Multi-Omic Dissection of Complex Human Diseases and Traits

Various individual omics data allow researchers to gain insights on the biological process of the human body, the mechanisms of complex disease, and the development of therapeutics. In recent years, a large amount and various types of omics data have been generated, and more biology has been uncovered by integrating multiple types of omics data. My dissertation presents three projects involving single omics, two omics, and more omics data into analysis, all of which bring new understanding to the molecular mechanism of phenotypes of interest. In my first project, utilizing only genomics data, I follow up and extend the Raffield et al.’s (2018) research by involving a larger sample of under-represented individuals to study gene-gene interaction between a ~3.7k length deletion in the hemoglobin α gene and sickle cell traits on the risk of anemia and chronic kidney disease. About ten times as many African American and Hispanic/Latino participants have substantially enhanced the statistical power for detecting and qualifying the interaction effects. This project reflects the essentiality of the genomic analysis for underrepresented individuals, especially for high-impact variants, as well as the importance of studying gene-gene interactions in understanding complex diseases. In my second project, I utilize proteomics and genomics data to study the genetic determinants for 21 inflammation-related proteins. This project enlarges our knowledge regarding the genetics underlying inflammatory biomarkers which could further elucidate mechanisms of a battery of inflammation induced or related diseases. Finally, in my third project, I improve the sparse multiple canonical correlation analysis proposed by Witten et al. (2009). Specifically, my improvements lie in two aspects: first, I adopt the Gram-Schmidt algorithm to improve orthogonality of inferred canonical vectors; second, I extend the supervised method to allow more than two omics data types, while the original implementation only allows two omics data. With my modified method, I found a strong association between blood cell counts and top canonical vectors from proteomic data, which has important implications for association studies involving proteomics data from blood. In summary, my dissertation projects studying various types of omics data have not only led to useful findings, but also present areas where the field can benefit from the development and application of statistical/computational frameworks for analyzing multi-omics data. We anticipate more biological insights can be gained by efficiently analyzing multi-omics data.Doctor of Philosoph

Interplay between Chiral Charge Density Wave and Superconductivity in Kagome Superconductors: A Self-consistent Theoretical Analysis

Inspired by the recent discovery of a successive evolutions of electronically ordered states, we present a self-consistent theoretical analysis that treats the interactions responsible for the chiral charge order and superconductivity on an equal footing. It is revealed that the self-consistent theory captures the essential features of the successive temperature evolutions of the electronic states from the high-temperature ``triple-$Q$" $2\times 2$ charge-density-wave state to the nematic charge-density-wave phase, and finally to the low-temperature superconducting state coexisting with the nematic charge density wave. We provide a comprehensive explanation for the temperature evolutions of the charge ordered states and discuss the consequences of the intertwining of the superconductivity with the nematic charge density wave. Our findings not only account for the successive temperature evolutions of the ordered electronic states discovered in experiments but also provide a natural explanation for the two-fold rotational symmetry observed in both the charge-density-wave and superconducting states. Moreover, the intertwining of the superconductivity with the nematic charge density wave order may also be an advisable candidate to reconcile the divergent or seemingly contradictory experimental outcomes regarding the superconducting properties

Quantized charge-pumping in higher-order topological insulators

We study the quantized charge pumping of higher-order topological insulators (HOTIs) with edge-corner correspondences based on the combination of the rotation of in-plane magnetic field and the quantum spin Hall effect. A picture of a specific charge pumping process is uncovered with the help of the non-equilibrium Green's function method. Significantly, we demonstrate that the quantized charge pumping current is achieved without the participation of bulk states, and the charges move along the boundary of the sample. Furthermore, the effects of external parameters on the pumping current is also studied. We find that the magnitude and direction of the pumping current can be manipulated by adjusting the coupling strength between the leads and sample. Our work deepens the understanding of the charge pumping in HOTIs and extends the study of their transport properties.Comment: 8 pages, 5 figure

Millimeter Spectral Line Mapping Observations Toward Four Massive Star Forming HII Regions

