Назад

An exon-centric perspective

During the past ten years, remarkable progress has been made in our understanding of the complexity and regulation of alternative splicing. The generation of large datasets of quantitative alternative splicing profiling information has revealed that transcripts from at least 95% of multi-exon human genes undergo alternative splicing, and that thousands of exons in mammalian transcriptomes are subject to striking regulatory patterns. Together with advanced computational methods, these datasets have enabled the inference of a predictive code for tissue-dependent alternative splicing. This code has further provided new insight into splicing regulatory mechanisms. Collectively, these approaches are revealing the existence of discrete networks of exons that are coordinately regulated in diverse biologically normal and disease contexts. A major challenge ahead is to systematically determine the functions of exons comprising these exon networks as well as the factors and mechanisms responsible for their regulation. This perspective provides an account of progress in these areas and also discusses future avenues of exon-centric exploration.
Автор: Benjamin J. Blencowe 
Рік видання: 2012. Тип документу: Складова частина документу 
Розмір: 408 Кб     Кількість завантажень: 41

32nd Annual International Asilomar Chromatin and Chromosomes Conference


Рік видання: 2012. Тип документу: Складова частина документу 
Розмір: 286 Кб     Кількість завантажень: 41

Transgenic milk containing recombinant human lactoferrin modulates the intestinal flora in piglets

Lactoferrin (LF) is a beneficial multifunctional protein in milk. The objective of this study was to determine whether bovine transgenic milk containing recombinant human lactoferrin (rhLF) can modulate intestinal flora in the neonatal pig as an animal model for the human infant. We fed 7-day-old piglets (i) ordinary whole milk (OM), (ii) a 1:1 mixture of OM and rhLF milk (MM), or (iii) rhLF milk (LFM). LFM provided better average daily mass gain than OM (P = 0.007). PCR–denaturing gradient gel electrophoresis and 16S rDNA sequencing analysis revealed that the LFM piglets exhibited more diversity of the intestinal flora than the OM group. Except for the colon in the LFM group, an increasing trend in microbial diversity occurred from the duodenum to the colon. Fecal flora was not different across different ages or different treatment groups, but a cluster analysis showed that the fecal flora of OM- and MM-fed piglets had a higher degree of similarity than that of LFM-fed piglets. Based on culture-based bacterial counts of intestinal content samples, concentrations of Salmonella spp. in the colon and of Escherichia coli throughout the intestine were reduced with LFM (P < 0.01). Concentrations of Bifidobacterium spp. in the ileum and of Lactobacillus spp. throughout the intestine were also increased with LFM (P ≤ 0.01). We suggest that rhLF can modulate the intestinal flora in piglets.
Автор: Wenping Hu, Jie Zhao, Jianwu Wang, Tian Yu, Jing Wang, and Ning Li 
Рік видання: 2012. Тип документу: Складова частина документу 
Розмір: 564 Кб     Кількість завантажень: 41

Lactoferrin, a bird’s eye view

Lactoferrin is an abundant iron-binding protein in milk. This 80 kDa bilobal glycoprotein is also present in several other secreted bodily fluids, as well as in the secondary granules of neutrophils. The potent iron-binding properties of lactoferrin can locally create iron deficiency, and this is an important factor in host defense as it prevents bacteria from growing and forming biofilms. In addition to having antibacterial activity, lactoferrin is now known to have a long list of other beneficial biological properties. It has direct antiviral, antifungal, and even some anticancer activities. It can also promote wound healing and bone growth, or it can act as an iron carrier. Moreover, lactoferrin displays a cytokine-like “alarmin” activity, and it activates the immune system. Simultaneously, it can bind endotoxin (lipopolysaccharide), and in doing so, it modulates the activity of the host immune response. The majority of these intriguing biological activities reside in the unique positively charged N-terminal region of the protein. Interestingly, several peptides, which retain many of the beneficial activities, can be released from this region of lactoferrin. An isoform of the human protein, known as delta-lactoferrin, is expressed inside many cells, where it acts as a transcription factor. Lactoferrin purified from human and bovine milk have very similar but not completely identical properties. Lactoferrin receptors have been identified on the surface of various cells, and some of these can bind both the human and the bovine protein. Because of the extensive health-promoting effects of lactoferrin, there has been considerable interest in the use of bovine or human lactoferrin as a “protein nutraceutical” or as a therapeutic protein. When lactoferrin is used as a “biologic drug”, it seems to be orally active in contrast to most other therapeutic proteins.
Автор: Hans J. Vogel 
Рік видання: 2012. Тип документу: Складова частина документу 
Розмір: 412 Кб     Кількість завантажень: 41

