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Hematopoietic transcriptional mechanisms: from locus-specific to genome-wide vantage points.

ABSTRACT: Hematopoiesis is an exquisitely regulated process in which stem cells in the developing embryo and the adult generate progenitor cells that give rise to all blood lineages. Master regulatory transcription factors control hematopoiesis by integrating signals from the microenvironment and dynamically establishing and maintaining genetic networks. One of the most rudimentary aspects of cell type-specific transcription factor function, how they occupy a highly restricted cohort of cis-elements in chromatin, remains poorly understood. Transformative technologic advances involving the coupling of next-generation DNA sequencing technology with the chromatin immunoprecipitation assay (ChIP-seq) have enabled genome-wide mapping of factor occupancy patterns. However, formidable problems remain; notably, ChIP-seq analysis yields hundreds to thousands of chromatin sites occupied by a given transcription factor, and only a fraction of the sites appear to be endowed with critical, non-redundant function. It has become en vogue to map transcription factor occupancy patterns genome-wide, while using powerful statistical tools to establish correlations to inform biology and mechanisms. With the advent of revolutionary genome editing technologies, one can now reach beyond correlations to conduct definitive hypothesis testing. This review focuses on key discoveries that have emerged during the path from single loci to genome-wide analyses, specifically in the context of hematopoietic transcriptional mechanisms.

SUBMITTER: DeVilbiss AW

PROVIDER: S-EPMC4125519 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Hematopoietic transcriptional mechanisms: from locus-specific to genome-wide vantage points.

DeVilbiss Andrew W AW Sanalkumar Rajendran R Johnson Kirby D KD Keles Sunduz S Bresnick Emery H EH

Experimental hematology 20140509 8

Hematopoiesis is an exquisitely regulated process in which stem cells in the developing embryo and the adult generate progenitor cells that give rise to all blood lineages. Master regulatory transcription factors control hematopoiesis by integrating signals from the microenvironment and dynamically establishing and maintaining genetic networks. One of the most rudimentary aspects of cell type-specific transcription factor function, how they occupy a highly restricted cohort of cis-elements in ch ...[more]

PMID: 24816274

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Project description:BackgroundNonadherence produces considerable health consequences and economic burden to patients and payers. One approach to improve medication nonadherence that has gained interest in recent years is the use of smartphone adherence apps. The development of smartphone adherence apps has increased rapidly since 2012; however, literature evaluating the clinical app and effectiveness of smartphone adherence apps to improve medication adherence is generally lacking.ObjectiveThe aims of this study were to (1) provide an updated evaluation and comparison of medication adherence apps in the marketplace by assessing the features, functionality, and health literacy (HL) of the highest-ranking adherence apps and (2) indirectly measure the validity of our rating methodology by determining the relationship between our app evaluations and Web-based consumer ratings.MethodsTwo independent reviewers assessed the features and functionality using a 4-domain rating tool of all adherence apps identified based on developer claims. The same reviewers downloaded and tested the 100 highest-ranking apps including an additional domain for assessment of HL. Pearson product correlations were estimated between the consumer ratings and our domain and total scores.ResultsA total of 824 adherence apps were identified; of these, 645 unique apps were evaluated after applying exclusion criteria. The median initial score based on descriptions was 14 (max of 68; range 0-60). As a result, 100 of the highest-scoring unique apps underwent user testing. The median overall user-tested score was 31.5 (max of 73; range 0-60). The majority of the user tested the adherence apps that underwent user testing reported a consumer rating score in their respective online marketplace. The mean consumer rating was 3.93 (SD 0.84). The total user-tested score was positively correlated with consumer ratings (r=.1969, P=.04).ConclusionsMore adherence apps are available in the Web-based marketplace, and the quality of these apps varies considerably. Consumer ratings are positively but weakly correlated with user-testing scores suggesting that our rating tool has some validity but that consumers and clinicians may assess adherence app quality differently.

Project description:Mutations in the hyperparathyroidism type 2 (HRPT2/CDC73) gene and alterations in the parafibromin protein have been established in the majority of parathyroid carcinomas and in subsets of parathyroid adenomas. While it is known that CDC73-mutated parathyroid tumors display specific gene expression changes compared to CDC73 wild-type cases, the molecular cytogenetic profile in CDC73-mutated cases compared to unselected adenomas (with an expected very low frequency of CDC73 mutations) remains unknown. For this purpose, nine parathyroid tumors with established CDC73 gene inactivating mutations (three carcinomas, one atypical adenoma and five adenomas) were analyzed for copy number alterations and loss of heterozygosity using array-comparative genomic hybridization (a-CGH) and single nucleotide polymorphism (SNP) microarrays, respectively. Furthermore, CDC73 gene promoter methylation levels were assessed using bisulfite Pyrosequencing. The panel included seven tumors with single mutation and three with double mutations of the CDC73 gene. The carcinomas displayed copy number alterations in agreement with previous studies, whereas the CDC73-mutated adenomas did not display the same pattern of alterations at loci frequently deleted in unselected parathyroid tumors. Furthermore, gross losses of chromosomal material at 1p and 13 were significantly (p = 0.012) associated with parathyroid carcinomas as opposed to adenomas. Quantitative PCR-based copy number loss regarding CDC73 was observed in three adenomas, while all the carcinomas were diploid or showed copy number gain for CDC73 gene. Hypermethylation of the CDC73 gene promoter was not observed. Our data could suggest that CDC73-mutated parathyroid adenomas exhibit a partly unique cytogenetic profile in addition to that of carcinomas and unselected adenomas. Furthermore, CDC73-mutated carcinomas displayed losses at 1p and 13 which are not seen in CDC73-mutated adenomas, making these regions of interest for further studies regarding malignant properties in tumors from CDC73-mutated cases. However, due to the small sample size, validation of the results in a larger cohort is warranted.

Dataset Information

Hematopoietic transcriptional mechanisms: from locus-specific to genome-wide vantage points.

Publications

Hematopoietic transcriptional mechanisms: from locus-specific to genome-wide vantage points.

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