Post-translational regulation of the maternal-to-zygotic transition

The maternal-to-zygotic transition (MZT) is essential for the developmental control handed from maternal products to newly synthesized zygotic genome in the earliest stages of embryogenesis, including maternal component (mRNAs and proteins) degradation and zygotic genome activation (ZGA). Various protein post-translational modifications have been identified during the MZT, such as phosphorylation, methylation and ubiquitination. Precise post-translational regulation mechanisms are essential for the timely transition of early embryonic development. In this review, we summarize recent progress regarding the molecular mechanisms underlying post-translational regulation of maternal component degradation and ZGA during the MZT and discuss some important issues in the field.     

Bridging epigenomics and complex disease: the basics

The DNA sequence largely defines gene expression and phenotype. However, it is becoming increasingly clear that an additional chromatin-based regulatory network imparts both stability and plasticity to genome output, modifying phenotype independently of the genetic blueprint. Indeed, alterations in this “epigenetic” control layer underlie, at least in part, the reason for monozygotic twins being discordant for disease. Functionally, this regulatory layer comprises post-translational modifications of DNA and histones, as well as small and large noncoding RNAs. Together these regulate gene expression by changing chromatin organization and DNA accessibility. Successive technological advances over the past decade have enabled researchers to map the chromatin state with increasing accuracy and comprehensiveness, catapulting genetic research into a genome-wide era. Here, aiming particularly at the genomics/epigenomics newcomer, we review the epigenetic basis that has helped drive the technological shift and how this progress is shaping our understanding of complex disease.     

Endothelial nitric oxide synthase: insight into cell-specific gene regulation in the vascular endothelium

The vascular endothelium plays a crucial role in regulating normal blood vessel physiology. The gene products responsible are commonly expressed exclusively, or preferentially, in this cell type. However, despite the importance of regulated gene expression in the vascular endothelium, relatively little is known about the mechanisms that restrict endothelial-specific gene expression to this cell type. While significant progress has been made towards understanding the regulation of endothelial genes through cis/trans paradigms, it has become apparent that additional mechanisms must also be operative. For example, chromatin-based mechanisms, including cell-specific DNA methylation patterns and post-translational histone modifications, have recently been demonstrated to play important roles in the cell-specific expression of endothelial nitric oxide synthase (eNOS). This review investigates the involvement of epigenetic regulatory mechanisms in vascular endothelial cell-specific gene expression using eNOS as a prototypical model, and will address the possible contributions of these pathways to diseases of the vasculature. Received 13 September 2005; received after revision 13 October 2005; accepted 19 October 2005     

Propagation of histone marks and epigenetic memory during normal and interrupted DNA replication

Although all nucleated cells within a multicellular organism contain a complete copy of the genome, cell identity relies on the expression of a specific subset of genes. Therefore, when cells divide they must not only copy their genome to their daughters, but also ensure that the pattern of gene expression present before division is restored. While the carrier of this epigenetic memory has been a topic of much research and debate, post-translational modifications of histone proteins have emerged in the vanguard of candidates. In this paper we examine the mechanisms by which histone post-translational modifications are propagated through DNA replication and cell division, and we critically examine the evidence that they can also act as vectors of epigenetic memory. Finally, we consider ways in which epigenetic memory might be disrupted by interfering with the mechanisms of DNA replication.     

Influence of bacteria on epigenetic gene control

Cellular information is inherited by daughter cells through epigenetic routes in addition to genetic routes. Epigenetics, which is primarily mediated by inheritable DNA methylation and histone post-translational modifications, involves changes in the chromatin structure important for regulating gene expression. It is widely known that epigenetic control of gene expression plays an essential role in cell differentiation processes in vertebrates. Furthermore, because epigenetic changes can occur reversibly depending on environmental factors in differentiated cells, they have recently attracted considerable attention as targets for disease prevention and treatment. These environmental factors include diet, exposure to bacteria or viruses, and air pollution, of which this review focuses on the influence of bacteria on epigenetic gene control in a host. Host-bacterial interactions not only occur upon pathogenic bacterial infection but also continuously exist between commensal bacteria and the host. These bacterial stimuli play an essential role in various biological responses involving external stimuli and in maintaining physiological homeostasis by altering epigenetic markers and machinery.     

Huntington’s disease: from huntingtin function and dysfunction to therapeutic strategies

Huntington’s disease (HD) is a neurodegenerative disorder that usually starts in middle age and is characterized by involuntary movements (chorea), personality changes and dementia, leading to death within 10–20 years. The defective gene in HD contains a trinucleotide CAG repeat expansion within its coding region that expresses a polyglutamine repeat in the protein huntingtin. Together with the characteristic formation of aggregates in HD, aberrant protein interactions and several post-translational modifications affect huntingtin during disease progression and lead to the dysfunction and death of selective neurons in the brains of patients. The exact molecular mechanisms by which mutant huntingtin induces cell death are not completely understood but may involve the gain of new toxic functions and the loss of the beneficial properties of huntingtin. This review focuses on the cellular functions in which huntingtin is involved and how a better understanding of pathogenic pathways can lead to new therapeutic approaches. Received 24 May 2006; received after revision 5 July 2006; accepted 23 August 2006     

Histone methylation and ubiquitination with their cross-talk and roles in gene expression and stability

Methylation of lysine residues of histones is associated with functionally distinct regions of chromatin, and, therefore, is an important epigenetic mark. Over the past few years, several enzymes that catalyze this covalent modification on different lysine residues of histones have been discovered. Intriguingly, histone lysine methylation has also been shown to be cross-regulated by histone ubiquitination or the enzymes that catalyze this modification. These covalent modifications and their cross-talks play important roles in regulation of gene expression, heterochromatin formation, genome stability, and cancer. Thus, there has been a very rapid progress within past several years towards elucidating the molecular basis of histone lysine methylation and ubiquitination, and their aberrations in human diseases. Here, we discuss these covalent modifications with their cross-regulation and roles in controlling gene expression and stability. Received 24 September 2008; received after revision 21 November 2008; accepted 28 November 2008     

PTEN proteoforms in biology and disease

Proteoforms are specific molecular forms of protein products arising from a single gene that possess different structures and different functions. Therefore, a single gene can produce a large repertoire of proteoforms by means of allelic variations (mutations, indels, SNPs), alternative splicing and other pre-translational mechanisms, post-translational modifications (PTMs), conformational dynamics, and functioning. Resulting proteoforms that have different sizes, alternative splicing patterns, sets of post-translational modifications, protein–protein interactions, and protein–ligand interactions, might dramatically increase the functionality of the encoded protein. Herein, we have interrogated the tumor suppressor PTEN for its proteoforms and find that this protein exists in multiple forms with distinct functions and sub-cellular localizations. Furthermore, the levels of each PTEN proteoform in a given cell may affect its biological function. Indeed, the paradigm of the continuum model of tumor suppression by PTEN can be better explained by the presence of a continuum of PTEN proteoforms, diversity, and levels of which are associated with pathological outcomes than simply by the different roles of mutations in the PTEN gene. Consequently, understanding the mechanisms underlying the dysregulation of PTEN proteoforms by several genomic and non-genomic mechanisms in cancer and other diseases is imperative. We have identified different PTEN proteoforms, which control various aspects of cellular function and grouped them into three categories of intrinsic, function-induced, and inducible proteoforms. A special emphasis is given to the inducible PTEN proteoforms that are produced due to alternative translational initiation. The novel finding that PTEN forms dimers with biological implications supports the notion that PTEN proteoform–proteoform interactions may play hitherto unknown roles in cellular homeostasis and in pathogenic settings, including cancer. These PTEN proteoforms with unique properties and functionalities offer potential novel therapeutic opportunities in the treatment of various cancers and other diseases.     

GSK3 and β-catenin determines functional expression of sodium channels at the axon initial segment

Neuronal action potentials are generated through voltage-gated sodium channels, which are tethered by ankyrinG at the membrane of the axon initial segment (AIS). Despite the importance of the AIS in the control of neuronal excitability, the cellular and molecular mechanisms regulating sodium channel expression at the AIS remain elusive. Our results show that GSK3α/β and β-catenin phosphorylated by GSK3 (S33/37/T41) are localized at the AIS and are new components of this essential neuronal domain. Pharmacological inhibition of GSK3 or β-catenin knockdown with shRNAs decreased the levels of phosphorylated-β-catenin, ankyrinG, and voltage-gated sodium channels at the AIS, both “in vitro” and “in vivo”, therefore diminishing neuronal excitability as evaluated via sodium current amplitude and action potential number. Thus, our results suggest a mechanism for the modulation of neuronal excitability through the control of sodium channel density by GSK3 and β-catenin at the AIS.     

Regulation of cyclin-Cdk activity in mammalian cells

Cell cycle progression is driven by the coordinated regulation of the activities of cyclin-dependent kinases (Cdks). Of the several mechanisms known to regulate Cdk activity in response to external signals, regulation of cyclin gene expression, post-translational modification of Cdks by phosphorylation-dephosphorylation cascades, and the interaction of cyclin/Cdk complexes with protein inhibitors have been thoroughly studied. During recent years, much attention has also been given to mechanisms that regulate protein degradation by the ubiquitin/proteasome pathway, as well as to the regulation of subcellular localization of the proteins that comprise the intrinsic cell cycle clock. The purpose of the present review is to summarize the most important aspects of the various mechanisms implicated in cell cycle regulation.