Dataset Information

Molecular hallmarks of endogenous chromatin complexes containing master regulators of hematopoiesis.

ABSTRACT: Combinatorial interactions among trans-acting factors establish transcriptional circuits that orchestrate cellular differentiation, survival, and development. Unlike circuits instigated by individual factors, efforts to identify gene ensembles controlled by multiple factors simultaneously are in their infancy. A paradigm has emerged in which the important regulators of hematopoiesis GATA-1 and GATA-2 function combinatorially with Scl/TAL1, another key regulator of hematopoiesis. The underlying mechanism appears to involve preferential assembly of a multimeric complex on a composite DNA element containing WGATAR and E-box motifs. Based on this paradigm, one would predict that GATA-2 and Scl/TAL1 would commonly co-occupy such composite elements in cells. However, chromosome-wide analyses indicated that the vast majority of conserved composite elements were occupied by neither GATA-2 nor Scl/TAL1. Intriguingly, the highly restricted set of GATA-2-occupied composite elements had characteristic molecular hallmarks, specifically Scl/TAL1 occupancy, a specific epigenetic signature, specific neighboring cis elements, and preferential enhancer activity in GATA-2-expressing cells. Genes near the GATA-2-Scl/TAL1-occupied composite elements were regulated by GATA-2 or GATA-1, and therefore these fundamental studies on combinatorial transcriptional mechanisms were also leveraged to discover novel GATA factor-mediated cell regulatory pathways.

SUBMITTER: Wozniak RJ

PROVIDER: S-EPMC2573226 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular hallmarks of endogenous chromatin complexes containing master regulators of hematopoiesis.

Wozniak Ryan J RJ Keles Sunduz S Lugus Jesse J JJ Young Ken H KH Boyer Meghan E ME Tran Tuan M TM Choi Kyunghee K Bresnick Emery H EH

Molecular and cellular biology 20080908 21

Combinatorial interactions among trans-acting factors establish transcriptional circuits that orchestrate cellular differentiation, survival, and development. Unlike circuits instigated by individual factors, efforts to identify gene ensembles controlled by multiple factors simultaneously are in their infancy. A paradigm has emerged in which the important regulators of hematopoiesis GATA-1 and GATA-2 function combinatorially with Scl/TAL1, another key regulator of hematopoiesis. The underlying m ...[more]

PMID: 18779319

Similar Datasets

Project description:BACKGROUND:Alzheimer's disease (AD) is a multifactorial and complex neuropathology that involves impairment of many intricate molecular mechanisms. Despite recent advances, AD pathophysiological characterization remains incomplete, which hampers the development of effective treatments. In fact, currently, there are no effective pharmacological treatments for AD. Integrative strategies such as transcription regulatory network and master regulator analyses exemplify promising new approaches to study complex diseases and may help in the identification of potential pharmacological targets. METHODS:In this study, we used transcription regulatory network and master regulator analyses on transcriptomic data of human hippocampus to identify transcription factors (TFs) that can potentially act as master regulators in AD. All expression profiles were obtained from the Gene Expression Omnibus database using the GEOquery package. A normal hippocampus transcription factor-centered regulatory network was reconstructed using the ARACNe algorithm. Master regulator analysis and two-tail gene set enrichment analysis were employed to evaluate the inferred regulatory units in AD case-control studies. Finally, we used a connectivity map adaptation to prospect new potential therapeutic interventions by drug repurposing. RESULTS:We identified TFs with already reported involvement in AD, such as ATF2 and PARK2, as well as possible new targets for future investigations, such as CNOT7, CSRNP2, SLC30A9, and TSC22D1. Furthermore, Connectivity Map Analysis adaptation suggested the repositioning of six FDA-approved drugs that can potentially modulate master regulator candidate regulatory units (Cefuroxime, Cyproterone, Dydrogesterone, Metrizamide, Trimethadione, and Vorinostat). CONCLUSIONS:Using a transcription factor-centered regulatory network reconstruction we were able to identify several potential molecular targets and six drug candidates for repositioning in AD. Our study provides further support for the use of bioinformatics tools as exploratory strategies in neurodegenerative diseases research, and also provides new perspectives on molecular targets and drug therapies for future investigation and validation in AD.

Dataset Information

Molecular hallmarks of endogenous chromatin complexes containing master regulators of hematopoiesis.

Publications

Molecular hallmarks of endogenous chromatin complexes containing master regulators of hematopoiesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets