Stowers Institute for Medical Research

Kansas City, United States

Stowers Institute for Medical Research

Kansas City, United States

The Stowers Institute for Medical Research is a biomedical research organization that conducts basic research on genes and proteins that control fundamental processes in living cells to analyze diseases and find keys to their causes, treatment, and prevention. The main facility is located in Kansas City, Missouri. Wikipedia.

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Henikoff S.,Fred Hutchinson Cancer Research Center | Shilatifard A.,Stowers Institute for Medical Research
Trends in Genetics | Year: 2011

Histone modifications are key components of chromatin packaging but whether they constitute a 'code' has been contested. We believe that the central issue is causality: are histone modifications responsible for differences between chromatin states, or are differences in modifications mostly consequences of dynamic processes, such as transcription and nucleosome remodeling? We find that inferences of causality are often based on correlation and that patterns of some key histone modifications are more easily explained as consequences of nucleosome disruption in the presence of histone modifying enzymes. We suggest that the 35-year-old DNA accessibility paradigm provides a mechanistically sound basis for understanding the role of nucleosomes in gene regulation and epigenetic inheritance. Based on this view, histone modifications and variants contribute to diversification of a chromatin landscape shaped by dynamic processes that are driven primarily by transcription and nucleosome remodeling. © 2011 Elsevier Ltd.

Li R.,Stowers Institute for Medical Research | Li R.,University of Kansas Medical Center | Albertini D.F.,University of Kansas Medical Center
Nature Reviews Molecular Cell Biology | Year: 2013

Mammalian oocytes go through a long and complex developmental process while acquiring the competencies that are required for fertilization and embryogenesis. Recent advances in molecular genetics and quantitative live imaging reveal new insights into the molecular basis of the communication between the oocyte and ovarian somatic cells as well as the dynamic cytoskeleton-based events that drive each step along the pathway to maturity. Whereas self-organization of microtubules and motor proteins direct meiotic spindle assembly for achieving genome reduction, actin filaments are instrumental for spindle positioning and the establishment of oocyte polarity needed for extrusion of polar bodies. Meiotic chromatin provides key instructive signals while being 'chauffeured' by both cytoskeletal systems. © 2013 Macmillan Publishers Limited. All rights reserved.

Shilatifard A.,Stowers Institute for Medical Research
Annual Review of Biochemistry | Year: 2012

The Saccharomyces cerevisiae Set1COMPASS was the first histone H3 lysine 4 (H3K4) methylase identified over 10 years ago. Since then, it has been demonstrated that Set1COMPASS and its enzymatic product, H3K4 methylation, is highly conserved across the evolutionary tree. Although there is only one COMPASS in yeast, Drosophila possesses three and humans bear six COMPASS family members, each capable of methylating H3K4 with nonredundant functions. In yeast, the histone H2B monoubiquitinase Rad6Bre1 is required for proper H3K4 and H3K79 trimethylations. The machineries involved in this process are also highly conserved from yeast to human. In this review, the process of histone H2B monoubiquitination-dependent and-independent histone H3K4 methylation as a mark of active transcription, enhancer signatures, and developmentally poised genes is discussed. The misregulation of histone H2B monoubiquitination and H3K4 methylation result in the pathogenesis of human diseases, including cancer. Recent findings in this regard are also examined. © 2012 by Annual Reviews. All rights reserved.

Venkatesh S.,Stowers Institute for Medical Research | Workman J.L.,Stowers Institute for Medical Research
Nature Reviews Molecular Cell Biology | Year: 2015

The packaging of DNA into strings of nucleosomes is one of the features that allows eukaryotic cells to tightly regulate gene expression. The ordered disassembly of nucleosomes permits RNA polymerase II (Pol II) to access the DNA, whereas nucleosomal reassembly impedes access, thus preventing transcription and mRNA synthesis. Chromatin modifications, chromatin remodellers, histone chaperones and histone variants regulate nucleosomal dynamics during transcription. Disregulation of nucleosome dynamics results in aberrant transcription initiation, producing non-coding RNAs. Ongoing research is elucidating the molecular mechanisms that regulate chromatin structure during transcription by preventing histone exchange, thereby limiting non-coding RNA expression. © 2015 Macmillan Publishers Limited.

Suganuma T.,Stowers Institute for Medical Research | Workman J.L.,Stowers Institute for Medical Research
Annual Review of Biochemistry | Year: 2011

Alterations of chromatin structure have been shown to be crucial for response to cell signaling and for programmed gene expression in development. Posttranslational histone modifications influence changes in chromatin structure both directly and by targeting or activating chromatin-remodeling complexes. Histone modifications intersect with cell signaling pathways to control gene expression and can act combinatorially to enforce or reverse epigenetic marks in chromatin. Through their recognition by protein complexes with enzymatic activities cross talk is established between different modifications and with other epigenetic pathways, including noncoding RNAs (ncRNAs) and DNA methylation. Here, we review the functions of histone modifications and their exploitation in the programming of gene expression during several events in development. © 2011 by Annual Reviews. All rights reserved.

Aulehla A.,Stowers Institute for Medical Research
Cold Spring Harbor perspectives in biology | Year: 2010

The sequential formation of somites along the anterior-posterior axis is under control of multiple signaling gradients involving the Wnt, FGF, and retinoic acid (RA) pathways. These pathways show graded distribution of signaling activity within the paraxial mesoderm of vertebrate embryos. Although Wnt and FGF signaling show highest activity in the posterior, unsegmented paraxial mesoderm (presomitic mesoderm [PSM]), RA signaling establishes a countergradient with the highest activity in the somites. The generation of these graded activities relies both on classical source-sink mechanisms (for RA signaling) and on an RNA decay mechanism (for FGF signaling). Numerous studies reveal the tight interconnection among Wnt, FGF, and RA signaling in controlling paraxial mesoderm differentiation and in defining the somite-forming unit. In particular, the relationship to a molecular oscillator acting in somite precursors in the PSM-called the segmentation clock-has been recently addressed. These studies indicate that high levels of Wnt and FGF signaling are required for the segmentation clock activity. Furthermore, we discuss how these signaling gradients act in a dose-dependent manner in the progenitors of the paraxial mesoderm, partly by regulating cell movements during gastrulation. Finally, links between the process of axial specification of vertebral segments and Hox gene expression are discussed.

Si K.,Stowers Institute for Medical Research
Annual Review of Cell and Developmental Biology | Year: 2015

Prions, a self-templating amyloidogenic state of normal cellular proteins such as PrP, have been identified as the basis of a number of disease states, particularly diseases of the nervous system. This finding has led to the notion that protein aggregation, namely prionogenic aggregates and amyloids, is primarily harmful for the organism. However, identification of proteins in a prion-like state that are not harmful and may even be beneficial has begun to change this perception. This review discusses when and how a prion-based protein conformational switch may be utilized to generate a sustained physiological change in response to a transient stimulus. © 2015 by Annual Reviews. All rights reserved.

Smith E.,Stowers Institute for Medical Research | Shilatifard A.,Stowers Institute for Medical Research
Nature Structural and Molecular Biology | Year: 2014

Enhancers are cis-regulatory elements that enable precise spatiotemporal patterns of gene expression during development and are notable for being able to function at large distances from their target genes. Such regulatory elements often bypass intervening genes and typically comprise binding sites for multiple transcription factors that can also be transcribed by RNA polymerase II (Pol II) to produce noncoding enhancer RNAs (eRNAs). Genome-wide analyses have revealed chromatin signatures of enhancers, such as the enrichment for monomethylation of histone H3 lysine 4 (H3K4me1) and the acetylation or methylation of histone H3 lysine 27 (H3K27). Enhancer signatures have been used to describe the transitions of these regulatory elements from inactive to primed and from activated to decommissioned states during development. New mutations of enhancer sequences and of the protein factors regulating enhancer function in human disease continue to be identified, contributing to a growing class of 'enhanceropathies'. © 2014 Nature America, Inc.

Stowers Institute for Medical Research | Date: 2016-05-17

The present invention relates to methods and kits for expanding a stem cell population. More particularly, the invention relates, inter alia, to methods, kits, and compositions for expanding a stem cell population, particularly a hematopoietic stem cell population.

Stowers Institute for Medical Research | Date: 2016-04-22

The present invention is directed to isolated polypeptides and antibodies suitable for producing therapeutic preparations, methods, and kits relating to bone deposition. One objective of the present invention is to provide compositions that improve bone deposition. Yet another objective of the present invention is to provide methods and compositions to be utilized in diagnosing bone dysregulation. The therapeutic compositions and methods of the present invention are related to the regulation of Wise, Sost, and closely related sequences. In particular, the nucleic acid sequences and polypeptides include Wise and Sost as well as a family of molecules that express a cysteine knot polypeptide.

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