Although alterations in chromatin structure are known to exist in tumors, how these alterations relate to molecular phenotypes in cancer remains to be demonstrated. Multi-omics profiling of human ...tumors can provide insight into how alterations in chromatin structure are propagated through the pathway of gene expression to result in malignant protein expression. We applied multi-omics profiling of chromatin accessibility, RNA abundance, and protein abundance to 36 human thyroid cancer primary tumors, metastases, and patient-match normal tissue. Through quantification of chromatin accessibility associated with active transcription units and global protein expression, we identify a local chromatin structure that is highly correlated with coordinated RNA and protein expression. In particular, we identify enhancers located within gene-bodies as predictive of correlated RNA and protein expression, that is independent of overall transcriptional activity. To demonstrate the generalizability of these findings we also identify similar results in an independent cohort of human breast cancers. Taken together, these analyses suggest that local enhancers, rather than distal enhancers, are likely most predictive of cancer gene expression phenotypes. This allows for identification of potential targets for cancer therapeutic approaches and reinforces the utility of multi-omics profiling as a methodology to understand human disease.
Physical interactions between distal regulatory elements have a key role in regulating gene expression, but the extent to which these interactions vary between cell types and contribute to ...cell-type-specific gene expression remains unclear. Here, to address these questions as part of phase III of the Encyclopedia of DNA Elements (ENCODE), we mapped cohesin-mediated chromatin loops, using chromatin interaction analysis by paired-end tag sequencing (ChIA-PET), and analysed gene expression in 24 diverse human cell types, including core ENCODE cell lines. Twenty-eight per cent of all chromatin loops vary across cell types; these variations modestly correlate with changes in gene expression and are effective at grouping cell types according to their tissue of origin. The connectivity of genes corresponds to different functional classes, with housekeeping genes having few contacts, and dosage-sensitive genes being more connected to enhancer elements. This atlas of chromatin loops complements the diverse maps of regulatory architecture that comprise the ENCODE Encyclopedia, and will help to support emerging analyses of genome structure and function.
The number of researchers using multi-omics is growing. Though still expensive, every year it is cheaper to perform multi-omic studies, often exponentially so. In addition to its increasing ...accessibility, multi-omics reveals a view of systems biology to an unprecedented depth. Thus, multi-omics can be used to answer a broad range of biological questions in finer resolution than previous methods. We used six omic measurements-four nucleic acid (i.e., genomic, epigenomic, transcriptomics, and metagenomic) and two mass spectrometry (proteomics and metabolomics) based-to highlight an analysis workflow on this type of data, which is often vast. This workflow is not exhaustive of all the omic measurements or analysis methods, but it will provide an experienced or even a novice multi-omic researcher with the tools necessary to analyze their data. This review begins with analyzing a single ome and study design, and then synthesizes best practices in data integration techniques that include machine learning. Furthermore, we delineate methods to validate findings from multi-omic integration. Ultimately, multi-omic integration offers a window into the complexity of molecular interactions and a comprehensive view of systems biology.
Omic technologies have been applied to cancer since they were invented and have yielded extremely powerful results. Common tumor types have been profiled extensively for their cancer drivers and ...genetic landscapes, identifying the extent of to which mutations alter the gene expression in cancer. However, other molecular features have not been comprehensively studied. As omic technologies become more widely available and more accurate, the unprofiled molecular landscape of cancer is ripe for investigation. This dissertation focuses on scientific investigations that utilize state-of-the-art omic tools to characterize the molecular phenotypes in human cancers. In addition, this dissertation addresses the topic of diversity, equity, and inclusion (DEI) and shares results from a program that I founded for Stanford Biosciences and the Medical Scientist Training Program (MSTP). The first chapter provides an overview of gene regulation studies based on multi-omics methodology, current molecular knowledge of thyroid cancer, and the state of DEI in biomedical graduate training programs. Chapter 2 clarifies mechanisms in which chromatin regulation affects protein-transcript correlation in progression and development of thyroid and breast cancer. It points to an interesting mechanism by which transcription factors mediate coordinated transcription and translation. Chapter 3 outlines the preliminary findings from a multi-omic analysis of genotype, chromatin regulatory landscape, transcripts, and proteins in metastatic thyroid cancer. This analysis classifies tumors and metastases according to regulons that have direct and indirect effects on the comprehensive profile of biomolecules. Chapter 4 describes an approach to a diversity recruitment program that has potential to scale across biomedical graduate programs. Results from the program show there are many underrepresented minorities that have the potential to thrive in biomedical training if supported. Lastly, Chapter 5 discusses the potential impact of multi-omics integration on the cancer field and other disease types. Taken together, these chapters represent key insights, improvements, and applications of multi-omics integration on human disease and opportunities for our graduate programs to be more engaged with DEI.