Structure of the H1 C-terminal domain and function in chromatin condensation

Linker histones are multifunctional proteins that are involved in a myriad of processes ranging from stabilizing the folding and condensation of chromatin to playing a direct role in regulating gene expression. However, how this class of enigmatic proteins binds in chromatin and accomplishes these functions remains unclear. Here we review data regarding the H1 structure and function in chromatin, with special emphasis on the C-terminal domain (CTD), which typically encompasses approximately half of the mass of the linker histone and includes a large excess of positively charged residues. Owing to its amino acid composition, the CTD was previously proposed to function in chromatin as an unstructured polycation. However, structural studies have shown that the CTD adopts detectable secondary structure when interacting with DNA and macromolecular crowding agents. We describe classic and recent experiments defining the function of this domain in chromatin folding and emerging data indicating that the function of this protein may be linked to intrinsic disorder.
Автор: Tamara L. Caterino and Jeffrey J. Hayes 
Рік видання: 2011. Тип документу: Складова частина документу 
Розмір: 205 Кб     Кількість завантажень: 41

MeCP2: structure and function

Despite a vast body of literature linking chromatin structure to regulation of gene expression, the role of architectural proteins in higher order chromatin transitions required for transcription activation and repression has remained an under-studied field. To demonstrate the current knowledge of the role of such proteins, we have focused our attention on the methylated DNA binding and chromatin-associated protein MeCP2. Structural studies using chromatin assembled in vitro have revealed that MeCP2 can associate with nucleosomes in an N-terminus dependent manner and efficiently condense nucleosome arrays. The present review attempts to match MeCP2 structural domains, or lack thereof, and specific chromatin features needed for the proper recruitment of MeCP2 to its multiple functions as either activator or repressor. We specifically focused on MeCP2’s role in Rett syndrome, a neurological disorder associated with specific MeCP2 mutations.
Автор: Nicholas L. Adkins and Philippe T. Georgel 
Рік видання: 2011. Тип документу: Складова частина документу 
Розмір: 455 Кб     Кількість завантажень: 41

Heterochromatin and the DNA damage response: the need to relax

Higher order chromatin structure has an impact on all nuclear functions, including the DNA damage response. Over the past several years, it has become increasingly clear that heterochromatin and euchromatin represent separate entities with respect to both damage sensitivity and repair. The chromatin compaction present in heterochromatin helps to protect this DNA from damage; however, when lesions do occur, the compaction restricts the ability of DNA damage response proteins to access the site, as evidenced by its ability to block the expansion of H2AX phosphorylation. As such, DNA damage in heterochromatin is refractory to repair, which requires the surrounding chromatin structure to be decondensed. In the case of DNA double-strand breaks, this relaxation is at least partially mediated by the ATM kinase phosphorylating and inhibiting the function of the transcriptional repressor KAP1. This review will focus on the functions of KAP1 and other proteins involved in the maintenance or restriction of heterochromatin, including HP1 and TIP60, in the DNA damage response. As heterochromatin is important for maintaining genomic stability, cells must maintain a delicate balance between allowing repair factors access to these regions and ensuring that these regions retain their organization to prevent increased DNA damage and chromosomal mutations.
Автор: Kendra L. Cann and Graham Dellaire 
Рік видання: 2011. Тип документу: Складова частина документу 
Розмір: 516 Кб     Кількість завантажень: 41

WSTF does it all: a multifunctional protein in transcription, repair, and replication

Williams syndrome transcription factor (WSTF) has emerged as an incredibly versatile nuclear protein. WSTF and the ATP-dependent chromatin remodeling complexes in which it exists, WINAC, WICH, and B-WICH, have been studied in a variety of organisms. This research has revealed roles for WSTF in a number of diverse molecular events. WSTF function includes chromatin assembly, RNA polymerase I and III gene regulation, vitamin D metabolism, and DNA repair. In addition to functioning as a subunit of several ATP-dependent chromatin remodeling complexes, WSTF binds specifically to acetylated histones and is itself a histone kinase as well as a target of phosphorylation. This review will describe the three known WSTF-containing complexes and discuss their various roles as well as mechanisms of regulating WSTF activity.
Автор: Chris Barnett and Jocelyn E. Krebs 
Рік видання: 2011. Тип документу: Складова частина документу 
Розмір: 561 Кб     Кількість завантажень: 41

