Systemic properties of metabolic networks lead to an epistasis-based model for heterosis

The genetic and molecular approaches to heterosis usually do not rely on any model of the genotype–phenotype relationship. From the generalization of Kacser and Burns’ biochemical model for dominance and epistasis to networks with several variable enzymes, we hypothesized that metabolic heterosis could be observed because the response of the flux towards enzyme activities and/or concentrations follows a multi-dimensional hyperbolic-like relationship. To corroborate this, we used the values of systemic parameters accounting for the kinetic behaviour of four enzymes of the upstream part of glycolysis, and simulated genetic variability by varying in silico enzyme concentrations. Then we “crossed” virtual parents to get 1,000 hybrids, and showed that best-parent heterosis was frequently observed. The decomposition of the flux value into genetic effects, with the help of a novel multilocus epistasis index, revealed that antagonistic additive-by-additive epistasis effects play the major role in this framework of the genotype–phenotype relationship. This result is consistent with various observations in quantitative and evolutionary genetics, and provides a model unifying the genetic effects underlying heterosis

Antimetastatic gene expression profiles mediated by retinoic acid receptor beta 2 in MDA-MB-435 breast cancer cells

BACKGROUND: The retinoic acid receptor beta 2 (RARβ2) gene modulates proliferation and survival of cultured human breast cancer cells. Previously we showed that ectopic expression of RARβ2 in a mouse xenograft model prevented metastasis, even in the absence of the ligand, all-trans retinoic acid. We investigated both cultured cells and xenograft tumors in order to delineate the gene expression profiles responsible for an antimetastatic phenotype. METHODS: RNA from MDA-MB-435 human breast cancer cells transduced with RARβ2 or empty retroviral vector (LXSN) was analyzed using Agilent Human 1A Oligo microarrays. The one hundred probes with the greatest differential intensity (p < 0.004, jointly) were determined by selecting the top median log ratios from eight-paired microarrays. Validation of differences in expression was done using Northern blot analysis and quantitative RT-PCR (qRT-PCR). We determined expression of selected genes in xenograft tumors. RESULTS: RARβ2 cells exhibit gene profiles with overrepresentation of genes from Xq28 (p = 2 × 10(-8)), a cytogenetic region that contains a large portion of the cancer/testis antigen gene family. Other functions or factors impacted by the presence of exogenous RARβ2 include mediators of the immune response and transcriptional regulatory mechanisms. Thirteen of fifteen (87%) of the genes evaluated in xenograft tumors were consistent with differences we found in the cell cultures (p = 0.007). CONCLUSION: Antimetastatic RARβ2 signalling, direct or indirect, results in an elevation of expression for genes such as tumor-cell antigens (CTAG1 and CTAG2), those involved in innate immune response (e.g., RIG-I/DDX58), and tumor suppressor functions (e.g., TYRP1). Genes whose expression is diminished by RARβ2 signalling include cell adhesion functions (e.g, CD164) nutritional or metabolic processes (e.g., FABP6), and the transcription factor, JUN

Identification of target genes for wild type and truncated HMGA2 in mesenchymal stem-like cells

Background The HMGA2 gene, coding for an architectural transcription factor involved in mesenchymal embryogenesis, is frequently deranged by translocation and/or amplification in mesenchymal tumours, generally leading to over-expression of shortened transcripts and a truncated protein. Methods To identify pathways that are affected by sarcoma-associated variants of HMGA2, we have over-expressed wild type and truncated HMGA2 protein in an immortalized mesenchymal stem-like cell (MSC) line, and investigated the localisation of these proteins and their effects on differentiation and gene expression patterns. Results Over-expression of both transgenes blocked adipogenic differentiation of these cells, and microarray analysis revealed clear changes in gene expression patterns, more pronounced for the truncated protein. Most of the genes that showed altered expression in the HMGA2-overexpressing cells fell into the group of NF-κB-target genes, suggesting a central role for HMGA2 in this pathway. Of particular interest was the pronounced up-regulation of SSX1, already implicated in mesenchymal oncogenesis and stem cell functions, only in cells expressing the truncated protein. Furthermore, over-expression of both HMGA2 forms was associated with a strong repression of the epithelial marker CD24, consistent with the reported low level of CD24 in cancer stem cells. Conclusions We conclude that the c-terminal part of HMGA2 has important functions at least in mesenchymal cells, and the changes in gene expression resulting from overexpressing a protein lacking this domain may add to the malignant potential of sarcomas