Abstract
Molecular profiling of papillary thyroid carcinoma has largely been confined to exome sequencing of non-aggressive cancer.1,2 Canonical mutations in BRAF and RAS are significantly ...represented in thyroid tumors, but these mutations have not resulted in diagnostics and therapeutics for advanced disease. To broadly examine the molecular landscape of advanced disease, we conducted a multi-omic analysis of 34 cases of advanced papillary thyroid carcinoma, including patient-matched lymph node metastases, primary tumor, adjacent-normal thyroid and germline. Our genome-wide multi-omic analysis links the regions of activated chromatin with expressed transcripts and proteins, identifying regulatory elements at primary tumor and nodal metastases stages of thyroid cancer progression. Distal regulatory elements putatively upregulate expression of MAPK-pathway genes in both tumors and metastases (36 genes (p =0.0057) in tumors and 76 genes (p =0.0011) in metastases). Furthermore, tumors and metastases harbor accessible chromatin regions that appear to be bound by MAPK transcription factors, FOS and JUN (p-value <10-150 for tumors and metastases). This study identifies regulatory elements that mediate MAPK activity in tumors and metastases of advanced papillary thyroid carcinoma and may ultimately lead to diagnostics and therapeutics that utilize advanced-thyroid-cancer-specific epigenetic targets. References
• Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014
• Masoodi T, et al. Whole-Exome Sequencing of Matched Primary and Metastatic Papillary Thyroid Cancer. Thyroid. 2020
A knowledge base of vasopressin actions in the kidney Sanghi, Akshay; Zaringhalam, Matthew; Corcoran, Callan C ...
American journal of physiology. Renal physiology,
09/2014, Letnik:
307, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Biological information is growing at a rapid pace, making it difficult for individual investigators to be familiar with all information that is relevant to their own research. Computers are beginning ...to be used to extract and curate biological information; however, the complexity of human language used in research papers continues to be a critical barrier to full automation of knowledge extraction. Here, we report a manually curated knowledge base of vasopressin actions in renal epithelial cells that is designed to be readable either by humans or by computer programs using natural language processing algorithms. The knowledge base consists of three related databases accessible at https://helixweb.nih.gov/ESBL/TinyUrls/Vaso_portal.html. One of the component databases reports vasopressin actions on individual proteins expressed in renal epithelia, including effects on phosphorylation, protein abundances, protein translocation from one subcellular compartment to another, protein-protein binding interactions, etc. The second database reports vasopressin actions on physiological measures in renal epithelia, and the third reports specific mRNA species whose abundances change in response to vasopressin. We illustrate the application of the knowledge base by using it to generate a protein kinase network that connects vasopressin binding in collecting duct cells to physiological effects to regulate the water channel protein aquaporin-2.
A knowledge base of vasopressin actions in the kidney Sanghi, Akshay; Zaringhalam, Matthew; Corcoran, Callan C ...
American journal of physiology. Renal physiology,
09/2014, Letnik:
206, Številka:
6
Journal Article
Recenzirano
Biological information is growing at a rapid pace, making it difficult for individual investigators to be familiar with all information that is relevant to their own research. Computers are beginning ...to be used to extract and curate biological information; however, the complexity of human language used in research papers continues to be a critical barrier to full automation of knowledge extraction. Here, we report a manually curated knowledge base of vasopressin actions in renal epithelial cells that is designed to be readable either by humans or by computer programs using natural language processing algorithms. The knowledge base consists of three related databases accessible at https://helixweb.nih.gov/ESBL/TinyUrls/Vaso_portal.html. One of the component databases reports vasopressin actions on individual proteins expressed in renal epithelia, including effects on phosphorylation, protein abundances, protein translocation from one subcellular compartment to another, protein-protein binding interactions, etc. The second database reports vasopressin actions on physiological measures in renal epithelia, and the third reports specific mRNA species whose abundances change in response to vasopressin. We illustrate the application of the knowledge base by using it to generate a protein kinase network that connects vasopressin binding in collecting duct cells to physiological effects to regulate the water channel protein aquaporin-2.
