VISTA Enhancer Browser—a database of tissue-specific human enhancers

Despite the known existence of distant-acting cis-regulatory elements in the human genome, only a small fraction of these elements has been identified and experimentally characterized in vivo. This paucity of enhancer collections with defined activities has thus hindered computational approaches for the genome-wide prediction of enhancers and their functions. To fill this void, we utilize comparative genome analysis to identify candidate enhancer elements in the human genome coupled with the experimental determination of their in vivo enhancer activity in transgenic mice [L. A. Pennacchio et al. (2006) Nature, in press]. These data are available through the VISTA Enhancer Browser (). This growing database currently contains over 250 experimentally tested DNA fragments, of which more than 100 have been validated as tissue-specific enhancers. For each positive enhancer, we provide digital images of whole-mount embryo staining at embryonic day 11.5 and an anatomical description of the reporter gene expression pattern. Users can retrieve elements near single genes of interest, search for enhancers that target reporter gene expression to a particular tissue, or download entire collections of enhancers with a defined tissue specificity or conservation depth. These experimentally validated training sets are expected to provide a basis for a wide range of downstream computational and functional studies of enhancer function

Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease.

How stage-specific enhancer dynamics modulate gene expression patterns essential for organ development, homeostasis and disease is not well understood. Here, we addressed this question by mapping chromatin occupancy of GATA4--a master cardiac transcription factor--in heart development and disease. We find that GATA4 binds and participates in establishing active chromatin regions by stimulating H3K27ac deposition, which facilitates GATA4-driven gene expression. GATA4 chromatin occupancy changes markedly between fetal and adult heart, with a limited binding sites overlap. Cardiac stress restored GATA4 occupancy to a subset of fetal sites, but many stress-associated GATA4 binding sites localized to loci not occupied by GATA4 during normal heart development. Collectively, our data show that dynamic, context-specific transcription factors occupancy underlies stage-specific events in development, homeostasis and disease

Multiple conserved regulatory domains promote Fezf2 expression in the developing cerebral cortex.

BackgroundThe genetic programs required for development of the cerebral cortex are under intense investigation. However, non-coding DNA elements that control the expression of developmentally important genes remain poorly defined. Here we investigate the regulation of Fezf2, a transcription factor that is necessary for the generation of deep-layer cortical projection neurons.ResultsUsing a combination of chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) we mapped the binding of four deep-layer-enriched transcription factors previously shown to be important for cortical development. Building upon this we characterized the activity of three regulatory regions around the Fezf2 locus at multiple stages throughout corticogenesis. We identified a promoter that was sufficient for expression in the cerebral cortex, and enhancers that drove reporter gene expression in distinct forebrain domains, including progenitor cells and cortical projection neurons.ConclusionsThese results provide insight into the regulatory logic controlling Fezf2 expression and further the understanding of how multiple non-coding regulatory domains can collaborate to control gene expression in vivo

Место комбинированной терапии М-холинолитиком и β2-адреномиметиком короткого действия в терапии бронхообструктивного синдрома

A role of combined therapy with M-cholinolytic and β2-adrenomimetic drugs for bronchial obstruction.Место комбинированной терапии М-холинолитиком и β2-адреномиметиком короткого действия в терапии бронхообструктивного синдрома

Саркоидоз: обзор работ последних лет

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Противовоспалительный препарат фенспирид

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Large-scale discovery of enhancers from human heart tissue.

Development and function of the human heart depend on the dynamic control of tissue-specific gene expression by distant-acting transcriptional enhancers. To generate an accurate genome-wide map of human heart enhancers, we used an epigenomic enhancer discovery approach and identified ∼6,200 candidate enhancer sequences directly from fetal and adult human heart tissue. Consistent with their predicted function, these elements were markedly enriched near genes implicated in heart development, function and disease. To further validate their in vivo enhancer activity, we tested 65 of these human sequences in a transgenic mouse enhancer assay and observed that 43 (66%) drove reproducible reporter gene expression in the heart. These results support the discovery of a genome-wide set of noncoding sequences highly enriched in human heart enhancers that is likely to facilitate downstream studies of the role of enhancers in development and pathological conditions of the heart

