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"Fraser, Peter"
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Nuclear organization of the genome and the potential for gene regulation
Much work has been published on the
cis
-regulatory elements that affect gene function locally, as well as on the biochemistry of the transcription factors and chromatin- and histone-modifying complexes that influence gene expression. However, surprisingly little information is available about how these components are organized within the three-dimensional space of the nucleus. Technological advances are now helping to identify the spatial relationships and interactions of genes and regulatory elements in the nucleus and are revealing an unexpectedly extensive network of communication within and between chromosomes. A crucial unresolved issue is the extent to which this organization affects gene function, rather than just reflecting it.
Journal Article
Cell-cycle dynamics of chromosomal organization at single-cell resolution
Chromosomes in proliferating metazoan cells undergo marked structural metamorphoses every cell cycle, alternating between highly condensed mitotic structures that facilitate chromosome segregation, and decondensed interphase structures that accommodate transcription, gene silencing and DNA replication. Here we use single-cell Hi-C (high-resolution chromosome conformation capture) analysis to study chromosome conformations in thousands of individual cells, and discover a continuum of
cis
-interaction profiles that finely position individual cells along the cell cycle. We show that chromosomal compartments, topological-associated domains (TADs), contact insulation and long-range loops, all defined by bulk Hi-C maps, are governed by distinct cell-cycle dynamics. In particular, DNA replication correlates with a build-up of compartments and a reduction in TAD insulation, while loops are generally stable from G1 to S and G2 phase. Whole-genome three-dimensional structural models reveal a radial architecture of chromosomal compartments with distinct epigenomic signatures. Our single-cell data therefore allow re-interpretation of chromosome conformation maps through the prism of the cell cycle.
Single-cell Hi-C analysis in thousands of mouse embryonic stem cells shows that chromosomal compartments, topological-associated domains and long-range loops all have distinct cell-cycle dynamics.
Chromosomal organization dynamics
Eukaryotic chromosomes undergo a cycle of compaction and decondensation during the cell cycle. Here, Peter Fraser and colleagues have developed an improved single-cell Hi-C method to characterize the 3D organization of chromosomes through the cell cycle in thousands of individual mouse embryonic stem cells. They find that chromosomal compartments, topological-associated domains and loops are each governed by distinct dynamics and reveal a continuum of dynamic chromosomal structural features throughout the cell cycle. The results will be a new point of reference for interpreting chromosome conformation Hi-C maps.
Journal Article
Long-range enhancer–promoter contacts in gene expression control
Spatiotemporal gene expression programmes are orchestrated by transcriptional enhancers, which are key regulatory DNA elements that engage in physical contacts with their target-gene promoters, often bridging considerable genomic distances. Recent progress in genomics, genome editing and microscopy methodologies have enabled the genome-wide mapping of enhancer–promoter contacts and their functional dissection. In this Review, we discuss novel concepts on how enhancer–promoter interactions are established and maintained, how the 3D architecture of mammalian genomes both facilitates and constrains enhancer–promoter contacts, and the role they play in gene expression control during normal development and disease.For appropriate control of gene expression, enhancers must communicate with the right target genes at the right time, typically over large genomic distances. In this Review, Schoenfelder and Fraser discuss our latest understanding of long-range enhancer–promoter crosstalk, including target-gene specificity, interaction dynamics, protein and RNA architects of interactions, roles of 3D genome organization and the pathological consequences of regulatory rewiring.
Journal Article
Alexandra : Greek text, translation, commentary, and introduction
\"The Alexandra attributed to Lykophron is a minor poetic masterpiece. At 1474 lines, it is one of the most important and notoriously difficult Greek poems dating from the Hellenistic period (most likely the early second century BC). Most of the poem purports to be a prophecy by the mythical Trojan princess, Kassandra, the most beautiful of the daughters of King Priam, and her prophecy ranges from the Trojan War to the historical Roman conquest of Greece, which took place in the poet's own time. The poem's importance arises from the light which it sheds on Greek religion (in particular the role of women), on foundation myths and myths of colonial identity, and on local - especially Italian - cults and cult places. The difficulty of the poem stems from its unusual vocabulary - many words of ancient Greek are found only in this poem - and the riddling and meandering way in which most of the many mythological characters are referenced. As well as providing the Greek text in full and its English translation, this volume provides the first ever full-length commentary in English on the poem.\" -- back cover
Book
CHiCAGO: robust detection of DNA looping interactions in Capture Hi-C data
Capture Hi-C (CHi-C) is a method for profiling chromosomal interactions involving targeted regions of interest, such as gene promoters, globally and at high resolution. Signal detection in CHi-C data involves a number of statistical challenges that are not observed when using other Hi-C-like techniques. We present a background model and algorithms for normalisation and multiple testing that are specifically adapted to CHi-C experiments. We implement these procedures in CHiCAGO (
http://regulatorygenomicsgroup.org/chicago
), an open-source package for robust interaction detection in CHi-C. We validate CHiCAGO by showing that promoter-interacting regions detected with this method are enriched for regulatory features and disease-associated SNPs.
Journal Article
Hi-C as a tool for precise detection and characterisation of chromosomal rearrangements and copy number variation in human tumours
Chromosomal rearrangements occur constitutionally in the general population and somatically in the majority of cancers. Detection of balanced rearrangements, such as reciprocal translocations and inversions, is troublesome, which is particularly detrimental in oncology where rearrangements play diagnostic and prognostic roles. Here we describe the use of Hi-C as a tool for detection of both balanced and unbalanced chromosomal rearrangements in primary human tumour samples, with the potential to define chromosome breakpoints to bp resolution. In addition, we show copy number profiles can also be obtained from the same data, all at a significantly lower cost than standard sequencing approaches.
Journal Article