Mesoproterozoic geology of the Nampula Sub-province, northern Mozambique

The Nampula Subprovince (NSP) of the Mozambique Metamorphic Province covers over 100 000 km2, making it the largest Mesoproterozoic crustal block in northern Mozambique and an important component of the Neoproterozoic to Cambrian (Pan-African) East African Orogen. It is bounded in the north by the WSW–ENE trending Lúrio Belt. The oldest rocks (Mocuba Suite) are a polydeformed sequence of upper amphibolite grade layered grey gneisses and migmatites associated with intrusive TTG and granitic orthogneisses. A sample of banded gneiss, interpreted as a meta-volcanic rock, yielded a U-Pb SHRIMP zircon date of 1127 ± 9 Ma. Metamorphic rims, dated at ca. 1090 Ma, probably grew during the emplacement of a later magmatic phase, represented by the tonalitic Rapale orthogneiss, two samples of which were dated at 1095 ± 19 and 1091 ± 14 Ma respectively. The earliest (D1) deformation and associated amphibolite-grade metamorphism and migmatisation recognised, took place at approximately this time. The geochemistry of these rocks suggests that they were generated in a juvenile, island-arc setting. The Mocuba Suite is interlayered with extensive belts of meta-pelitic/psammitic, calc-silicate and felsic to mafic meta-volcanic supracrustal gneisses termed the Molòcué Group. U-Pb data from detrital zircons from a calc-silicate paragneiss gave a bimodal age distribution at ca. 1100 and 1800 Ma, showing derivation from rocks of the same age as the Mocuba Suite and a Palaeoproterozoic source region. The age of the Molòcué Group has been directly determined by dates of 1092 ± 13 and 1090 ± 22 Ma, obtained from two samples of the leucocratic (meta-acid volcanic?) Mamala gneiss, one of its major constituent formations. The final phase of Mesoproterozoic activity is represented by voluminous plutons and sheet-like bodies of foliated megacrystic granite, augen gneiss and granitic orthogneiss (Culicui Suite) which have A-type granite geochemical characteristics, and were interpreted to have been generated in a late tectonic, extensional setting. Three samples from the suite gave identical ages of ca. 1075 Ma. The NSP was extensively re-worked during the major (D2: Pan-African) collision orogen in Late Neoproterozoic to Cambrian times, when the major regional fabrics were imposed upon the Mesoproterozoic rocks under amphibolite grade metamorphic conditions. In the dated samples, this major orogenic event is represented by metamorphic zircon rims and lower intercept ages of ca 550 to 500 Ma. The Nampula Subprovince probably made up the NE part of a major Mesoproterozoic mobile belt which was accreted to the old cratonic nucleus of the Kalahari craton (combined Archaean Kaapvaal- Zimbabwe-Grunehogna cratons and various Palaeoproterozoic blocks). This mobile belt, fragmented by Gondwana break-up, consisted of (from west to east) the Namaqua-Natal belt (South Africa), the Falkland microplate, the Haag Nunatak block (West Antarctica) and the Maudheim (East Antarctica)(Jacobs et al., 2008). The belt, with a restored length of over 3000 km is a major part of a worldwide in a system of “Grenvillian” orogens associated with the amalgamation of the supercontinent of Rodinia (e.g. Li et al., 2008)

Mesoproterozoic evolution of the Nampula Block, N. Mozambique.

The Nampula Block is the largest Mesoproterozoic crustal domain in northern Mozambique, covering >100,000 km2 and constituting one of the most important components of the southern part of the Neoproterozoic to Cambrian (“Pan-African”) East African Orogen. The Nampula Block is bounded in the north by the WSW–ENE-trending Lúrio Belt and by younger rocks to the south and east. The oldest rocks of the Nampula Block, the Mocuba Suite, are a polydeformed sequence of upper amphibolite-grade layered grey gneisses and migmatites associated with intrusive trondhjemite-tonalite-granodiorite and granitic orthogneisses

Mesoproterozoic geology of the Nampula Block, northern Mozambique : tracing fragments of Mesoproterozoic crust in the heart of Gondwana

The Nampula Block covers over 100,000 km2, making it the largest Mesoproterozoic crustal segment in northern Mozambique and an important component of the Neoproterozoic to Cambrian (Pan-African) East African Orogen. It is bounded in the north by the WSW–ENE trending Lúrio Belt. The oldest rocks (Mocuba Suite) are a polydeformed sequence of upper amphibolite-grade layered grey gneisses and migmatites associated with intrusive trondhjemite-tonalite-granodiorite and granitic orthogneisses. A banded gneiss, interpreted as a meta-volcanic rock, yielded a U-Pb SIMS zircon date of 1127 ± 9 Ma. Metamorphic rims, dated at ca. 1090 Ma, probably grew during a later magmatic phase, represented by the tonalitic Rapale Gneiss, two samples of which were dated at 1095 ± 19 and 1091 ± 14 Ma, respectively. The earliest (D1) deformation that took place at approximately this time, was associated with high grade metamorphism and migmatisation of the Mocuba Suite. The geochemistry of these rocks suggests that they were generated in a juvenile, island-arc setting. The Mocuba Suite is interlayered with extensive belts of meta-pelitic/psammitic, calc-silicate and felsic to mafic meta-volcanic paragneisses termed the Molócuè Group. U-Pb data from detrital zircons from a calc-silicate paragneiss gave a bimodal age distribution at ca. 1100 and 1800 Ma, showing derivation from rocks of the same age as the Mocuba Suite and a Palaeoproterozoic source region. The age of the Molócuè Group has been directly determined by dates of 1092 ± 13 and 1090 ± 22 Ma, obtained from two samples of the leucocratic Mamala Gneiss (meta-felsic volcanics?), one of its major constituent components. The final phase of Mesoproterozoic activity is represented by voluminous plutons and sheet-like bodies of foliated megacrystic granite, augen gneiss and granitic orthogneiss of the Culicui Suite, which have A-type granite geochemical characteristics and are interpreted to have been generated in a late tectonic, extensional setting. Three samples from the suite gave identical ages of ca. 1075 Ma. The Nampula Block was extensively re-worked during the major (D2: Pan-African) collision orogen in Late Neoproterozoic to Cambrian times, when the major regional fabrics were imposed upon the Mesoproterozoic rocks under amphibolite-facies metamorphic conditions. In the dated samples, this orogenic event is represented by metamorphic zircon rim ages of ca. 550 to 500 Ma. The new data indicate that the Mesoproterozoic rocks of the Nampula Block were originally accreted to a Palaeoproterozic crustal Block and the Nampula Block only reached its current position, separated from the other Mesoproterozoic blocks of NE Mozambique by the Lúrio Belt, during Neoproterozoic collision and plate movements. The geological history of the Nampula Block is comparable with that described from other parts of the Mesoproterozoic orogenic belts of the Kalahari craton and helps to constrain an integrated model of their evolution