-OH No! hiPSCs Misplace Their 5hmCs

hiPSCs and hESCs are thought to display subtle genetic and epigenetic variability. Recently in Nature Cell Biology, Wang et al. (2013) demonstrated a role for TET1 during reprogramming of human cells and showed that hiPSCs lack appropriate 5hmC marks in subtelomeric regions, contributing to epigenetic variation common to hiPSCs

Exploiting the origins of Ras mediated squamous cell carcinoma to develop novel therapeutic interventions

The small GTPase Ras is activated in a high proportion of human cancers. Attempts to clinically block Ras activity through pharmacological means has proven largely ineffective thus far. We employed an inducible mouse model of squamous cell carcinoma (SCC) to study the effect of Ras activation and show that hair follicle stem cells (HFSCs) are a cell of origin for SCC, whereas their more restricted progeny cannot serve as cancer cells of origin and are refractory to Ras activation. We propose that by identifying the unique mechanisms by which HFSCs are mobilized to initiate Ras mediated tumorigenesis, the molecular process behind SCC can be more completely elucidated and context dependent activities for Ras more clearly defined. Here, we summarize our recent results and point to future experiments designed to create novel therapeutics by exploiting the differential sensitivities of various cells within the epidermis to Ras activation

Molecular Analyses of Human Induced Pluripotent Stem Cells and Embryonic Stem Cells

SummaryRecent work from our group and others has argued that human induced pluripotent stem cells (hiPSCs) generated by the introduction of four viruses bearing reprogramming factors differ from human embryonic stem cells (hESCs) at the level of gene expression (Chin et al., 2009). Many of the differences seen were common across independent labs and, at least to some extent, are thought to be a result of residual expression of donor cell-specific genes (Chin et al., 2009; Ghosh et al., 2010; Marchetto et al., 2009). Two new reports reanalyze similar expression data sets as those used in Chin et al. (2009) and come to different conclusions (Newman and Cooper, 2010; Guenther et al., 2010). We compare various approaches to perform gene expression meta-analysis that all support our original conclusions and present new data to demonstrate that polycistronic delivery of the reprogramming factors and extended culture brings hiPSCs transcriptionally closer to hESCs

Defining the role of oxygen tension in human neural progenitor fate.

Hypoxia augments human embryonic stem cell (hESC) self-renewal via hypoxia-inducible factor 2α-activated OCT4 transcription. Hypoxia also increases the efficiency of reprogramming differentiated cells to a pluripotent-like state. Combined, these findings suggest that low O2 tension would impair the purposeful differentiation of pluripotent stem cells. Here, we show that low O2 tension and hypoxia-inducible factor (HIF) activity instead promote appropriate hESC differentiation. Through gain- and loss-of-function studies, we implicate O2 tension as a modifier of a key cell fate decision, namely whether neural progenitors differentiate toward neurons or glia. Furthermore, our data show that even transient changes in O2 concentration can affect cell fate through HIF by regulating the activity of MYC, a regulator of LIN28/let-7 that is critical for fate decisions in the neural lineage. We also identify key small molecules that can take advantage of this pathway to quickly and efficiently promote the development of mature cell types

Samuel Lowry Latimer, Jr. Papers - Accession 530

The personal papers of Samuel Lowry Latimer, Jr. (1891-1975) include insurance, financial and tax records, various state-related pamphlets, photographs (mainly from The State newspaper) and postcards, and galley proofs of Three Scores and Ten, a history of The State written by Mr. Latimer (published in 1970 under the title The Story of The State and the Gonzales Brothers, see appendix #2). Also included are items of personal and business correspondence of Mr. Latimer and Major McDavid Horton (1884-1941) (editor of The State from 1938 to 1941), various personal items and memorabilia from Mr. Latimer’s two trips abroad, newspaper clippings and articles relating to or published in The State, critiques of The Story of The State and the Gonzales Brothers done by Mrs. Albert D. (May) Oliphant, and several miscellaneous newspaper articles. One of the major subjects of the collection is founding of The State newspapers and the Gonzales Brothers. The Gonzales brothers are Narciso Gener Gonzales (1858-1903), Ambrose Elliott Gonzales (1857-1926), and William Gonzales (1866-1937) and the former two founded The State newspaper in Columbia, SC in 1891. Narciso would later be gunned down on January 15, 1903 (he died four days later) by James H. Tillman. James Tillman was Lieutenant Governor of South Carolina (and nephew of SC Senator Benjamin Tillman) and was a frequent target of criticism by the paper. Tillman would be acquitted by a jury despite many witnesses and received no punishment.https://digitalcommons.winthrop.edu/manuscriptcollection_findingaids/1623/thumbnail.jp

Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence.

To determine the role for mutations of MECP2 in Rett syndrome, we generated isogenic lines of human induced pluripotent stem cells, neural progenitor cells, and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal-specific gene expression changes, including induction of a senescence-associated secretory phenotype (SASP) program. Patient-derived neurons made without MECP2 showed signs of stress, including induction of P53, and senescence. The induction of P53 appeared to affect dendritic branching in Rett neurons, as P53 inhibition restored dendritic complexity. The induction of P53 targets was also detectable in analyses of human Rett patient brain, suggesting that this disease-in-a-dish model can provide relevant insights into the human disorder

Csk, a Critical Link of G Protein Signals to Actin Cytoskeletal Reorganization

AbstractHeterotrimeric G proteins can signal to reorganize the actin cytoskeleton, but the mechanism is unclear. Here we report that, in tyrosine kinase Csk-deficient mouse embryonic fibroblast cells, G protein (Gβγ, Gα12, Gα13, and Gαq)-induced, and G protein-coupled receptor-induced, actin stress fiber formation was completely blocked. Reintroduction of Csk into Csk-deficent cells restored the G protein-induced actin stress fiber formation. Chemical rescue experiments with catalytic mutants of Csk demonstrated that the catalytic activity of Csk was required for this process. Furthermore, we uncovered that Gβγ can both translocate Csk to the plasma membrane and directly increase Csk kinase activity. Our genetic and biochemical studies demonstrate that Csk plays a critical role in mediating G protein signals to actin cytoskeletal reorganization

Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I

Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I

Correction to: Differentiation of RPE cells from integration-free iPS cells and their cell biological characterization.

The original article [1] contains an error in the legend of Fig 5 whereby the descriptions for panels 5d and 5e are incorrect; as such, the corrected legend can be viewed below with its respective figure images