The Generation and Propagation of Variegated Chromosome Structures

Weintraub, Harold; Flint, S. J.; Leffak, I.M.; Groudine, Mark; Grainger, Robert M.

doi:10.1101/sqb.1978.042.01.042

Cited by 63 publications

(40 citation statements)

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“…BIOL. formulation of a model by which replication origin selection could influence chromatin structure and gene activity (49). This proposal has recently been restated by Smithies (42), who suggested that a gene must be replicated from an upstream origin to be expressed in the following cell generation.…”

Section: Discussionmentioning

confidence: 99%

“…The apparent nonrandom selection of sites for replication initiation and the asymmetry of chromatin replication at the level of DNA synthesis (16,35) and protein deposition (28) have contributed to the proposal that replication origin selection may regulate gene activity (42,49). As an initial step toward testing this hypothesis we have used a runoff replication assay to determine the direction of replication of the chicken alpha-globin genes in cells where these sequences are expressed (erythrocytes) or quiescent (lymphocytes).…”

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Polarity of DNA replication through the avian alpha-globin locus.

James

Leffak

1986

Mol. Cell. Biol.

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Toward understanding the controls affecting eucaryotic chromosome replication, we used a runoff replication assay to investigate whether the activity of a gene is related to its use of an upstream or downstream replication origin. When in vivo-initiated DNA polymerases are allowed to complete replication in vitro in the presence of bromodeoxyuridine triphosphate the density label is preferentially incorporated into origin-distal regions of DNA. Isopycnic centrifugation and blot hybridization analysis of the relative bromodeoxyuridine triphosphate incorporation into fragments spanning the chicken alpha-globin locus indicate that this region is replicated from an upstream origin both in chicken lymphocytes and in erythrocytes. Thus the replication polarity of these genes does not change as a function of transcriptional activity, consistent with earlier suggestions that DNA replication in the transcriptional direction may be a necessary but not sufficient condition for gene expression.The ordered nature of eucaryotic chromosome replication is evident in the replication of particular chromosome domains during discrete intervals of the S phase and in the synchronous initiation of replicon clusters whose size and number vary in a tissue-specific and developmentally regulated manner (reviewed in references 16, 21, and 47). These observations are consistent with recent data showing that DNA sequences complementary to probes for individual transcribed genes preferentially replicate early in the S phase and that chromosome position influences the timing of gene replication (6,11,17,20). In Saccharomyces cerevisiae, electron microscopic and biochemical data imply that DNA synthesis initiates at specific loci (5,7,18,46,50); the clearest evidence for the existence of discrete origins in higher eucaryotes comes from studies of the amplification of dihydrofolate reductase genes in CHO cells (22,23) and chorion genes in Drosophila follicle cells (36,44), where the extent -of amplification decreases bidirectionally from a central domain.The apparent nonrandom selection of sites for replication initiation and the asymmetry of chromatin replication at the level of DNA synthesis (16, 35) and protein deposition (28) have contributed to the proposal that replication origin selection may regulate gene activity (42, 49). As an initial step toward testing this hypothesis we have used a runoff replication assay to determine the direction of replication of the chicken alpha-globin genes in cells where these sequences are expressed (erythrocytes) or quiescent (lymphocytes). Following the logic used to locate the simian virus 40 origin of replication (12, 34), isolated nuclei were incubated in a replication cocktail containing bromodeoxyuridine (BrdU) triphosphate (BrdUTP) and allowed to complete the synthesis of DNA chains initiated in vivo. The direction of replication was deduced based on the relative incorporation of BrdU into DNA fragments encompassing the globin locus; those fragments farthest from the origin of replication incorpora...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Polarity of DNA replication through the avian alpha-globin locus.

James

Leffak

1986

Mol. Cell. Biol.

