| 1. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Margulies, Elliott H, et al.
(författare)
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Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome
- 2007
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 17:6, s. 760-774
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Tidskriftsartikel (refereegranskat)abstract
- A key component of the ongoing ENCODE project involves rigorous comparative sequence analyses for the initially targeted 1% of the human genome. Here, we present orthologous sequence generation, alignment, and evolutionary constraint analyses of 23 mammalian species for all ENCODE targets. Alignments were generated using four different methods; comparisons of these methods reveal large-scale consistency but substantial differences in terms of small genomic rearrangements, sensitivity (sequence coverage), and specificity (alignment accuracy). We describe the quantitative and qualitative trade-offs concomitant with alignment method choice and the levels of technical error that need to be accounted for in applications that require multisequence alignments. Using the generated alignments, we identified constrained regions using three different methods. While the different constraint-detecting methods are in general agreement, there are important discrepancies relating to both the underlying alignments and the specific algorithms. However, by integrating the results across the alignments and constraint-detecting methods, we produced constraint annotations that were found to be robust based on multiple independent measures. Analyses of these annotations illustrate that most classes of experimentally annotated functional elements are enriched for constrained sequences; however, large portions of each class (with the exception of protein-coding sequences) do not overlap constrained regions. The latter elements might not be under primary sequence constraint, might not be constrained across all mammals, or might have expendable molecular functions. Conversely, 40% of the constrained sequences do not overlap any of the functional elements that have been experimentally identified. Together, these findings demonstrate and quantify how many genomic functional elements await basic molecular characterization.
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| 3. |
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| 4. |
- Schnabel, R., et al.
(författare)
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Global cell sorting in the C. elegans embryo defines a new mechanism for pattern formation
- 2006
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Ingår i: Developmental Biology. - : Academic Press Inc.. - 0012-1606 .- 1095-564X. ; 294:2, s. 418-431
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Tidskriftsartikel (refereegranskat)abstract
- 4D microscopic observations of Caenorhabditis elegans development show that the nematode uses an unprecedented strategy for development. The embryo achieves pattern formation by sorting cells, through far-ranging movements, into coherent regions before morphogenesis is initiated. This sorting of cells is coupled to their particular fate. If cell identity is altered by experiment, cells are rerouted to positions appropriate to their new fates even across the whole embryo. This cell behavior defines a new mechanism of pattern formation, a mechanism that is also found in other animals. We call this new mechanism "cell focusing". When the fate of cells is changed, they move to new positions which also affect the shape of the body. Thus, this process is also important for morphogenesis. © 2006 Elsevier Inc. All rights reserved.
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| 5. |
- Toom, A., et al.
(författare)
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Bone formation zones in heterotopic ossifications : histologic findings and increased expression of bone morphogenetic protein 2 and transforming growth factors beta2 and beta3
- 2007
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Ingår i: Cell Calcium. - 0143-4160 .- 1532-1991. ; 80:4, s. 259-67
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Tidskriftsartikel (refereegranskat)abstract
- Heterotopic ossifications (HOs) formed after total endoprosthetic replacement of the hip joint were collected during revision surgery (n = 7). Tissues collected during regular hip arthroplasty (n = 12) were used as reference. Histomorphometric analysis was performed for assessment of bone formation activity in HOs and reference bone. HOs were dissected with histological guidance into three zones: formed bone, zone of active bone formation, and zone with fibrous connective and fibrocartilagineous tissue. Relative expression of the mRNA for bone morphogenetic protein 2 (BMP-2), transforming growth factor beta2 (TGF-beta2), and TGF-beta3 was determined by reverse-transcription polymerase chain reaction relative to beta-actin. Expression of all three growth factors was higher than in orthotopic bone. Similarly, the osteoid surface density was increased in HOs. The levels of all growth factors were higher in the zone of active bone formation or remodeling than in the zone of formed bone. In matured HOs, the osteoid surface density as well as mRNA levels were lower, although still significantly raised, indicating that bone formation slows down after 2 years. Immunohistochemical analysis demonstrated the presence of TGF-beta1, TGF-beta2, TGF-beta3, and BMP-2 proteins in the zone of bone formation. We conclude that bone formation after heterotopic bone induction is initially intense, slows down within 2 years, and thereupon continues as active remodeling mainly on the border of HO. Our data indicate that BMP-2, TGF-beta2, and TGF-beta3 are involved in bone formation in HO.
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| 6. |
- Arend, A, et al.
(författare)
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Prostaglandins of the E-series inhibit connective tissue proliferation in the liver wound of the rat
- 2005
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Ingår i: Annals of Anatomy. - Jena : Urban & Fischer. - 0940-9602 .- 1618-0402. ; 187:1, s. 57-62
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Tidskriftsartikel (refereegranskat)abstract
- The present study was undertaken to relate wound heating of an internal organ to prostaglandins of the E and F series. A small liver wound was induced by a galvanic cauter via the abdominal route under general anesthesia and prostaglandin E-1, E-2 and F-2 alpha were injected twice daily at a dose of 250 mu g/kg. Proliferation of the connective tissue in the liver wound was estimated morphometrically 6 days after liver wound infliction. Levels of prostaglandins E-2 and F-2 alpha were measured in the liver wound as well as in normal liver tissue from adjacent lobes using radioimmunoassay. The results show that exogenous prostaglandins of the E-series suppress connective tissue proliferation. Three minutes after the last prostaglandin E-2 injection, high prostaglandin concentrations were measured both in the tiver wound and in the liver tissue of the adjacent lobe. Prostaglandin F-2 alpha injections had no effect on wound heating. We believe that the rat thermic liver wound model can be used for different studies on wound heating mechanisms and that prostaglandins of the E-series are involved in wound heating in the specific time period studied.
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