Big genes and little genes and deadlines for transcription

O’Farrell, Patrick H.

doi:10.1038/359366a0

Cited by 41 publications

(16 citation statements)

References 9 publications

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“…We reasoned that if Sna acted by repressing initiation of gene expression, then longer genes would take more time to be repressed than shorter ones since it would take more time for previously loaded RNA Polymerase (RNAP) molecules to traverse longer genes. For example, a long transcription unit such as sog (~22 kb in length) requires ≈ 20 minutes to be fully transcribed, whereas a short gene such as brk (~3.5 kb) would take only about 3.5 minutes to be transcribed assuming that RNAP progresses at its typical rate of ≈1 kb per minute (O'Brien and Lis, 1993; O'Farrell, 1992). Thus, completion of transcription and hence onset of repression for such a pair of long versus short genes could amount to a differential delay of ≈ 15 minutes, which is a significant fraction of the cellularization stage of nuclear cycle 14.…”

Section: Resultsmentioning

confidence: 99%

Gene length may contribute to graded transcriptional responses in the Drosophila embryo

McHale

Mizutani

Kosman

et al. 2011

Developmental Biology

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An important question in developmental biology is how relatively shallow gradients of morphogens can reliably establish a series of distinct transcriptional readouts. Current models emphasize interactions between transcription factors binding in distinct modes to cis-acting sequences of target genes. Another recent idea is that the cis-acting interactions may amplify preexisting biases or prepatterns to establish robust transcriptional responses. In this study, we examine the possible contribution of one such source of prepattern, namely gene length. We developed quantitative imaging tools to measure gene expression levels for several loci at a time on a single-cell basis and applied these quantitative imaging tools to dissect the establishment of a gene expression border separating the mesoderm and neuroectoderm in the early Drosophila embryo. We first characterized the formation of a transient ventral-to-dorsal gradient of the Snail (Sna) repressor and then examined the relationship between this gradient and repression of neural target genes in the mesoderm. We found that neural genes are repressed in a nested pattern within a zone of the mesoderm abutting the neuroectoderm, where Sna levels are graded. While several factors may contribute to the transient graded response to the Sna gradient, our analysis suggests that gene length may play an important, albeit transient, role in establishing these distinct transcriptional responses. One prediction of the gene-length-dependent transcriptional patterning model is that the co-regulated genes knirps (a short gene) and knirps-related (a long gene) should be transiently expressed in domains of differing widths, which we confirmed experimentally. These findings suggest that gene length may contribute to establishing graded responses to morphogen gradients by providing transient prepatterns that are subsequently amplified and stabilized by traditional cis-regulatory interactions.

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Section: Resultsmentioning

confidence: 99%

Gene length may contribute to graded transcriptional responses in the Drosophila embryo

McHale

Mizutani

Kosman

et al. 2011

Developmental Biology

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“…The gene for this comparatively small protein (166 amino acids) contains six exons and five introns dispersed over 35 kb of rat DNA. The time required for RNA polymerase to transcribe genes of this large size could have several biologic consequences (41), notably, a significant lag between changes in transcription initiation rate and corresponding changes Figure 6. Deletion analysis of the RTI40 promoter in cultured type II cells.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Gene and Promoter for RTI40, a Differentiation Marker of Type I Alveolar Epithelial Cells

Vanderbilt

Dobbs

1998

Am J Respir Cell Mol Biol

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In an effort to understand the processes that establish and maintain the differentiated state of the alveolar epithelium, we have analyzed the gene for rat type I cell 40 kD protein (RTI40), an apical integral plasma membrane protein expressed in type I but not type II alveolar epithelial cells. The RTI40 gene spans 35 kilobase pairs; it contains 6 exons and at least 6 rat Identifier repetitive elements. Three exons encode the predicted RTI40 extracellular domain and one encodes the single transmembrane spanning domain. The final exon encodes one amino acid followed by a stop codon. RTI40 gene transcription starts downstream from a TATA homology, which is immediately adjacent to putative binding sites for thyroid transcription factor 1 and Sp1. In H441 cell transfections, mutagenesis of a 5 Ј -flanking fragment ( Ϫ 2496 to ϩ 104) revealed two regions that contribute to promoter activity: Ϫ 1247 through Ϫ 795 and Ϫ 163 through Ϫ 81. Heterologous promoter fusion experiments suggest that a cooperative interaction between these regions activates transcription. In transfected type II cells, deletion across the proximal region produced a 6-fold drop in promoter activity, whereas deletion across the distal region was without apparent effect. These results provide a foundation to analyze further the factors that govern alveolar epithelial cell phenotype. Vanderbilt, J. N., and L. G. Dobbs. 1998. Characterization of the gene and promoter for RTI40, a differentiation marker of type I alveolar epithelial cells. Am. J. Respir. Cell Mol. Biol. 19:662-671.The distal respiratory epithelium of the vertebrate lung contains two anatomically distinct highly differentiated cell types. Type II alveolar epithelial cells are cuboidal cells that synthesize and secrete pulmonary surfactant (1). In contrast, type I alveolar epithelial cells are much larger cells with very thin cytoplasmic extensions; these cells cover more than 95% of the alveolar surface (2). During recovery from alveolar injury, type I cells slough from the epithelium and are replenished via a poorly understood differentiative process, with cells of type II origin (3, 4). In this scenario, a highly specialized, well-differentiated cell, synthesizing and secreting surfactant lipids and proteins, apparently shuts this system down, rearranges its cytoskeleton, and activates a new set of type I cell-associated genes. Recent cell culture studies lend strong support to the concept of a plasticity in the expression of type I and type II phenotypes by two cell populations (5, 6). For either biologic phenomenon-lung injury or cell culturethe molecular mechanisms underlying this transdifferentiation process are unknown.A limited number of type I cell markers have been identified (7-10). Of these, the first described was rat type I cell 40-kD protein (RTI40), a 40-kD glycoprotein defined by a monoclonal antibody raised against partially purified type I cells (7). In the lung, RTI40 is localized to the apical plasma membranes of type I cells, which in turn cover more than 95% of th...

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“…The cyclic stripping and reassociation of RNAP II and transcription factors at each mitosis could have several regulatory consequences. First, as Shermoen and O'Farrell point out, the rapid mitotic cycles of early embryos could preclude expression of long transcription units, as nascent RNAs would be truncated at each mitosis and transcription would need to reinitiate anew at the end of each cleavage cycle (42,59). Expression of long transcription units (such as Ubx) would be precluded until cell cycles were long enough to allow full-length transcription.…”

Section: Discussionmentioning

confidence: 99%

“…Expression of long transcription units (such as Ubx) would be precluded until cell cycles were long enough to allow full-length transcription. This could be one mechanism that operates during early development to regulate the expression of long transcription units (42,49).…”

Section: Discussionmentioning

confidence: 99%

Mitotic Repression of RNA Polymerase II Transcription Is Accompanied by Release of Transcription Elongation Complexes

Parsons

Spencer

1997

Molecular and Cellular Biology

121

111

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Nuclear RNA synthesis is repressed during the mitotic phase of each cell cycle. Although total RNA synthesis remains low throughout mitosis, the degree of RNA polymerase II transcription repression on specific genes has not been examined. In addition, it is not known whether mitotic repression of RNA polymerase II transcription is due to polymerase pausing or ejection of transcription elongation complexes from mitotic chromosomes. In this study, we show that RNA polymerase II transcription is repressed in mammalian cells on a number of specific gene regions during mitosis. We also show that the majority of RNA polymerase II transcription elongation complexes are physically excluded from mitotic chromosomes between late prophase and late telophase. Despite generalized transcription repression and stripping of RNA polymerase II complexes from DNA, arrested RNA polymerase II ternary complexes appear to remain on some gene regions during mitosis. The cyclic repression of transcription and ejection of RNA polymerase II transcription elongation complexes may help regulate the transcriptional events that control cell cycle progression and differentiation.In higher eukaryotes, mitosis is accompanied by dramatic and reversible transformations to the structural organization of both cytoplasm and nucleus (reviewed in references 12, 28, 39, and 40). Mitosis is also accompanied by profound biochemical changes, including a decline in nuclear RNA synthesis. Mitotic repression of transcription was first noted over 30 years ago, in studies analyzing incorporation of RNA precursors during the cell cycle (22,29,44,68,69). In these studies, it was observed that incorporation of radioactive precursors into nuclear RNA declines in early to mid-prophase and resumes in late telophase. The precise degree of mitotic transcription repression remains uncertain, with some studies detecting mitotic RNA synthesis at 16 to 24% of interphase levels (22,27,29,80). In addition, it is not clear to what degree transcription by each of the three nuclear RNA polymerases (RNAPs) is repressed during mitosis. As approximately 75 to 80% of RNA synthesis in cycling cells is due to RNAP I activity (32,46,77), it is possible that some RNAP I, II, or III transcription may escape mitotic repression but be undetectable by pulse-labeling. In addition, pulse-labeling assays measure steady-state RNA levels, which arise through a combination of RNA synthesis and degradation. Therefore, it is possible that part of the loss of labeled steady-state RNA in mitotic cells is due to degradation of nascent labeled RNAs.Although mitotic repression of RNAP I and III activity has been examined in some detail in the last few years (16,19,23,51,54,72,73), few studies of RNAP II transcription during mitosis have been reported. The in situ hybridization studies of Shermoen and O'Farrell (59) demonstrate that nascent transcripts from the Drosophila RNAP II-transcribed gene Ubx are aborted and degraded during mitosis. These data suggest that RNAP II transcription complexes may be ...

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Big genes and little genes and deadlines for transcription

Cited by 41 publications

References 9 publications

Gene length may contribute to graded transcriptional responses in the Drosophila embryo

Gene length may contribute to graded transcriptional responses in the Drosophila embryo

Characterization of the Gene and Promoter for RTI40, a Differentiation Marker of Type I Alveolar Epithelial Cells

Mitotic Repression of RNA Polymerase II Transcription Is Accompanied by Release of Transcription Elongation Complexes

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