A5014042900- CRISPR and Genetic Engineering
- Pluripotent Stem Cells Research
- RNA Research and Splicing
- Genetics, Aging, and Longevity in Model Organisms
- Immune Response and Inflammation
- RNA modifications and cancer
- Epigenetics and DNA Methylation
- RNA Interference and Gene Delivery
- Circadian rhythm and melatonin
- Protein Kinase Regulation and GTPase Signaling
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Reproductive Biology and Fertility
- Sperm and Testicular Function
- Genomics and Chromatin Dynamics
- Renal and related cancers
- Immune Cell Function and Interaction
- NF-κB Signaling Pathways
- Melanoma and MAPK Pathways
- Cancer-related gene regulation
- Genomics, phytochemicals, and oxidative stress
- ATP Synthase and ATPases Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Aging and Gerontology Research
- Cell Image Analysis Techniques
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
National Institute of Environmental Health Sciences
2010-2025
National Institutes of Health
2009-2013
Triangle
2011
National Heart Lung and Blood Institute
2008
In response to infection, Caenorhabditis elegans produces an array of antimicrobial proteins. To understand the C. immune response, we have investigated regulation a large, representative sample candidate genes. We found that all these putative genes are expressed in tissues exposed environment, position from which they can ward off infection. Using RNA interference inhibit function signaling pathways elegans, different regulate expression distinct but overlapping sets also show bacterial...
The TET family of FE(II) and 2-oxoglutarate-dependent enzymes (Tet1/2/3) promote DNA demethylation by converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), which they further oxidize into 5-formylcytosine 5-carboxylcytosine. Tet1 is robustly expressed in mouse embryonic stem cells (mESCs) has been implicated mESC maintenance. Here we demonstrate that, unlike genetic deletion, RNAi-mediated depletion mESCs led a significant reduction 5hmC loss identity. differentiation phenotype due...
To reveal regulators of innate immunity, we used RNAi assays to monitor the immune response when genes are inhibited in Caenorhabditis elegans and mouse macrophages. Genes that altered responsiveness C. were validated murine macrophages, resulting discovery 11 regulate both systems subsequent identification a protein interaction network with conserved role immunity regulation. We confirmed four these antimicrobial gene regulation using available mutants elegans. Several (acy-1, tub-2, tbc-1)...
The relationship between the mechanisms that control an organism's lifespan and its ability to respond environmental challenges are poorly understood. In Caenorhabditis elegans, insulin-like signaling pathway modulates innate immune response bacterial pathogens via a common mechanism involving transcriptional regulation by DAF-16/FOXO transcription factor. C. elegans germ line also in daf-16-dependent manner. Here, we show controls of somatic cells two different Gram-negative bacteria....
Embryonic stem cell (ESC) identity and self‐renewal is maintained by extrinsic signaling pathways intrinsic gene regulatory networks. Here, we show that three members of the Ccr4‐Not complex, Cnot1, Cnot2, Cnot3, play critical roles in maintaining mouse human ESC as a protein complex inhibit differentiation into extraembryonic lineages. Enriched inner mass blastocysts, these Cnot genes are highly expressed downregulated during differentiation. In ESCs, Cnot3 important for maintenance both...
Innate immunity is the first line of defense against microbial infections. Although polymorphisms in toll-like receptors (TLRs) and downstream signaling molecules (CD14, TLR2, TLR4, TLR5, IRAK4) affect innate immune response, these variants account for only a portion ability host to respond bacteria, fungi, viruses. To identify other genes involved we challenged 16 inbred murine strains with lipopolysaccharide (LPS) systemically measured serum concentrations pro-inflammatory cytokines...
Retinoic acid (RA) is the proposed mammalian 'meiosis inducing substance'. However, evidence for this role comes from studies in fetal ovary, where germ cell differentiation and meiotic initiation are temporally inseparable. In postnatal testis, these events separated by more than 1 week. Exploiting difference, we discovered that, although RA required spermatogonial differentiation, it dispensable subsequent initiation, progression completion of meiosis. Indeed, absence RA, transcriptome...
