrays with 300 bp probe spacing. Formaldehyde-assisted isolation of regulatotry elements (FAIRE) was performed in Drosophila Kc167 cells. Samples were hybridized to 380k NimbleGen arrays with 300 bp probe spacing over non-crosslinked genomic DNA. Nucleosome positioning profiles were made by hybridizing mononucleosomal DNA over MNase digested purified genomic DNA on 380k NimbleGen arrays with 10 bp probe spacing. Expression profiles were made as H3.3 RNAi over white RNAi cohybridizations on spotted INDAC long oligo arrays. Every experiment was done in duplicate in the reverse dye orientation.
2010-06-23 | E-GEOD-16882 | biostudies-arrayexpress
Project description:Experiments performed over the past three decades have shown that nucleosomes are transcriptional repressors. In Saccharomyces cerevisiae, depletion of histone H4 results in the genome-wide transcriptional de-repression of hundreds genes. The mechanism of de-repression is hypothesized to be rooted directly in chromatin changes. To test this, we reproduced classical H4 depletion experiments by conditional repression of all histone H3 transcription, which depletes the supply of nucleosomes in vivo. RNA-seq results were consistent with the earlier studies, but much more sensitive, revealing nearly 2500 de-repressed genes. Changes in chromatin organization were determined by MNase-seq. Nucleosomes that were preferentially retained occurred in regions of high DNA-encoded nucleosome affinity, and were marked with H3K36me2, which is linked to transcription elongation. Nucleosomes harboring acetyl marks or that contained the variant histone H2A.z were preferentially lost. Genes that were de-repressed lost or rearranged nucleosomes at their promoter, but not in the gene body. Therefore, a combination of DNA-encoded nucleosome stability and nucleosome composition dictates which nucleosomes will be lost under conditions of limiting histone protein. This, in turn, governs which genes will experience a loss of regulatory fidelity. MNase-seq experiments consist of three wildtype (1 single-end and 2 paired-end) and four mutant (DCB200.1/H3 shutoff; 2 single-end, 2 paired-end) replicates. Each replicate contains two timepoints reflecting chromatin immediately after ("O hours") and 3 hours after transition to media containing dextrose. RNA-seq data includes three replicates from wildtype or H3 depleted cells after 3 hours in media containing dextrose.
2012-09-26 | E-GEOD-29293 | biostudies-arrayexpress
Project description:Experiments performed over the past three decades have shown that nucleosomes are transcriptional repressors. In Saccharomyces cerevisiae, depletion of histone H4 results in the genome-wide transcriptional de-repression of hundreds genes. The mechanism of de-repression is hypothesized to be rooted directly in chromatin changes. To test this, we reproduced classical H4 depletion experiments by conditional repression of all histone H3 transcription, which depletes the supply of nucleosomes in vivo. RNA-seq results were consistent with the earlier studies, but much more sensitive, revealing nearly 2500 de-repressed genes. Changes in chromatin organization were determined by MNase-seq. Nucleosomes that were preferentially retained occurred in regions of high DNA-encoded nucleosome affinity, and were marked with H3K36me2, which is linked to transcription elongation. Nucleosomes harboring acetyl marks or that contained the variant histone H2A.z were preferentially lost. Genes that were de-repressed lost or rearranged nucleosomes at their promoter, but not in the gene body. Therefore, a combination of DNA-encoded nucleosome stability and nucleosome composition dictates which nucleosomes will be lost under conditions of limiting histone protein. This, in turn, governs which genes will experience a loss of regulatory fidelity.
2012-09-26 | GSE29293 | GEO