| 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. |
- Polshin, Victor, et al.
(författare)
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Attaining control by design over the hydrolytic stability of Fe-TAML oxidation catalysts
- 2008
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 130:13, s. 4497-4506
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Tidskriftsartikel (refereegranskat)abstract
- The iron(III) complexes of tetra amidato macrocyclic ligands (TAMLs) ([Fe{1-X-1-2-X2C6H2-4,5-(NCOCMe2NCO)(2)CR2}(OH2)](-), 1: X-1 = X-2 = H, R-2 = Me-2 (a), R-2 = (CH2)(2) (b); X-1 = X-2 = Cl, R-2 = F-2, (c), etc.), which the proton is known to demetalate at pH < 3, are also subject to catalyzed demetalation by Bronsted acid buffer components at pH 4-9 such as H2PO4-, HSO3-, and CH3- CO2H, HO2CCH2CO2-. Buffers based on pyridine (py) and tris(hydroxymethyl)aminomethane (TRIS) are catalytically inactive. Where reactions proceed, the products are demetalated TAMLs and iron species of variable composition. Pseudo-first-order rate constants for the demetalation (k(obs)) are linear functions of the acid concentrations, and the effective second-order rate constants k(1),(eff) have a hyperbolic dependence on [H+] (k(1),eff = a(1)[H+]/(b(1)+[H+]). The rate of demetalation of 1a in H2PO4-/HPO42- buffer is appreciable, but the k(obs) values for 1b and 1c are immeasurably low, showing that the rates are strongly affected by the CR2 or "tail" fragments, which are known to potently affect the TAML basicity. The reactivities of 1 depend insignificantly on the aromatic ring or "head" group of 1. The proposed mechanism involves precoordination of the acidic buffer species followed by hydrolysis. The demetalating abilities of buffer species depend on their structures and acidities. Thus, although pyridine-2-carboxylic (picolinic) acid catalyzes the demetalation, its 3- and 4-isomers (nicotinic and isonicotininc acids) are inactive. The difference is rationalized to result from the ability that only coordinated picolinic acid has to deliver a proton to an amidato nitrogen in an intramolecular manner. The reaction order in picolinic acid equals one for la and two for 1a. For 1b, "inactive" pyridine and nicotinic acid speed up the demetalation in the presence of picolinic acid, suggesting that the second order arises from the axial binding of two pyridine molecules, one of which must be picolinic acid. The binding of pyridine- and imidazole-type ligands was confirmed by UV/vis equilibrium measurements and X-ray crystallography. The implications of these mechanistic findings for designing superior Fe-TAML oxidation catalysts and catalyst formulations are discussed using the results of DFT calculations.
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| 3. |
- Schwartz, Yuri B, et al.
(författare)
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Genome-wide analysis of Polycomb targets in Drosophila melanogaster
- 2006
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 38:6, s. 700-705
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Tidskriftsartikel (refereegranskat)abstract
- Polycomb group (PcG) complexes are multiprotein assemblages that bind to chromatin and establish chromatin states leading to epigenetic silencing. PcG proteins regulate homeotic genes in flies and vertebrates, but little is known about other PcG targets and the role of the PcG in development, differentiation and disease. Here, we determined the distribution of the PcG proteins PC, E(Z) and PSC and of trimethylation of histone H3 Lys27 (me3K27) in the D. melanogaster genome. At more than 200 PcG target genes, binding sites for the three PcG proteins colocalize to presumptive Polycomb response elements (PREs). In contrast, H3 me3K27 forms broad domains including the entire transcription unit and regulatory regions. PcG targets are highly enriched in genes encoding transcription factors, but they also include genes coding for receptors, signaling proteins, morphogens and regulators representing all major developmental pathways.
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