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Sexually-dimorphic targeting of functionally-related genes in COPD
Background: There is growing evidence that many diseases develop, progress, and respond to therapy differently in men and women. This variability may manifest as a result of sex-specific structures in gene regulatory networks that influence how those networks operate. However, there are few methods to identify and characterize differences in network structure, slowing progress in understanding mechanisms driving sexual dimorphism. Results: Here we apply an integrative network inference method, PANDA (Passing Attributes between Networks for Data Assimilation), to model sex-specific networks in blood and sputum samples from subjects with Chronic Obstructive Pulmonary Disease (COPD). We used a jack-knifing approach to build an ensemble of likely networks for each sex. By adapting statistical methods to compare these network ensembles, we were able to identify strong differential-targeting patterns associated with functionally-related sets of genes, including those involved in mitochondrial function and energy metabolism. Network analysis also identified several potential sex- and disease-specific transcriptional regulators of these pathways. Conclusions: Network analysis yielded insight into potential mechanisms driving sexual dimorphism in COPD that were not evident from gene expression analysis alone. We believe our ensemble approach to network analysis provides a principled way to capture sex-specific regulatory relationships and could be applied to identify differences in gene regulatory patterns in a wide variety of diseases and contexts. Electronic supplementary material The online version of this article (doi:10.1186/s12918-014-0118-y) contains supplementary material, which is available to authorized users
High Performance Computing of Gene Regulatory Networks using a Message-Passing Model
Gene regulatory network reconstruction is a fundamental problem in
computational biology. We recently developed an algorithm, called PANDA
(Passing Attributes Between Networks for Data Assimilation), that integrates
multiple sources of 'omics data and estimates regulatory network models. This
approach was initially implemented in the C++ programming language and has
since been applied to a number of biological systems. In our current research
we are beginning to expand the algorithm to incorporate larger and most diverse
data-sets, to reconstruct networks that contain increasing numbers of elements,
and to build not only single network models, but sets of networks. In order to
accomplish these "Big Data" applications, it has become critical that we
increase the computational efficiency of the PANDA implementation. In this
paper we show how to recast PANDA's similarity equations as matrix operations.
This allows us to implement a highly readable version of the algorithm using
