Although physiological steroid levels are often pulsatile (ultradian), the genomic effects of this pulsatility are poorly understood. By utilizing glucocorticoid receptor (GR) signaling as a model system, we uncovered striking spatiotemporal relationships between receptor loading, lifetimes of the DNase I hypersensitivity sites (DHSs), long-range interactions, and gene regulation. We found that hormone-induced DHSs were enriched within ± 50 kb of GR-responsive genes and displayed a broad spectrum of lifetimes upon hormone withdrawal. These lifetimes dictate the strength of the DHS interactions with gene targets and contribute to gene regulation from a distance. Our results demonstrate that pulsatile and constant hormone stimulations induce unique, treatment-specific patterns of gene and regulatory element activation. These modes of activation have implications for corticosteroid function in vivo and for steroid therapies in various clinical settings.

• MeSH
• buněčné linie MeSH
• chromatin genetika   metabolismus   MeSH
• chromatinová imunoprecipitace MeSH
• deoxyribonukleasa I genetika   metabolismus   MeSH
• glukokortikoidy farmakologie   MeSH
• membránové proteiny genetika   metabolismus   MeSH
• myši MeSH
• receptory glukokortikoidů genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• responzivní elementy * MeSH
• sekvenční analýza DNA MeSH
• transportní proteiny genetika   metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH

Rubinstein-Taybi syndrome (RSTS) is a well-known autosomal dominant mental retardation syndrome with typical facial and skeletal abnormalities. Previously, we have reported two patients presenting with RSTS and additional clinical features including failure to thrive, seizures, and intractable infections (Bartsch et al. in Eur J Hum Genet 7:748-756, 1999). Recently we identified a third patient with this condition, termed here severe RSTS, or chromosome 16p13.3 deletion syndrome. The three patients died in infancy, and all displayed a specific mutation, a chromosomal microdeletion including the 3'-end of the CREBBP gene. Using fluorescence in situ hybridization and closely spaced DNA probes, we characterized the deletion intervals in these patients and in three individuals with a deletion of CREBBP and typical RSTS. The deleted DNA segments were found to greatly vary in size, spanning from approximately 40 kb to >3 Mb. Four individuals, including the patients with severe RSTS, exhibited deletions containing gene/s in addition to CREBBP. The patients with severe RSTS all had deletions comprising telomeric neighbor genes of CREBBP, including DNASE1, a dominant gene encoding a nuclease that has been associated with systemic lupus erythematodes. Our findings suggest that severe RSTS is distinct from RSTS and represents a novel true contiguous gene syndrome (chromosome 16p13.3 deletion syndrome). Because of the risk of critical infections and high mortality rate, we recommend that the size of the deletion interval should be determined in CREBBP deletion-positive patients with RSTS, especially in young children. Further studies are needed to delineate the clinical spectrum of the new disorder and to clarify the role of DNASE1.

• MeSH
• chromozomální delece * MeSH
• delece genu MeSH
• deoxyribonukleasa I * genetika   MeSH
• hybridizace in situ fluorescenční MeSH
• kojenec MeSH
• lidé MeSH
• lidské chromozomy, pár 16 * MeSH
• protein vázající CREB * genetika   MeSH
• Rubinsteinův-Taybiho syndrom * genetika   patologie   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH