Topological domains in mammalian genomes identified by analysis of chromatin interactions

The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct chromosome territories, and numerous models have been proposed for how chromosomes fold within chromosome territories. These models, however, provide only few mechanistic details about the relationship between higher order chromatin structure and genome function. Recent advances in genomic technologies have led to rapid advances in the study of three-dimensional genome organization. In particular, Hi-C has been introduced as a method for identifying higher order chromatin interactions genome wide. Here we investigate the three-dimensional organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types at unprecedented resolution. We identify large, megabase-sized local chromatin interaction domains, which we term 'topological domains', as a pervasive structural feature of the genome organization. These domains correlate with regions of the genome that constrain the spread of heterochromatin. The domains are stable across different cell types and highly conserved across species, indicating that topological domains are an inherent property of mammalian genomes. Finally, we find that the boundaries of topological domains are enriched for the insulator binding protein CTCF, housekeeping genes, transfer RNAs and short interspersed element (SINE) retrotransposons, indicating that these factors may have a role in establishing the topological domain structure of the genome.     

Nonspecific reaction of a thiol: protein disulfide oxidoreductase with the disulfide bonds of insulin

A thiol: protein disulfide oxidoreductase from bovine liver was isolated after separation from protein disulfide isomerase. The enzyme, after activation (reduction) with glutathione, was reacted with stoichiometric amounts of insulin and the sulfhydryl groups of the partially reduced hormone were labeled with iodo (l-14C)acetamide. After separation of the insulin chains, the radioactivity was found in both the peptides, with a ratio A-chain/B-chain equal to 2/1.     

Trans-dominant inactivation of HTLV-I and HIV-1 gene expression by mutation of the HTLV-I Rex transactivator

The rex gene of the type I human T-cell leukaemia virus (HTLV-I) encodes a phosphorylated nuclear protein of relative molecular mass 27,000 which is required for viral replication. The Rex protein acts by promoting the cytoplasmic expression of the incompletely spliced viral messenger RNAs that encode the virion structural proteins. To identify the biologically important peptide domains within Rex, we introduced a series of mutations throughout its sequence. Two distinct classes of mutations lacking Rex biological activity were identified. One class corresponds to trans-dominant repressors as they inhibit the function of the wild-type Rex protein. The second class of mutants, in contrast, are recessive negative, rather than dominant negative, as they are not appropriately targeted to the cell nucleus. These results indicate the presence of at least two functionally distinct domains within the Rex protein, one involved in protein localization and a second involved in effector function. The trans-dominant Rex mutants may represent a promising new class of anti-viral agents.     

Disappearance of radioactivity from plasma following intravenous administration of tritiated thyrotrophin-releasing hormone (Ro 8-6270) to man

Zusammenfassung Nach i. v. Verabreichung von Thyrotrophin-releasing Hormonen an Versuchspersonen ergibt sich eine biphasische Kurve für den Abfall der Tritiumaktivität im Plasma mit einer Exkretions-Halbwertszeit von 3 h.

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Acknowledgements. The authors wish to express their gratitude to Hoffmann-La Roche and Co. AG, Basel for the research funds which supported this work. We are indebted to Dr.C. Metzler, Upjohn Co., Kalamazoo for a gift of the NON-LIN computer programme.     

Ecology. Global amphibian population declines

The decline and disappearance of relatively undisturbed populations of amphibians in several high-altitude regions since the 1970s suggests that they may have suffered a global decline, perhaps with a common cause or causes. Houlahan et al. examined means of trends for 936 amphibian populations and concluded that global declines began in the late 1950s, peaked in the 1960s, and have continued at a reduced rate since. Here we re-analyse their data using a method that accounts for the sampling of different populations over different time periods, and find evidence of a mean global decline in monitored populations only in the 1990s. However it is calculated, the global mean not only masks substantial spatial and temporal variation in population trends and sampling effort, but also fails to distinguish between a global decline with global causes and the cumulative effects of local declines with local causes.