A5035829700- Circadian rhythm and melatonin
- Light effects on plants
- Genetics, Aging, and Longevity in Model Organisms
- Wnt/β-catenin signaling in development and cancer
- Photoreceptor and optogenetics research
- Hippo pathway signaling and YAP/TAZ
- Renal and related cancers
- Dietary Effects on Health
- Neurobiology and Insect Physiology Research
- Sleep and Wakefulness Research
- Computational Drug Discovery Methods
- Hedgehog Signaling Pathway Studies
- Cancer-related gene regulation
- Spaceflight effects on biology
- Genetic and Kidney Cyst Diseases
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Cellular transport and secretion
- Developmental Biology and Gene Regulation
- Psychological and Temporal Perspectives Research
- Gene Regulatory Network Analysis
- Free Radicals and Antioxidants
- RNA Research and Splicing
- Cancer Genomics and Diagnostics
- Urological Disorders and Treatments
Morehouse School of Medicine
2014-2022
Translational Therapeutics (United States)
2009-2018
University of Pennsylvania
2008-2018
Neuroscience Institute
2017
The University of Texas Southwestern Medical Center
2009
Yale University
2009
Science Foundation Ireland
2008
Scripps Research Institute
2005-2006
University of Virginia
2003-2005
The circadian clock is a molecular and cellular oscillator found in most mammalian tissues that regulates rhythmic physiology behavior. Numerous investigations have addressed the contribution of rhythmicity to cellular, organ, organismal physiology. We recently developed method look at transcriptional oscillations with unprecedented precision accuracy using high-density time sampling. Here, we report comparison oscillating transcription from mouse liver, NIH3T3, U2OS cells. Several...
The mammalian circadian clock is a cell-autonomous system that drives oscillations in behavior and physiology anticipation of daily environmental change. To assess the robustness human molecular clock, we systematically depleted known components observed are maintained over wide range disruptions. We developed novel strategy termed Gene Dosage Network Analysis (GDNA) which small interfering RNA (siRNA)-induced dose-dependent changes gene expression were used to build association networks...
Sleep loss can severely impair the ability to perform, yet recover from sleep is not well understood. regulatory processes are assumed lie exclusively within brain mainly due strong behavioral manifestations of sleep. Whole-body knockout circadian clock gene Bmal1 in mice affects several aspects sleep, however, cells/tissues responsible unknown. We found that restoring expression brains Bmal1-knockout did rescue Bmal1-dependent phenotypes. Surprisingly, most sleep-amount, but sleep-timing,...
Over the last decades, researchers have characterized a set of "clock genes" that drive daily rhythms in physiology and behavior. This arduous work has yielded results with far-reaching consequences metabolic, psychiatric, neoplastic disorders. Recent attempts to expand our understanding circadian regulation moved beyond mutagenesis screens identified first clock components, employing higher throughput genomic proteomic techniques. In order further accelerate gene discovery, we utilized...
Endoderm-mesenchyme cross-talk is a central process in the development of foregut-derived organs. How signaling pathways integrate activity multiple ligands to guide organ poorly understood. We show that two Wnt ligands, Wnt2 and Wnt7b, cooperatively induce without affecting stabilization canonical effector β-catenin despite it being necessary for Wnt2–Wnt7b cooperativity. cooperation specific mesenchymal cell lineages combined loss Wnt7b leads more severe developmental defects lung than or...
Loss of Pax3, a developmentally regulated transcription factor expressed in premigratory neural crest, results severe developmental defects and embryonic lethality. Although Pax3 mutations produce profound phenotypes, the intrinsic transcriptional activation exhibited by is surprisingly modest. We postulated existence coactivators that function with to mediate functions. A high-throughput screen identified Hippo effector proteins Taz Yap65 as coactivators. Synergistic coactivation target...
Significance Rhythmic expression of most core clock genes is believed to be essential for maintaining proper timekeeping the circadian clock. In turn, rhythmic degradation clockwork proteins also crucial. However, we know comparatively little about these specific processes. Here describe a simple screening approach aimed at identifying ubiquitin ligases that degrade interest and apply it target rhythmically abundant nuclear hormone receptor, RevErbα (Nr1d1), degradation. This found ligase...
