Biomedical subjects

Sylvia Marecki

Publications and source records attributed to Sylvia Marecki.

4 recordsLinked to original sources

PubMed2006

The interleukin-1beta gene is transcribed from a poised promoter architecture in monocytes.

Cytokine transcription is usually regulated by transcription factor binding and chromatin remodeling following an inducing signal. By contrast, these data showed the interleukin (IL)-1beta promoter assembles into a "poised" structure, as evidenced by nuclease accessibility and loss of core histones immediately surrounding the transcription start site. Strikingly, these properties do not change upon transcriptional activation by lipopolysaccharide. Furthermore, association of two key transcriptional activators, PU.1 and C/EBPbeta, is robust pre- and post-stimulation indicating the IL-1beta promoter is packaged into a nontranscribed but poised promoter architecture in cells capable of rapidly inducing IL-1beta. Monocyte stimulation causes recruitment of a third factor, IRF-4, to the IL-1beta enhancer. PU.1 phosphorylation at a CK2 kinase consensus element is required for this recruitment. We showed that CK2 phosphorylates PU.1, CK2 inhibitors abrogate IL-1beta induction, and CK2 inducibly associates with the IL-1beta enhancer. Taken together, these data indicate a novel two-step mechanism for IL-1beta transcription: 1) formation of a poised chromatin architecture, and 2) phosphorylation of an enhancer-bound factor that recruits other activators. We propose that this poised structure may generally characterize rapidly activated genes.

Casein Kinase II↗

PubMed2004

PU.1 as a chromatin accessibility factor for immunoglobulin genes.

The hematopoietic-specific transcription factor PU.1 is a chromatin accessibility factor, based on analysis of the immunoglobulin heavy chain intronic (mu) enhancer. Whether PU.1 functions as an accessibility factor for additional PU.1-regulated genes is unknown. Outside the constraints of chromatin, PU.1 binds and activates transcription through both mu and kappa3' immunoglobulin enhancers, among others. The DNA-binding ETS domain of PU.1 is sufficient for activating both enhancers in an extrachromosomal context. New data show that the ETS domain of PU.1 is sufficient for increasing accessibility of a closed mu enhancer chromatin structure proximal to the PU.1-binding site. In contrast, PU.1 does not alter widespread chromatin accessibility. Furthermore, PU.1 does not induce accessibility proximal or distal to its binding site on the kappa3' enhancer. Taken together the data demonstrate that PU.1 induces chromatin accessibility proximal to its binding site at a locus activated early in development, the mu locus. PU.1 does not function as an accessibility factor for the kappa3' enhancer, which regulates a locus important for later stages of B cell development. We conclude that PU.1 is a context-dependent chromatin accessibility factor that, alone, cannot establish widespread accessibility required for critical developmental processes such as antigen receptor recombination.

Animals↗

PubMed2004

Efalizumab.

Explore the source record for details and available documents.

Antibodies, Monoclonal↗

PubMed2002

The role of IRF-4 in transcriptional regulation.

Gene expression is a tightly regulated process involving multiple levels of control spanning histone acetylation to protein turnover. One of the first events in this cascade is transcription, which itself is a multistep process involving protein-protein interaction and macromolecular assembly. Here we review the role of the interferon (IFN) regulatory factor (IRF) transcription factor family member IRF-4 in transcriptional regulation. IRF-4 was initially characterized in lymphocytes and was shown to function as both a transcriptional repressor and activator. More recently, IRF-4 expression and function have been reported in macrophages. The ability of IRF-4 to serve as both a transcriptional activator and repressor is determined, in part, by binding to distinct DNA-binding motifs and through interaction with various additional transcription factors, most notably with the Ets family member PU.1. The details governing these functional differences are the focus of this review. Importantly, the role of posttranslational modification and nuclear translocation of IRF-4 in transcriptional regulation are addressed. Several possible paradigms of transcriptional regulation by IRF-4 are proposed, where these paradigms may describe regulatory mechanisms common to many distinct transcription factor families.

Animals↗