We present spectral line mapping observations toward four massive star-forming regions (Cepheus A, DR21S, S76E and G34.26+0.15), with the IRAM 30 meter telescope at 2 mm and 3 mm bands. Totally 396 spectral lines from 51 molecules, one helium recombination line, ten hydrogen recombination lines, and 16 unidentified lines were detected in these four sources. An emission line of nitrosyl cyanide (ONCN, 14$_{0,14}$-13$_{0,13}$) was detected in G34.26+0.15, as first detection in massive star-forming regions. We found that the $c$-C$_{3}$H$_{2}$ and NH$_{2}$D show enhancement in shocked regions as suggested by evidences of SiO and/or SO emission. Column density and rotational temperature of CH$_{3}$CN were estimated with the rotational diagram method for all four sources. Isotope abundance ratios of $^{12}$C/$^{13}$C were derived using HC$_{3}$N and its $^{13}$C isotopologue, which were around 40 in all four massive star-forming regions and slightly lower than the local interstellar value ($\sim$65). $^{14}$N/$^{15}$N and $^{16}$O/$^{18}$O abundance ratios in these sources were also derived using double isotopic method, which were slightly lower than that in local interstellar medium. Except for Cep A, $^{33}$S/$^{34}$S ratio in the other three targets were derived, which were similar to that in the local interstellar medium. The column density ratios of N(DCN)/N(HCN) and N(DCO$^{+}$)/N(HCO$^{+}$) in these sources were more than two orders of magnitude higher than the elemental [D]/[H] ratio, which is 1.5$\times$10$^{-5}$. Our results show the later stage sources, G34.26+0.15 in particular, present more molecular species than earlier stage ones. Evidence of shock activity is seen in all stages studied.Comment: 32 pages, 11 figures, 8 tables, accepted for publication in MNRA

MiRNA-145 increases therapeutic sensibility to gemcitabine treatment of pancreatic adenocarcinoma cells.

Pancreatic adenocarcinoma is one of the most leading causes of cancer-related deaths worldwide. Although recent advances provide various treatment options, pancreatic adenocarcinoma has poor prognosis due to its late diagnosis and ineffective therapeutic multimodality. Gemcitabine is the effective first-line drug in pancreatic adenocarcinoma treatment. However, gemcitabine chemoresistance of pancreatic adenocarcinoma cells has been a major obstacle for limiting its treatment effect. Our study found that p70S6K1 plays an important role in gemcitabine chemoresistence. MiR-145 is a tumor suppressor which directly targets p70S6K1 for inhibiting its expression in pancreatic adenocarcinoma, providing new therapeutic scheme. Our findings revealed a new mechanism underlying gemcitabine chemoresistance in pancreatic adenocarcinoma cells

Chronic Arsenic Exposure and Angiogenesis in Human Bronchial Epithelial Cells via the ROS/miR-199a-5p/HIF-1α/COX-2 Pathway.

Background: Environmental and occupational exposure to arsenic is a major public health concern. Although it has been identified as a human carcinogen, the molecular mechanism underlying the arsenic-induced carcinogenesis is not well understood.Objectives: We aimed to determine the role and mechanisms of miRNAs in arsenic-induced tumor angiogenesis and tumor growth.Methods: We utilized an in vitro model in which human lung epithelial BEAS-2B cells were transformed through long-term exposure to arsenic. A human xenograft tumor model was established to assess tumor angiogenesis and tumor growth in vivo. Tube formation assay and chorioallantoic membranes assay were used to assess tumor angiogenesis.Results: We found that miR-199a-5p expression levels were more than 100-fold lower in arsenic-transformed cells than parental cells. Re-expression of miR-199a-5p impaired arsenic-induced angiogenesis and tumor growth through its direct targets HIF-1α and COX-2. We further showed that arsenic induced COX-2 expression through HIF-1 regulation at the transcriptional level. In addition, we demonstrated that reactive oxygen species are an upstream event of miR-199a-5p/ HIF-1α/COX-2 pathway in arsenic-induced carcinogenesis.Conclusion: The findings establish critical roles of miR-199a-5p and its downstream targets HIF-1/COX-2 in arsenic-induced tumor growth and angiogenesis.Citation: He J, Wang M, Jiang Y, Chen Q, Xu S, Xu Q, Jiang BH, Liu LZ. 2014. Chronic arsenic exposure and angiogenesis in human bronchial epithelial cells via the ROS/miR-199a-5p/HIF-1α/COX-2 Pathway. Environ Health Perspect 122:255-261; http://dx.doi.org/10.1289/ehp.1307545