Abstract Summary: Oscillations in mRNA and protein of circadian clock components can be continuously monitored vitro using synchronized cell lines. These rhythms highly variable due to culture conditions are non-stationary baseline trends, damping drift period length. We present a technique for characterizing the modal frequencies oscillation continuous wavelet decomposition non-parametrically model changes amplitude while removing effects noise. Availability: The method has been implemented...
Polycystin-1 (PC1), encoded by the PKD1 gene that is mutated in autosomal dominant polycystic kidney disease, regulates a number of processes including bone development. Activity transcription factor RunX2, which controls osteoblast differentiation, reduced Pkd1 mutant mice but mechanism governing PC1 activation RunX2 unclear. undergoes regulated cleavage releases its C-terminal tail (CTT), translocates to nucleus modulate transcriptional pathways involved proliferation and apoptosis. We...
The protozoan parasite, Toxoplasma, like many intracellular pathogens, suppresses interferon gamma (IFN-γ)-induced signal transducer and activator of transcription 1 (STAT1) activity. We exploited this well-defined host–pathogen interaction as the basis for a high-throughput screen, identifying nine factors that enhance STAT1 function in nucleus, including orphan nuclear hormone receptor TLX. Expression profiling revealed upon IFN-γ treatment TLX enhances output subset target genes, which we...
CRYPTOCHOME proteins are necessary for mammalian circadian rhythms and have many well-established biochemical roles within the molecular clock. While studies examining effect of null Cry alleles been informative, they failed to dissect out relative importance of, mechanisms behind, CRY1 CRY2 proteins. To address this, we created an allelic series mutants through random mutagenesis, followed by a cell-based screen isolate with aberrant repression CLOCK-BMAL1. We identified 22 mutations...
Syntaxins are a conserved family of SNARE proteins and contain C-terminal transmembrane anchors required for their membrane fusion activity. Here we show that Stx3 (syntaxin 3) unexpectedly also functions as nuclear regulator gene expression. We found alternative splicing creates soluble isoform termed Stx3S, lacking the anchor. Soluble Stx3S binds to import factor RanBP5 (RAN-binding protein 5), targets nucleus, interacts physically functionally with several transcription factors, including...
Within the retina there is a circadian clock that controls 24-h timing of processes such as hormone release, cell movement, and gene transcription. In an effort to better understand molecular nature this retinal clock, differential display (DD) screen was performed isolate with high amplitude rhythmicity in Xenopus retina. A novel expressed early evening photoreceptor cells isolated named nocturnin for night factor. This article outlines steps we took study protein unknown function,...
Circadian clocks enable organisms to predict and align their behaviors physiologies constant daily day-night environmental cycle. Because the ubiquitin ligase Siah2 has been identified as a potential regulator of circadian clock function in cultured cells, we have used SIAH2-deficient mice examine its vivo . Our experiments demonstrate striking unexpected sexually dimorphic effect SIAH2-deficiency on regulation rhythmically expressed genes liver. The absence SIAH2 females, but not males,...
The conventional target centric model of drug discovery is pinned under the weight prior success and traditional problems safety efficacy for new molecules. An alternative to development shift focus pathways that mediate both biology pathophysiology. This method has advantage not requiring a priori knowledge small molecule target, but also comes with it several challenges including determination. We suggest extending this notion more broadly across process using quantitative network...
Previous studies have demonstrated that certain Wnt ligands can promote high levels of cooperative signaling in a cell type specific manner. To explore the underlying mechanism this signaling, we performed high-throughput screen more than 14,000 cDNAs to identify genes context single ligand, Wnt2. This identified several homeobox factors including Msx2, Nkx5.2, and Esx1, addition other known Pias4. Generation dominant-active or dominant-negative forms Msx2 indicate by which cooperatively is...
Polycystin‐1 (PC1) plays an important regulatory role in bone growth and development, as evidenced by decreased density found Pkd1 mutant mice. The activity of the transcription factor RunX2, master control gene for osteoblast differentiation, is downregulated mice, suggesting a relationship between PC1 RunX2. mechanism RunX2 activation PC1, however, has not yet been established. We have shown that carboxy‐terminal tail (PC1‐CTT) released γ‐secretase‐mediated cleavage traffics to nucleus,...