Volume 20 Issue 3, March 2013

SMC (structural maintenance of chromosomes) protein complexes act in chromosome processing in all domains of life. In this issue, a study of the prokaryotic SMC complex Smc–ScpAB reveals an unanticipated asymmetry despite Smc forming a symmetric homodimer. This asymmetry—contributed by two distinct binding sites in Smc for the kleisin ScpA—is crucial for function in vivo and bears similarities to the eukaryotic complexes formed by Smc heterodimers.

Pluripotent cells have been derived from the inner cell mass of mouse embryos and also from primordial germ cells. A new study shows that cell lines of both origins exhibit highly similar transcriptomes and surprisingly low DNA methylation levels when maintained in culture conditions that support naive pluripotency. These 2i conditions thus provide a closer approximation of in vivo development and new insights into the regulation of DNA methylation.

Dynamic supercoiling is a steady-state mechanical regulatory mechanism that influences DNA topology, transcription factor binding, gene expression, chromatin structure and long-range chromosome interactions. How genes and nongene regions are organized into supercoiled domains and remodeled by transcriptional activity in human cells has now been analyzed in two large-scale studies at the chromosome and genome levels, providing new insight into the organization and expression of genes within chromosomes.

The dynamic nature of functional information present in the genome—such as DNA methylation, histone modifications and chromatin organization—is beginning to be uncovered, along with the relationship between epigenomic patterning and developmental decisions or disease.

The properties of nucleosomes can be altered in various ways, including by covalent modification of histones. In this Review, the known properties of key histone modifications and the biological processes to which they are linked are examined to place the modifications in the context of nucleosome dynamics—that is, processes in which nucleosomes are translocated, unwrapped, evicted or replaced.

Nucleosome positioning is crucial for gene expression and other DNA-related processes. In this Review, the authors consider mechanisms by which the genomic pattern of nucleosome positioning is achieved and conclude that nucleosome positioning is determined by the combined effects of several factors including DNA sequence, DNA-binding proteins, nucleosome remodelers and the transcription machinery.

DNA methylation is an epigenetic mark that is erased in the early embryo and then re-established at the time of implantation. In this Review, dynamics of DNA methylation during normal development in vivo are discussed, starting from fertilization through embryogenesis and postnatal growth, as well as abnormal methylation changes that occur in cancer.

Global erasure and re-establishment of chromatin-based and DNA-based epigenetic marks occurs naturally in the mammalian life cycle, but it can also be artificially engineered using various reprogramming strategies. In this Review, recent advances in understanding how epigenetic remodeling contributes to cell-fate reprogramming in vivo and in vitro are summarized.

A fundamental property of genomes is their topological organization in three-dimensional space in the cell nucleus. New imaging technologies and genome-wide biochemical approaches combined with functional data are starting to reveal the functional implications of genome topology, as discussed in this Review, and will enable a better understanding of how genome organization influences gene function, and vice versa.

Long noncoding RNAs (lncRNAs) fulfill a variety of regulatory roles in gene expression, which are dictated by their RNA structure, chemistry and modular domain structure. In this Review, the focus is on the well-characterized ability for lncRNAs to function as epigenetic modulators as part of a broad epigenetic regulatory network.

Naive pluripotent embryonic stem cells (ESCs) and embryonic germ cells (EGCs) have distinct developmental origins. Genome-wide expression and global DNA-methylation analyses now reveal that ESCs and ESGs are highly similar at the transcriptome level and, contrary to previous assumptions, are both characterized by DNA hypomethylation. Also, global methylation levels in both ESCs and EGCs are directly responsive to culture conditions.

Competitive binding of 53BP1 and BRCA1 determines DNA repair pathway choice at double-strand breaks. New work shows that acetylation of H4K16 by TIP60 tips the balance in favor of BRCA1 by limiting 53BP1 binding, thereby promoting repair through homologous recombination over nonhomologous end joining.

