DNA methylation control of tissue polarity and cellular differentiation in the mammary epithelium

Alterations in gene expression accompany cell-type-specific differentiation. In complex systems where functional differentiation depends on the organization of specific cell types into highly specialized structures (tissue morphogenesis), it is not known how epigenetic mechanisms that control gene expression influence this stepwise differentiation process. We have investigated the effect of DNA methylation, a major epigenetic pathway of gene silencing, on the regulation of mammary acinar differentiation. Our in vitro model of differentiation encompasses human mammary epithelial cells that form polarized and hollow tissue structures (acini) when cultured in the presence of basement membrane components. We found that acinar morphogenesis was accompanied with chromatin remodeling, as shown by alterations in histone 4 acetylation, heterochromatin 1 protein, and histone 3 methylated on lysine 9, and with an increase in expression of MeCP2, a mediator of DNA-methylation-induced gene silencing. DNA hypomethylation induced by treatment with 5-aza-2' deoxycytidine during acinar differentiation essentially prevented the formation of apical tissue polarity. This treatment also induced the expression of CK19, a marker of cells that are in a transitional differentiation stage. These results suggest that DNA methylation is a mechanism by which mammary epithelial differentiation is coordinated both at the tissue and cellular levels.     

Emergentism as a default: Cancer as a problem of tissue organization

During the last fifty years the dominant stance in experimental biology has been reductionism. For the most part, research programs were based on the notion that genes were in ’the driver’s seat’ controlling the developmental program and determining normalcy and disease (genetic reductionism and genetic determinism). Philosophers were the first to realize that the belief that the Mendelian genes were reduced to DNA molecules was questionable. Soon after these pronouncements, experimental data confirmed their misgivings. The optimism of molecular biologists, fueled by early success in tackling relatively simple problems, has now been tempered by the difficulties found when attempting to understand complex biological problems. Here, we analyse experimental data that illustrate the shortcomings of this sort of reductionism. We also examine the prevailing paradigm in cancer research, the somatic mutation theory (SMT), the premises of which are: (i) cancer is derived from a single somatic cell that has accumulated multiple DNA mutations; (ii) the default state of cell proliferation in metazoa is quiescence; and (iii) cancer is a disease of cell proliferation caused by mutations in genes that control proliferation and the cell cycle. We challenge the notion that cancer is a cellular problem caused by mutated genes by assessing data gathered both from within the reductionist paradigm and from an alternative view that regards carcinogenesis as a developmental process gone awry. This alternative view, explored under the name of the tissue organization field theory (TOFT), is based on premises that place cancer in a different hierarchical level of complexity from that proposed by the SMT, namely: (i) carcinogenesis represents a problem of tissue organization comparable to organogenesis, and (ii) proliferation is the default state of all cells. We propose that the organicist view, in which the TOFT is based, is a good starting point from which to explore emergent phenomena. However, new theoretical concepts are needed in order to grapple with the apparent circular causality of complex biological phenomena in development and carcinogenesis.     

Food Shortage Disrupts Social Organization: The Case of Red Squirrels in Conifer Forests

A recent conceptual model of spatial organization in vertebrates, based upon changes in home range overlap with habitat quality, ‘the space-use model’, predicts large and strongly overlapping home ranges and absence of territorial behaviour in habitats with poor food availability. We investigated whether the model can be extended to predict intra-population variation in space-use in a habitat with strong temporal variation in resource abundance. We studied space use of Eurasian red squirrels (Sciurus vulgaris) in subalpine conifer forests over 4 years with strong fluctuations in seed production. Norway spruce dominated forests are resource limited habitats for squirrels, and tree seed availability is gradually depleted in the year following a poor seed-crop. Male and female squirrels responded to spruce seed-crop failure in 2000 by strongly increasing their home ranges and core-areas in the following year (mean MCP ± SE in summer and autumn, respectively: 2001, 122.9±14.1 ha and 84.3±9.4 ha, against 43.0±6.4 ha and 20.8±3.8 ha in 2002, and 22.7±1.5 ha and 21.4±2.0 ha in 2003). In 2001, half of the animals, those with the poorest quality pre-dispersal home ranges, emigrated to areas with more larch. Residents had multi-nuclear core-areas. Also, intra-sexual core-area overlap (males by males, females by females) was higher in 2001 and summer 2002, than in autumn 2002 and in 2003 (means ± SE in summer and autumn, respectively: males by males, 2001, 52±8 and 44±7%, 2002, 80±30 and 15±11%, 2003, 37±19 and 26±14%; females by females 2001, 52±10 and 112±32%, 2002, 55±27 and 0±0%, 2003, 12±8 and 0.1±0%). Red squirrels responded to food shortage by moving to patches with other food resources and abandoned the spacing pattern of reduced core-area overlap among males and nearly exclusive core-areas among females, found in less variable habitats. After richer seed-crops in 2001 and 2002, it took squirrels about a year to reduce the size of their home ranges and core-areas and return to a spacing pattern of stable home ranges and intra-sexual territoriality of adult females. These results are consistent with the space-use model and show that spacing behaviour in red squirrels is a plastic, conditional strategy with individuals adapting the size and/or location of their home ranges in relation to local distribution and abundance of food resources.Co-ordinating editor: R. Härdling     

Spatial selectivity to manipulate portable objects in wedge-capped capuchins (Cebus olivaceus)

We studied the manipulative activity of five wedge-capped capuchins (Cebus olivaceus) confronted with different types of unfamiliar and portable objects: wooden blocks, plastic rings, spoons, and coconuts. Combinatorial manipulations involving two portable objects of the same type were quite frequent. The lately introduced objects, whatever their kind, appeared as the most attractive. Nevertheless, some objects remained very attractive throughout the overall experiment, especially the wooden blocks which elicited more combinatorial and striking behaviors than the other objects. Concerning space, we observed that the individuals choose specific locations to perform their manipulative acts. The spatial distributions of these acts were more concentrated, and less concordant between individuals, in the present study than in two others conducted with the same group but involving the manipulation of familiar objects. This suggests that individual differences were more marked when the subjects manipulated unfamiliar objects than when they manipulated familiar ones. This finding may have applications when the members of a group have to benefit from an enrichment of their environment.     

The Quality of merC, a Module of the mer Mosaic

We examined a region of high variability in the mosaic mercury resistance (mer) operon of natural bacterial isolates from the primate intestinal microbiota. The region between the merP and merA genes of nine mer loci was sequenced and either the merC, the merF, or no gene was present. Two novel merC genes were identified. Overall nucleotide diversity, π (per 100 sites), of the merC gene was greater (49.63) than adjacent merP (35.82) and merA (32.58) genes. However, the consequences of this variability for the predicted structure of the MerC protein are limited and putative functional elements (metal-binding ligands and transmembrane domains) are strongly conserved. Comparison of codon usage of the merTP, merC, and merA genes suggests that several merC genes are not coeval with their flanking sequences. Although evidence of homologous recombination within the very variable merC genes is not apparent, the flanking regions have higher homologies than merC, and recombination appears to be driving their overall sequence identities higher. The synonymous codon usage bias (EN_C) values suggest greater variability in expression of the merC gene than in flanking genes in six different bacterial hosts. We propose a model for the evolution of MerC as a host-dependent, adventitious module of the mer operon. Received: 2 June 2000 / Accepted: 23 October 2000     

中国科学家在植物细胞骨架研究领域取得突破性进展

微管是细胞骨架的重要组成部分,为真核细胞生命活动所必需。与其它生物体类似,微管不仅在植物生长发育中起重要作用,而且参与响应外界环境信号。近期,中国科学家在解析植物微管精准切割及微管骨架动态重构调控机制的研究中取得突破性进展。