Activation and function of immediate-early genes in the nervous system

Immediate-early genes have important roles in processes such as brain development, learning, and responses to drug abuse. Further, immediate-early genes play an essential role in cellular responses that contribute to long-term neuronal plasticity. Neuronal plasticity is a characteristic of the nervous system that is not limited to the first stages of brain development but persists in adulthood and seems to be an inherent feature of everyday brain function. The plasticity refers to the neuron’s capability of showing short- or long-lasting phenotypic changes in response to different stimuli and cellular scenarios. In this review, we focus on the immediate-early genes encoding transcription factors (AP-1 and Egr) that are relevant for neuronal responses. Our current understanding of the mechanisms involved in the induction of the immediateearly genes is presented.
Автор: Beatriz Pe´ rez-Cadahı´a, Bojan Drobic, and James R. Davie 
Рік видання: 2011. Тип документу: Складова частина документу 
Розмір: 355 Кб     Кількість завантажень: 41

Nucleosome distribution and linker DNA: connecting nuclear function to dynamic chromatin structure

Genetic information in eukaryotes is managed by strategic hierarchical organization of chromatin structure. Primary chromatin structure describes an unfolded nucleosomal array, often referred to as ‘‘beads on a string’’. Chromatin is compacted by the nonlinear rearrangement of nucleosomes to form stable secondary chromatin structures. Chromatin conformational transitions between primary and secondary structures are mediated by both nucleosome-stacking interactions and the intervening linker DNA. Chromatin model system studies find that the topography of secondary structures is sensitive to the spacing of nucleosomes within an array. Understanding the relationship between nucleosome spacing and higher order chromatin structure will likely yield important insights into the dynamic nature of secondary chromatin structure as it occurs in vivo. Genome-wide nucleosome mapping studies find the distance between nucleosomes varies, and regions of uniformly spaced nucleosomes are often interrupted by regions of nonuniform spacing. This type of organization is found at a subset of actively transcribed genes in which a nucleosome-depleted region near the transcription start site is directly adjacent to uniformly spaced nucleosomes in the coding region. Here, we evaluate secondary chromatin structure and discuss the structural and functional implications of variable nucleosome distributions in different organisms and at gene regulatory junctions.
Автор: Heather J. Szerlong and Jeffrey C. Hansen 
Рік видання: 2011. Тип документу: Складова частина документу 
Розмір: 325 Кб     Кількість завантажень: 41

31st Annual International Asilomar Chromatin and Chromosomes Conference


Рік видання: 2011. Тип документу: Складова частина документу 
Розмір: 744 Кб     Кількість завантажень: 41

Synthesis, Biological, Spectral, and Thermal Investigations of Cobalt(II) and Nickel(II) Complexes of N-Isonicotinamido -2’,4’-Dichlorobenzalaldimine


Автор: Ram K. Agarwal, Deepak Sharma, Lakshman Singh, and Himanshu Agarwal 
Рік видання: 2006. Тип документу: Складова частина документу 
Розмір: 567 Кб     Кількість завантажень: 41

Erratum: Differential effects of c-Ras upon transformation, adipocytic differentiation, and apoptosis mediated by the simian virus 40 large tumor antigen

In the above-noted paper, the following error occurred. Parts C and D of Fig. 2 contained incorrect panels for the Hsp90 loading controls. The correct panels were derived by stripping and reprobing the same blots that gave rise to ADD1, shown in the top panels of Figs. 2C and 2D. The correct figure is reproduced here.
Автор: Jun Cao, Rozanne Arulanandam, Adina Vultur, Aikaterini Anagnostopoulou, and Leda Raptis 
Рік видання: 2008. Тип документу: Складова частина документу 
Розмір: 304 Мб     Кількість завантажень: 41

Erratum: Differential effects of c-Ras upon transformation, adipocytic differentiation, and apoptosis mediated by the simian virus 40 large tumor antigen

In the above-noted paper, the following error occurred. Parts C and D of Fig. 2 contained incorrect panels for the Hsp90 loading controls. The correct panels were derived by stripping and reprobing the same blots that gave rise to ADD1, shown in the top panels of Figs. 2C and 2D. The correct figure is reproduced here.
Автор: Jun Cao, Rozanne Arulanandam, Adina Vultur, Aikaterini Anagnostopoulou, and Leda Raptis 
Рік видання: 2008. Тип документу: Складова частина документу 
Розмір: 304 Кб     Кількість завантажень: 41