Genome-wide nucleosome positioning during embryonic stem cell development

Teif, Vladimir B.; Vainshtein, Yevhen; Caudron-Herger, Maïwen; Mallm, Jan‐Philipp; Marth, Caroline; Höfer, Thomas; Rippe, Karsten

doi:10.1038/nsmb.2419

Cited by 251 publications

(332 citation statements)

References 60 publications

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“…These regions are further not enriched for other repressive histone modifications, supporting the strong association of TOP2a with active chromatin ( Supplementary Fig. S1c) 29,30 . Correlation of TOP2a with H3K4me2 was also observed at other genomic regions, however, driven by lower enrichments (Supplementary Fig.…”

Section: Expression Of Topo II Isoforms Defines Developmental Statementioning

confidence: 88%

Gene regulation and priming by topoisomerase IIα in embryonic stem cells

et al. 2013

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Topoisomerases resolve torsional stress, while their function in gene regulation, especially during cellular differentiation, remains unknown. Here we find that the expression of topo II isoforms, topoisomerase IIa and topoisomerase IIb, is the characteristic of dividing and postmitotic tissues, respectively. In embryonic stem cells, topoisomerase IIa preferentially occupies active gene promoters. Topoisomerase IIa inhibition compromises genomic integrity, which results in epigenetic changes, altered kinetics of RNA Pol II at target promoters and misregulated gene expression. Common targets of topoisomerase IIa and topoisomerase IIb are housekeeping genes, while unique targets are involved in proliferation/ pluripotency and neurogenesis, respectively. Topoisomerase IIa targets exhibiting bivalent chromatin resolve upon differentiation, concomitant with their activation and occupancy by topoisomerase IIb, features further observed for long genes. These long silent genes display accessible chromatin in embryonic stem cells that relies on topoisomerase IIa activity. These findings suggest that topoisomerase IIa not only contributes to stem-cell transcriptome regulation but also primes developmental genes for subsequent activation upon differentiation.

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Section: Expression Of Topo II Isoforms Defines Developmental Statementioning

confidence: 88%

Gene regulation and priming by topoisomerase IIα in embryonic stem cells

et al. 2013

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“…Recent genome-wide studies of nucleosome dynamics and occupancy in differentiating ES cells and in comparing ES cells, iPSCs, NPCs, MEFs, and other somatic cells revealed that differences in occupancy specific to cell type and developmental stage are readily seen locally over small regions of the genome (TSS, specific genes) (62)(63)(64)(65). However, large (megabase) domains of differential occupancy between cell types were not observed in mammalian cells although they were observed in yeast.…”

Section: Discussionmentioning

confidence: 99%

Regulated large-scale nucleosome density patterns and precise nucleosome positioning correlate with V(D)J recombination

Pulivarthy

Lion

Kuzu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We show that the physical distribution of nucleosomes at antigen receptor loci is subject to regulated cell type-specific and lineagespecific positioning and correlates with the accessibility of these gene segments to recombination. At the Ig heavy chain locus (IgH), a nucleosome in pro-B cells is generally positioned over each IgH variable (VH) coding segment, directly adjacent to the recombination signal sequence (RSS), placing the RSS in a position accessible to the recombination activating gene (RAG) recombinase. These changes result in establishment of a specific chromatin organization at the RSS that facilitates accessibility of the genomic DNA for the RAG recombinase. In contrast, in mouse embryonic fibroblasts the coding segment is depleted of nucleosomes, which instead cover the RSS, thereby rendering it inaccessible. Pro-T cells exhibit a pattern intermediate between pro-B cells and mouse embryonic fibroblasts. We also find large-scale variations of nucleosome density over hundreds of kilobases, delineating chromosomal domains within IgH, in a cell typedependent manner. These findings suggest that developmentally regulated changes in nucleosome location and occupancy, in addition to the known chromatin modifications, play a fundamental role in regulating V(D)J recombination. Nucleosome positioning-which has previously been observed to vary locally at individual enhancers and promoters-may be a more general mechanism by which cells can regulate the accessibility of the genome during development, at scales ranging from several hundred base pairs to many kilobases.T he diverse repertoire of antigen receptors in vertebrates is generated by an ordered series of somatic site-specific DNA rearrangement events, collectively termed V(D)J recombination. Antigen receptor genes are assembled from V, D, and J gene segments organized into seven different loci [T-cell receptor (TCR) α, β, γ, and δ, and Ig H, κ, and λ], each of which undergoes a series of recombination reactions to generate a functional TCR or B-cell receptor (BCR) (1, 2) Rearrangement is lineage-specific, such that BCR genes are fully rearranged only in B cells and TCR genes are assembled only in T cells. Rearrangement also occurs in a preferred temporal order. For example, at the human and murine IgH loci, joining of D to J segments precedes V to DJ joining, and IgH joining precedes joining at Igκ (or Igλ) (3). In addition, recombination at several loci shows "allelic exclusion": Functional VDJH or VJκ/Jλ joining occurs only on one allele (4).Recombination is initiated by the lymphocyte-specific recombination activating gene (RAG)1/RAG2 endonuclease. RAG1/2 cleaves at the recombination signal sequences (RSSs) flanking all antigen receptor gene segments. The consensus RSS consists of a heptamer sequence directly adjacent to the coding element and an A/T-rich nonamer separated from the heptamer by a spacer region of conserved length (12 or 23 bp) but relatively nonconserved sequence. The broken ends are then joined with the aid of DNA repair proteins,...