RNA abundance is controlled by rates of synthesis and degradation. Although mis-regulation turnover linked to neurodevelopmental disorders, how it contributes cortical development largely unknown. Here, we discover the landscape stability regulation in cerebral cortex demonstrate that intact decay machinery essential for corticogenesis vivo. We use SLAM-seq measure half-lives transcriptome-wide across multiple stages development. Leveraging these data, cis -acting features associated with...
Rho GTPases are critical components of cellular signal transduction pathways. Both hyperactivity and overexpression these proteins have been observed in human cancers implicated as important factors metastasis. We previously showed that dietary n-6 fatty acids increase cancer cell adhesion to extracellular matrix proteins, such type IV collagen. Here we report MDA-MB-435 melanoma cells, arachidonic acid activates RhoA, inhibition RhoA signaling with either C3 exoenzyme or dominant negative...
Poly(A) tail length and mRNA deadenylation play important roles in gene regulation. However, how they regulate embryonic development pluripotent cell fate is not fully understood. Here we present evidence that CNOT3-dependent governs the state. We show CNOT3, a component of Ccr4-Not deadenylase complex, required for mouse epiblast maintenance. It highly expressed blastocysts its deletion leads to peri-implantation lethality. The cells Cnot3 embryos are quickly lost during diapause fail...
Abstract The INO80 chromatin remodeler is involved in many chromatin-dependent cellular functions. However, its role pluripotency and cell fate transition not fully defined. We examined the impact of Ino80 deletion naïve primed pluripotent stem cells. found that had minimal effect on self-renewal gene expression state, but led to differentiation de-repression developmental genes toward maintenance state. In pre-marked promoters would adopt bivalent histone modifications by H3K4me3 H3K27me3...
Our understanding of the role that host genetic factors play in initiation and severity infections caused by gram-negative bacteria is incomplete. To identify novel regulators response to lipopolysaccharide (LPS), 11 inbred murine strains were challenged with LPS systemically. In addition two lacking functional TLR4 (C3H/HeJ C57BL/6J(TLR4-/-)), three (C57BL/6J, 129/SvImJ, NZW/LacJ) found be relatively resistant systemic challenge; other six classified as sensitive. RNA from lung, liver,...
Significance A key step to understanding a phenotype of interest is the identification genes defining that phenotype. We propose computational framework for systematic integration published gene expression data identify cell identity interest. demonstrate utility proposed approach by identifying essential maintenance ES (ESC) identity. Follow-up functional studies on candidate Nucleolin ( Ncl ) reveal 's role in ESC homeostasis. deficiency increases endogenous reactive oxygen species levels...
We previously identified Tbc1d23 as a candidate novel regulator of innate immunity using comparative genomics RNA interference screens in Caenorhabditis elegans and mouse macrophages. Using knockout mice macrophages engineered to overexpress Tbc1d23, we now show that is general inhibitor signaling, strongly inhibiting multiple TLR dectin-signaling pathways. likely acts downstream the TLR-signaling adaptors MyD88 Trif upstream transcription factor XBP1. Importantly, like XBP1, affects...
A hallmark of AIDS progression is a switch cytokines from Th1 to Th2 in the plasma patients. IL-12, critical cytokine secreted by antigen presenting cells (APCs) suppressed Vpr, implicating it as an important virulence factor. We hypothesize that Vpr protein packaged virion may be required for disabling APCs first infected mucosal tissues. Consistent with this idea are reports defects C-terminus associated long-term non-progression.Vpr RNA amplified various sources was electroporated into...
Abstract RNA expression levels are controlled by the complementary processes of synthesis and degradation. Although mis-regulation turnover is linked to neurodevelopmental disorders, how it contributes cortical development largely unknown. Here, we profile stability landscape cortex across demonstrate that control CCR4-NOT complex essential for corticogenesis in vivo . First, use SLAM-seq measure half-lives transcriptome-wide multiple stages development. We characterize cis -acting features...
Arachidonic acid stimulates cell adhesion by activating α2β1 integrins in a process that depends on protein kinases, including p38 mitogen activated kinase. Here, we describe the interaction of cytoskeletal components with key signaling molecules contribute to spreading of, and morphological changes in, arachidonic acid-treated MDA-MB-435 human breast carcinoma cells. cells showed increased attachment collagen type IV, as measured electric cell-substrate impedance sensing. Fatty displayed...