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“…The maintenance of repressed or activated transcription states represents an efficient mechanism for progressive cellular differentiation 30 . In such a model, fundamental decisions regarding the turning on or off of genes or groups of genes need to be made only once.…”

Section: Epigenetic Inheritancementioning

confidence: 99%

Controlling the double helix

Felsenfeld

Groudine

2003

Nature

975

782

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development in the sea urchin have delineated a regulatory network that has significant predictive power 16 (Fig. 2). Finally, systems approaches to metabolism in an archaeal halobacterium (an organism thriving in up to five-molar salt solutions, such as the Dead Sea) have revealed new insights into the inter-relationships among several modules controlling energy production in the cell 18 .The study of cellular and organismal biology using the systems approach is at its very beginning. It will require integrated teams of scientists from across disciplines -biologists, chemists, computer scientists, engineers, mathematicians and physicists. New methods for acquiring and analysing high-throughput biological data are needed. A powerful computational infrastructure must be leveraged to generate more effective approaches to the capture, storage, analysis, integration, graphical display and mathematic formulation of biological complexity. New technologies must be integrated with each other. Finally, hypothesis-driven and discovery science must be integrated. In short, both new science and technology must emerge for the systems biology approach to realize its promise. A cultural shift in the biological sciences is needed, and the education and training of the next generation of biologists will require significant reform.Gordon Moore, the founder of Intel, predicted that the number of transistors that could be placed on a computer chip would double every 18 months. It has for more than 30 years. This exponential growth has been a driver for the explosive growth of information technology. Likewise, the amount of DNA sequence information available to the scientific community is following a similar, perhaps even steeper, exponential increase. The critical issue is how sequence information can be converted into knowledge of the organism and how biology will change as a result. We believe that a systems approach to biology is the key. It is clear, however, that this approach poses significant challenges, both scientific and cultural 19 . The discovery of DNA structure started us on this journey, the end of which will be the grand unification of the biological sciences in the emerging, information-based view of biology.s s

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“…The epigenetic modification that involves DNA is methylation of cytosine residues in the context of symmetrical CpG dinucleotides, which are enriched in DNA stretches called CpG islands (9). Demethylation of CpG islands is associated with gene transcription (10) and is facilitated by DNA synthesis and cell division (11). Agents that inhibit DNA methylation enhance IFN-␥ or IL-4 expression, while the levels of DNA methylation in the cytokine promoters correlate inversely with differences in cytokine expression between naive and memory T cells, suggesting a role for DNA methylation in the regulation of T cell function (12,13).…”

Section: Onventional Mhc-restricted Cd4mentioning

confidence: 99%

Innate-Like Effector Differentiation of Human Invariant NKT Cells Driven by IL-7

Lalla

Festuccia

Albrecht

et al. 2008

The Journal of Immunology

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Conventional MHC-restricted T lymphocytes leave thymus with a naive phenotype and require Ag-dependent stimulation coupled to proliferation to acquire effector functions. Invariant (i)NKT cells are a subset of T lymphocytes considered innate because they display an effector memory phenotype independent of TCR stimulation by foreign Ags. We investigated the effector differentiation program followed by human iNKT cells by studying cells from a relevant set of fetal thymi and umbilical cord blood samples. We find that human fetal iNKT cells have already started a differentiation program that activates the epigenetic and transcriptional control of ifng and il4 genes, leading at birth to cells that express these cytokines upon TCR signaling but independently of proliferation in vitro. Both ex vivo and in vitro analysis of fetal and neonatal iNKT cells delineate an effector differentiation program linked to cell division in vivo, and they identify IL-7 as one of the crucial signals driving this program in the apparent absence of Ag stimulation. Consistent with these data, human fetal and neonatal iNKT cells are hyperresponsive in vitro to IL-7 in comparison to conventional T cells, owing to an increased expression and signaling function of the IL-7 receptor α-chain. The innate nature of human iNKT cells could thus derive from lineage-specific developmental cues that selectively make these cells efficient IL-7 responders following thymic selection.

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The Generation and Propagation of Variegated Chromosome Structures

Cited by 63 publications

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Polarity of DNA replication through the avian alpha-globin locus.

Polarity of DNA replication through the avian alpha-globin locus.

Controlling the double helix

Innate-Like Effector Differentiation of Human Invariant NKT Cells Driven by IL-7

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