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“…In higher eukaryotes, the DNA sequence at promoters, enhancers, and transcription factor-binding sites generally encode a high intrinsic nucleosome occupancy (Tillo et al 2010;Gaffney et al 2012). However, in disagreement with predicted high nucleosome occupancy, genome-wide mapping typically shows that nucleosomes are depleted at active promoters (Schones et al 2008;Valouev et al 2011;Teif et al 2012). DNA accessibility studies further indicate that promoters tend to open ubiquitously among multiple cell types (Thurman et al 2012), suggesting that generally expressed trans-factors keep promoters accessible.…”

Section: Nucleosomes At Enhancers: a Collaborator For Pioneer Factorsmentioning

confidence: 99%

Pioneer transcription factors in cell reprogramming

2014

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A subset of eukaryotic transcription factors possesses the remarkable ability to reprogram one type of cell into another. The transcription factors that reprogram cell fate are invariably those that are crucial for the initial cell programming in embryonic development. To elicit cell programming or reprogramming, transcription factors must be able to engage genes that are developmentally silenced and inappropriate for expression in the original cell. Developmentally silenced genes are typically embedded in ''closed'' chromatin that is covered by nucleosomes and not hypersensitive to nuclease probes such as DNase I. Biochemical and genomic studies have shown that transcription factors with the highest reprogramming activity often have the special ability to engage their target sites on nucleosomal DNA, thus behaving as ''pioneer factors'' to initiate events in closed chromatin. Other reprogramming factors appear dependent on pioneer factors for engaging nucleosomes and closed chromatin. However, certain genomic domains in which nucleosomes are occluded by higher-order chromatin structures, such as in heterochromatin, are resistant to pioneer factor binding. Understanding the means by which pioneer factors can engage closed chromatin and how heterochromatin can prevent such binding promises to advance our ability to reprogram cell fates at will and is the topic of this review.Cell fate control represents the most extreme form of gene regulation. Genes specific to the function of a particular type of cell may be antagonistic to the function of another type of cell, so nature has evolved diverse regulatory mechanisms to ensure stable patterns of gene activation and repression. In prokaryotes, self-sustaining regulatory networks of transcription factors bound to DNA can be sufficient to regulate gene activation and repression (Ptashne 2011). In eukaryotes, ;200-base-pair (bp) segments of the genome are wound nearly twice around an octamer of the four core histones to form nucleosomes, providing steric constraints on how transcription factors can bind DNA (Kornberg and Lorch 1999). As described below, pioneer transcription factors have the special property of being able to overcome such constraints, enabling the factors to engage closed chromatin that is not accessible by other types of transcription factors (Fig. 1). However, further higher-order packaging of nucleosomes into heterochromatin can occlude access to DNA altogether, presenting an additional barrier to cell fate conversion (Fig. 1). This review focuses on the most recent studies of pioneer factors in cell programming and reprogramming, how pioneer factors have special chromatinbinding properties, and facilitators and impediments to chromatin binding. We project that such knowledge will greatly aid future efforts to change the fates of cells at will for research, diagnostic, and therapeutic purposes.

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Genome-wide nucleosome positioning during embryonic stem cell development

Cited by 251 publications

References 60 publications

Gene regulation and priming by topoisomerase IIα in embryonic stem cells

Gene regulation and priming by topoisomerase IIα in embryonic stem cells

Regulated large-scale nucleosome density patterns and precise nucleosome positioning correlate with V(D)J recombination

Pioneer transcription factors in cell reprogramming

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