The role of co-chaperone and Hsp90 activator Aha1 is now examined in conjunction with other co-chaperones in vivo and in vitro, to reveal how they regulate the progression of the Hsp90 cycle. Aha1 and Cpr6 interact with and activate Hsp90 in a synergistic manner and displace the inhibitory co-chaperone Sti1. Aha1 is eventually released from Hsp90 by p23.

Repetitive elements in differentiated cells are usually silenced. Genome-wide analyses in early mouse development show that repetitive-element expression decreases during development accompanied by the loss of active chromatin marks. LINE-1 and IAP retrotransposons become reactivated after fertilization, and LINE-1 transcription is regulated by short LINE-1 RNAs, which suggests that repetitive elements may be regulated through RNA during the earliest developmental stages.

Trim24 and Trim33 are co-repressor complexes that suppress hepatocarcinogenesis. A new study now uncovers a function for Trim24 and Trim33 as repressors of VL30-type endogenous retroviruses in the liver. When derepressed, VL30 long terminal repeats (LTRs) function as promoter and enhancer elements deregulating expression of neighboring genes and generating noncoding enhancer RNAs that are required for LTR enhancer activity in hepatocytes.

The cytotoxic effects of topoisomerase I inhibitors such as camptothecin can be modulated by replication fork reversal, in a process that requires Poly(ADP-ribose) polymerase (PARP) activity. Here human RECQ1 helicase is shown to restore such regressed replication forks, whereas PARP1 activity restrains this RECQ1 function.

The regulatory importance of the C-terminal coiled-coil domain of PLCβ has long been known yet remains poorly understood. The crystal structure and cryo-EM reconstruction of full-length PLCβ3 bound to its activator Gα_q reveals that the C terminus makes contact with both the catalytic core and Gα_q to contribute to the complex regulation of the enzyme.

Influenza virus hemagglutinin (HA) binds to sialic acid receptors on the host cell, but receptor analogs have failed as viral-entry inhibitors. Now crystal structures of H2 HA in complex with Fab fragments from three neutralizing antibodies reveal a new mode to target HA. All three antibodies use an aromatic residue to plug a conserved cavity in the HA-binding site for sialic acid.

Prokaryotic condensins usually comprise an SMC homodimer, kleisin ScpA and ScpB. Structural and functional analyses of Bacillus subtilis condesin reveal an asymmetric bridge in which the termini of ScpA bind to distinct regions in each of the two SMC monomers. The findings suggest that the basic architecture for the tripartite condensin ring evolved before the emergence of eukaryotes.

Oligomeric Trax–Translin complexes, known as C3PO, are involved in RNA interference and tRNA processing in eukaryotic species including humans. Structural and functional analysis of a Trax-like protein from Archaeoglobus fulgidus that forms an octameric assembly resembling human C3PO provides insight into the mechanism of RNA recognition and cleavage.

A genome-wide mapping approach of DNA supercoiling in cells demonstrates that the genome is organized in supercoiling domains. Domains are formed and remodeled by transcription and topoisomerase activity and are flanked by GC-AT boundaries and CTCF binding sites. DNA supercoiling impacts on higher levels of chromatin organization and 'underwound' domains correlate with transcriptional activity.

The connection between dynamic DNA supercoiling and transcription is not well understood. High-resolution mapping of in vivo DNA supercoiling at transcription start sites (TSSs) now reveals that supercoils spread about 1.5 kb upstream of the TSSs of active genes. Highly expressed genes rely on topoisomerase II to dissipate dynamic supercoiling, whereas moderately expressed genes depend on topoisomerase I.

The dynamic nature of functional information present in the genome, such as DNA methylation, histone modifications and chromatin organization, is only beginning to be uncovered, along with the relationship between epigenomic patterning and developmental decisions or disease. This Focus, which comprises six Reviews written by leaders in the field, explores emerging themes and functional implications of epigenetic dynamics. The Review articles are freely available online for 3 months thanks to support from Active Motif