Geopolymers are traditionally used as construction and building material to partially replace Portland cement consumption. The versatile properties of geopolymer present it for use as a ...multifunctional material and geopolymer cementitious coating is an emerging part of it. In attempts to develop green and sustainable geopolymer coating material for advanced application, we studied geopolymeric coating of varying Na/Si ratio and alkaline molarities and their long term corrosion resistant properties on mild steel to protect it from surface corrosion. Chemical characterization was performed using combination of powerful characterization tools, more specifically mineralogical assessment by X-ray diffractometer, bonding arrangements by Fourier transform infrared spectroscopy and microstructural details by Field emission scanning electron microscopy techniques. Time of flight secondary ion mass spectroscopy was also used as novel characterization approach to envision the coating-substrate interface and for elemental mapping at the interface which delivered useful information about occurrence of strong covalent bonds between Si–O–Fe in the form of Fe2OSi+ mass fragment with m/z ratio 156. The material was further investigated in terms of adhesion strength and water/salt resistant, following accelerated salt fog test by ASTM codes. Geopolymer with varying Na/Si ratio and alkaline molarity exhibited change in XRD amorphicity and microstructure. Results also displayed that even at low Na/Si ratio geopolymeric coating performs high adhesion with iron with no considerable change in corrosion resistant properties. The maximum adhesion of developed material with mild steel was 14.68 M.Pa. after 28 day ambient curing which presented its functional suitability. Coating sustained point load upto 5 kgs and showed adequate water and salt resistance upto 3 months. In accelerated corrosion environment, optimized geopolymer coating displayed adequate corrosion resistance and displayed rust rating 9. Overall we obtained an optimized material which is well suited for coating of buried mild steel pipes to replace contemporary cement mortar coating in terms of properties, durability, cost effectiveness and environmental sustainability.
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•Multistep characterizations were performed to develop and optimize geopolymer coating for corrosion resistant application.•Developed fly ash based geopolymer coating was evaluated for different corrosion resistant test parameters.•Obtained corrosion resistant properties were suitable to replace OPC based coatings.•ToF-SIMS was applied and valuable insights regarding chemical bonds between geopolymer coating and substrate were obtained.
Ionizing radiations are hazardous in the long run if exposed to a limit higher than the permissible limit (20 mSv/year). It can cause serious health issues like cancer, cardiac disease, cataract, ...damage to central nervous system, and other acute radiation syndromes. With an increase in the application of ionizing radiations in different fields like medicinal industries, therapeutic treatment, diagnostic imaging, food preservation, research centers, etc., the need for shielding material has also become crucial. Conventionally metallic lead, concrete, and the composite of lead with other heavy metals are used for radiation shielding. Although their shielding properties are quite good, they are either toxic, heavy, corrosive, or have weak thermal or mechanical stability. Therefore new radiation shielding materials obviating these drawbacks are in demand. Lead-free metal-polymer composites which are fabricated by incorporating high Z metal compounds in the polymer matrix are found to be a better alternative as radiation shielding materials, due to their light weight, flexibility, nontoxicity, noncorrosiveness, and good mechanical properties. This review article focuses on the studies carried out in the area of the development of polymer composite materials with a variety of high Z metal compounds and polymers for shielding ionizing radiations. The existing gap and future direction of work are also presented here.
Advanced geopolymerization includes concept of just addition of water to ready mixture of dry precursor powder. For exploring the coordination environments of binary glass systems, this work presents ...multinuclear MAS NMR analysis of advanced geopolymer produced by solid state mechanochemical co‐grinding of raw materials. The crystalline and amorphous phases of advanced geopolymer were already characterized with XRD in our previous study. This study focus on multinuclear (29Si, 27Al and 23Na) MAS NMR analysis for exploring the coordination environments of Si/Al/Na nuclei in advanced geopolymer. 29Si, 27Al and 23Na MAS NMR spectra of fly ash, advanced geopolymeric precursor material and advanced geopolymer are qualitatively estimated which enables an understanding of insertion of Al in silicate network ensuing solid state reactions during mechanochemical co‐grinding process. By combining the NMR interpretations, it can be suitably said that mechanochemical co‐grinding is a feasible way to induce local defects in amorphous Si/Al content which lead to variation in bond angles and variations in Si/Al constellations. Results may be very useful to understand framework connectivity, chemistry and behavior of advanced geopolymers produced by solid state route and the developed advanced geopolymer finds its potential application as “ready to use” cementitious material for large scale commercialization.
Advanced geopolymerization with solid state chemistry mechanism proves to be very suitable for large scale commercialization of geopolymer. 29Si/27Al/23Na MAS NMR of advanced geopolymer is presented first time with the motive to qualitatively estimate and understand the insertion of Al in silicate network ensuing solid state reactions during mechanochemical co‐grinding process. From NMR results it is concluded that under the action of intensive and continuous mechanical force, formation of amorphous aluminosilicate precursor is favored which after addition of only water transformed into sodium aluminosilicate hydrate gel with stable Si‐O−Si/Si‐O−Al‐ network.
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