Life Sciences Research for Lifelong Health

Publications stefan-schoenfelder

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Transcription factories and nuclear organization of the genome.
Eskiw CH, Cope NF, Clay I, Schoenfelder S, Nagano T, Fraser P

The dynamic compartmental organization of the transcriptional machinery in mammalian nuclei places particular constraints on the spatial organization of the genome. The clustering of active RNA polymerase I transcription units from several chromosomes at nucleoli is probably the best-characterized and universally accepted example. RNA polymerase II localization in mammalian nuclei occurs in distinct concentrated foci that are several-fold fewer in number compared to the number of active genes and transcription units. Individual transcribed genes cluster at these shared transcription factories in a nonrandom manner, preferentially associating with heterologous, coregulated genes. We suggest that the three-dimensional (3D) conformation and relative arrangement of chromosomes in the nucleus has a major role in delivering tissue-specific gene-expression programs.

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Cold Spring Harbor symposia on quantitative biology, 75, 1943-4456, 501-6, 2010

PMID: 21467135

The transcriptional interactome: gene expression in 3D.
S Schoenfelder, I Clay, P Fraser

Transcription in the eukaryotic nucleus has long been thought of as conforming to a model in which RNA polymerase complexes are recruited to and track along isolated templates. However, a more dynamic role for chromatin in transcriptional regulation is materializing: enhancer elements interact with promoters forming loops that often bridge considerable distances and genomic loci, even located on different chromosomes, undergo chromosomal associations. These associations amass to form an extensive 'transcriptional interactome', enacted at functional subnuclear compartments, to which genes dynamically relocate. The emerging view is that long-range chromosomal associations between genomic regions, and their repositioning in the three-dimensional space of the nucleus, are key contributors to the regulation of gene expression.

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Current opinion in genetics & development, 20, 2, 127-33, 2010

PMID: 20211559
DOI: 10.1016/j.gde.2010.02.002

Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells.
S Schoenfelder, T Sexton, L Chakalova, NF Cope, A Horton, S Andrews, S Kurukuti, JA Mitchell, D Umlauf, DS Dimitrova, CH Eskiw, Y Luo, CL Wei, Y Ruan, JJ Bieker, P Fraser

The discovery of interchromosomal interactions in higher eukaryotes points to a functional interplay between genome architecture and gene expression, challenging the view of transcription as a one-dimensional process. However, the extent of interchromosomal interactions and the underlying mechanisms are unknown. Here we present the first genome-wide analysis of transcriptional interactions using the mouse globin genes in erythroid tissues. Our results show that the active globin genes associate with hundreds of other transcribed genes, revealing extensive and preferential intra- and interchromosomal transcription interactomes. We show that the transcription factor Klf1 mediates preferential co-associations of Klf1-regulated genes at a limited number of specialized transcription factories. Our results establish a new gene expression paradigm, implying that active co-regulated genes and their regulatory factors cooperate to create specialized nuclear hot spots optimized for efficient and coordinated transcriptional control.

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Nature genetics, 42, 1, 53-61, 2010

PMID: 20010836
DOI: 10.1038/ng.496

Open Access

Interchromosomal huddle kickstarts antiviral defense.
S Schoenfelder, P Fraser

Long-distance chromosomal interactions are emerging as a potential mechanism of gene expression control. In this issue, Apostolou and Thanos (2008) describe how viral infection elicits interchromosomal associations between the interferon-beta (IFN-beta) gene enhancer and DNA binding sites of the transcription factor NF-kappaB, resulting in the initiation of transcription and an antiviral response.

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Cell, 134, 1, 14-6, 2008

PMID: 18614003
DOI: 10.1016/j.cell.2008.06.041

Open Access

Non-coding transcripts in the H19 imprinting control region mediate gene silencing in transgenic Drosophila.
S Schoenfelder, G Smits, P Fraser, W Reik, R Paro

The imprinting control region (ICR) upstream of H19 is the key regulatory element conferring monoallelic expression on H19 and Igf2 (insulin-like growth factor 2). Epigenetic marks in the ICR regulate its interaction with the chromatin protein CCCTC-binding factor and with other control factors to coordinate gene silencing in the imprinting cluster. Here, we show that the H19 ICR is biallelically transcribed, producing both sense and antisense RNAs. We analyse the function of the non-coding transcripts in a Drosophila transgenic system in which the H19 upstream region silences the expression of a reporter gene. We show that knockdown of H19 ICR non-coding RNA (ncRNA) by RNA interference leads to the loss of reporter gene silencing. Our results are, to the best of our knowledge, the first to show that ncRNAs in the H19 ICR are functionally significant, and also indicate that they have a role in regulating gene expression and perhaps epigenetic marks at the H19/Igf2 locus.

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EMBO reports, 8, 11, 1068-73, 2007

PMID: 17948025
DOI: 10.1038/sj.embor.7401094

Open Access