Co-option of the transcription factor SALL1 in mole ovotestis formation

Changes in gene expression represent an important source for phenotypical innovation. Yet, how such changes emerge and impact the evolution of traits remains elusive. Here, we explore the molecular mechanisms associated with the development of masculinizing ovotestes in female moles. By performing comparative analyses of epigenetic and transcriptional data in mole and mouse, we identified SALL1 as a co-opted gene for the formation of testicular tissue in mole ovotestes. Chromosome conformation capture analyses highlight a striking conservation of the 3D organization at the SALL1 locus, but a prominent evolutionary turnover of enhancer elements. Interspecies reporter assays support the capability of mole-specific enhancers to activate transcription in urogenital tissues. Through overexpression experiments in transgenic mice, we further demonstrate the capability of SALL1 to induce the ectopic gene expression programs that are a signature of mole ovotestes. Our results highlight the co-option of gene expression, through changes in enhancer activity, as a prominent mechanism for the evolution of traits

Оценка влияния длительного приема фенспирида (Эреспала) на клинико-функциональное состояние больных хронической обструктивной болезнью легких

This open comparative randomized study has shown that fenspiride is an effective and well-tolerated drug while being administered in combined therapy of COPD for 3 to 12 months. The anti-inflammatory action of fenspiride 80 mg t. i. d. significantly reduced cough in COPD patients and enhanced the effect of bronchodilators. Fenspiride (Erespal) can be included in standards of combined treatment of patients with mild, moderate and severe COPD.В открытом сравнительном рандомизированном исследовании фенспирида (Эреспала) были показаны эффективность и хорошая переносимость при его включении в комплексную терапию больных хронической обструктивной болезнью легких (ХОБЛ) в течение как 3, так и 12 мес. Исследование подтвердило достоверное влияние Эреспала (80 мг 3 раза в день) на частоту кашлевого синдрома у больных ХОБЛ за счет противовоспалительного действия. Противовоспалительным эффектом можно объяснить также и потенцирование бронхолитического ответа. Эреспал может быть рекомендован для включения в протоколы комплексного лечения больных ХОБЛ легкой, среднетяжелой и тяжелой степени тяжести

Оценка клинико-функционального состояния и качества жизни больных хронической обструктивной болезнью легких до и после комплексной медикаментозной терапии в амбулаторных условиях

A comparative randomised trial of fenspirid (Erespal) had been administered for 3 months together with bronchodilating and mycolytic drugs involved 45 patients with chronic obstructive pulmonary disease (COPD). Clinical status, forced expiratory values and quality of life (QoL) were studied using World Organization of Health questionnaire (W H O Q O L -100). Thirty four patients completed the examination (24 males and 10 females, the average age was 52.7±1.9 yrs). The comparative group included 25 healthy non-smokers. The trial demonstrated that the therapy resulted in improvement of QoL in physical and psychical health scales. The patients becam e more active, their sleep becam e better. Their attention was transferred from their physical status to the surroundings. The application of fenspirid (Erespal) facilitated the improvement in the forced expiratory values and ESR. The drug was well tolerated and caused only mild adverse effects which rates were equal to those in patients not received fenspirid. The results permit fenspirid to be included to modern treatment protocols for patients with mild to moderate COPD when combined with bronchodilators.В сравнительное рандомизированное исследование препарата фенспирид (эреспал), применявшегося в течение 3 мес в сочетании с бронхолитическими и муколитическими средствами, было включено 45 больных хронической обструктивной болезнью легких (ХОБЛ). Изучали клинический статус пациентов, параметры форсированного выдоха и качество жизни больных ХОБЛ с помощью опросника Всемирной организации здравоохранения W H O Q O L-100. Полностью обследование завершили 34 больных ХОБЛ (24 мужчин и 10 женщин), средний возраст которых составил 52,7±1,9 года. 25 здоровых не курящих людей составили группу сравнения. Проведенное исследование показало, что после лечения качество жизни (КЖ), оцененное по методике, рекомендованной ВОЗ, улучшилось по шкалам, отражающим физическое и психическое здоровье. Больные стали более активными, у них улучшился сон. Акцентуация была перенесена с собственного физического состояния на окружающую среду. Использование фенспирида (эреспал) в лечении больных ХОБЛ потенцировало улучшение параметров форсированного выдоха, нормализацию СОЭ. Препарат хорошо переносился, вызывал только легкие побочные реакции, которые встречались не чаще, чем у пациентов, не получавших фенспирид. Полученные данные позволяют рекомендовать включение фенспирида (эреспал) в современные протоколы лечения больных ХОБЛ при легком и среднетяжелом течении в сочетании с бронхолитическими препаратами