Review Articles

The endoplasmic reticulum–associated degradation (ERAD) pathway maintains protein homeostasis in the ER by retrotranslocating unwanted proteins to the cytosol for proteasomal degradation. This Review discusses the integral role of the ubiquitin system in ERAD, highlighting how the two pathways intertwine to facilitate transport across the ER membrane.

Enhancers are cis-regulatory elements that enable precise spatiotemporal patterns of gene expression during development and are notable for their ability to function at large distances from their target genes. This Review discusses classic enhancer studies, placing these in the context of recent studies that confirm the role of enhancers in orchestrating gene expression during development and their significance in disease pathogenesis.

Differences in the sex-chromosome karyotype of many animal species create imbalances between X-chromosome and autosomal gene products that require compensation. Genome-wide analyses have been instrumental in driving recent progress in understanding the transcriptional regulatory mechanisms underlying dosage compensation. This Review focuses on emerging models for dosage compensation in mammals, flies and nematodes.

Polycomb group (PcG) proteins function within Polycomb repressive complexes (PRCs), which modify histones and other proteins and silence target genes. This Review highlights new insights into the role of PcG proteins in gene regulation, specifically in controlling self-renewal and differentiation of embryonic stem cells, and into how PRCs are targeted to chromatin.

Nucleosome-remodeling factors are instrumental in assembling and disassembling nucleosomes and moving nucleosomes along DNA in a process called nucleosome sliding. This Review summarizes recent progress in understanding of the basic nucleosome sliding mechanism and the interplay of the ATPase and accessory domains in optimizing and regulating nucleosome sliding.

To ensure replication success, DNA polymerases must negotiate encounters with actively transcribing RNA polymerases that share the genome. This Review highlights the strategies used by prokaryotic and eukaryotic cells to minimize the consequences of collisions between replication forks and transcription complexes to effect faithful DNA replication without compromising gene expression.

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.

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.

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.

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.

Nucleosome assembly is crucial for the maintenance of genome stability and epigenetic information and is aided by histone chaperones. This Review discusses recent insights into the mechanisms and roles of histone chaperones in regulating nucleosome assembly and how alterations in nucleosome-assembly factors may be implicated in human diseases.

Histone post-translational modifications (PTMs) can directly influence histone-DNA and histone-histone interactions, or they can be targeted by protein effectors, or histone readers. This Review outlines known readers of histone PTMs, details their mechanism of action and the functional significance of histone PTM recognition and discusses cross-talk between protein effectors and consequences of the combinatorial readout of PTMs.

The number and types of known functional noncoding RNAs (ncRNAs) has increased considerably over the past few years, and both cis- and trans-acting ncRNAs have been reported. This Review focuses on long- and short-sized ncRNAs that act in cis; that is, where both the regulatory RNA and the target gene are transcribed from the same locus.

Understanding how microRNAs (miRNAs) silence targeted mRNAs has been the focus of intensive research. This Review describes recent advances, with an emphasis on how the miRNA-mediated silencing complex (miRISC) controls gene expression by inhibiting translation and/or mRNA decay, and how trans-acting factors control miRNA action.

Translation initiation requires the formation of a pre-initiation complex that recruits the 5′ end of the mRNA and scans along it to locate the start codon. Genetic, biochemical and structural studies have shed light on the molecular mechanisms underlying the individual steps of this complex process. This Review describes our current understanding of eukaryotic translation initiation and outlines some important outstanding questions in the field.

Recent studies have revealed how poly(A) tail length and the selection of alternative polyadenylation sites contribute to translational control. This Review discusses how mechanisms of alternative polyadenylation, deadenylation and cytoplasmic polyadenylation are coordinated to modulate gene expression in inflammation, learning and memory acquisition, and early development.

The recent X-ray structures of the complete ribosome and large and small subunits from eukaryotes allow these structures to be compared to the previously determined structures of bacterial ribosomes. This Review describes bacterial and eukaryotic ribosomes as a conserved core and two specific shells and focuses on selected bacteria- and eukaryote-specific structural features and their functional implications.

PrP^Sc, the infective agent for transmissible spongiform encephalopathies, is the misfolded form of the prion protein that can template the conversion of the native fold of the protein (PrP^C). The high-resolution structure of PrPSc remains elusive. This review presents recent progress in the area and existing structural models, in addition to discussing the challenges ahead.