the MATLAB/Octave programming language. We find that the resulting M-code much
shorter (103 compared to 1128 lines) and more easily modifiable for potential
future applications. The new implementation also runs significantly faster,
with increasing efficiency as the network models increase in size. Tests
comparing the C-code and M-code versions of PANDA demonstrate that this
speed-up is on the order of 20-80 times faster for networks of similar
dimensions to those we find in current biological applications
Estimating sample-specific regulatory networks
Biological systems are driven by intricate interactions among the complex
array of molecules that comprise the cell. Many methods have been developed to
reconstruct network models of those interactions. These methods often draw on
large numbers of samples with measured gene expression profiles to infer
connections between genes (or gene products). The result is an aggregate
network model representing a single estimate for the likelihood of each
interaction, or "edge," in the network. While informative, aggregate models
fail to capture the heterogeneity that is represented in any population. Here
we propose a method to reverse engineer sample-specific networks from aggregate
network models. We demonstrate the accuracy and applicability of our approach
in several data sets, including simulated data, microarray expression data from
synchronized yeast cells, and RNA-seq data collected from human lymphoblastoid
cell lines. We show that these sample-specific networks can be used to study
changes in network topology across time and to characterize shifts in gene
regulation that may not be apparent in expression data. We believe the ability
to generate sample-specific networks will greatly facilitate the application of
network methods to the increasingly large, complex, and heterogeneous
multi-omic data sets that are currently being generated, and ultimately support
the emerging field of precision network medicine
๋ง์ดํ์ก ๋จํต๊ตฌ์์ ์ ์ ์ ๋ฐํ์ ํตํ ์ฒ์ ๋ณํ์๋ฆฌ์ ์ดํด
ํ์๋
ผ๋ฌธ (๋ฐ์ฌ) -- ์์ธ๋ํ๊ต ๋ํ์ : ์๊ณผ๋ํ ์ํ๊ณผ, 2021. 2. ๋ฐํฅ์ฐ.์ฝ๋ฅดํฐ์ฝ์คํ
๋ก์ด๋๋ ์ฒ์ ์น๋ฃ์ ์ค์ํ ์ฝ์ ์ด๋ค. ํ์ง๋ง ์ฝ๋ฅดํฐ์ฝ์คํ
๋ก์ด๋์ ๋ํ ์น๋ฃ ํจ๊ณผ๋ ํ์๋ง๋ค ์๋นํ ์ฐจ์ด๊ฐ ์๋ ๊ฒ์ผ๋ก ์๋ ค์ ธ ์๋ค. ํนํ ์ฝ๋ฅดํฐ์ฝ์คํ
๋ก์ด๋์ ๋ํ ๋ฎ์ ๋ฐ์์ฑ์ ์ค์ฆ ์ฒ์ ๋๋ ์ฆ์ ๊ธ์ฑ ์
ํ์ ๊ด๋ จ์ด ์์ ์ ์๋ค. ๋น๋ก ๋ง์ ์ ์ ์ฒด ์ฐ๊ตฌ๋ค์ด ์งํ๋์์ง๋ง, ์คํ
๋ก์ด๋ ์ ๋ฐ์์ฑ๊ณผ ๊ด๋ จ๋ ์ฒ์์ ๋ณํ ์๋ฆฌ์ ๋ํด์๋ ์์ง๊น์ง ์ถฉ๋ถํ ์ฐ๊ตฌ๋์ง ์์๋ค. ๋ฐ๋ผ์ ์์ฒด์ธ ๋ฑ์ฌ๋ฉํ์ ์ฒ๋ฆฌ์ ๋ฐ๋ฅธ ์ ์ ์ ๋ฐํ ์์์ ๋ณํ๋ฅผ ๋ถ์ํ๋ ๊ฒ์ ์คํ
๋ก์ด๋ ์ ๋ฐ์์ฑ๊ณผ ๊ด๋ จ๋ ์ฒ์ ๊ธ์ฑ์
ํ์ ๊ธฐ์ ์ ์ฐ๊ตฌํ๋๋ฐ ๋์์ด ๋ ์ ์๋ค. ๋ณธ ์ฐ๊ตฌ๋ ์ฒ์ ํ์์ ๋ง์ด ํ์ก ๋จํต๊ตฌ ์ธํฌ์ ์ ์ ์ ๋ฐํ ์์ ๋ฐ ์์ฒด์ธ ๋ฑ์ฌ๋ฉํ์ ์ฒ๋ฆฌ์ ๋ฐ๋ฅธ ๋ณํ๋ฅผ ๋ถ์ํจ์ผ๋ก์จ ์คํ
๋ก์ด๋ ์ ๋ฐ์์ฑ๊ณผ ๊ด๋ จ๋ ๋ณํ์๋ฆฌ ๊ธฐ์ ๋ฐ ์๋ฌผํ์ ๊ฒฝ๋ก๋ฅผ ํ์ํด๋ณด๊ณ ์ ํ๋ค.
๋ณธ ์ฐ๊ตฌ๋ ๋ ํํธ๋ก ๋๋์ด ์งํ๋์๋ค. ์ฒซ๋ฒ์งธ ํํธ๋ Weighted Gene Co-expression Network Analysis (WGCNA) ๋ฐฉ๋ฒ๋ก ์ ํตํด, ์์์ฒ์ ํ์์ ์ฑ์ธ์ฒ์ ํ์์์ ๊ณตํต์ ์ผ๋ก ๊ด์ฐฐ๋๋ ๊ธ์ฑ์
ํ์ ๊ด๋ จ๋ ์ ์ ์ฒด ๋ชจ๋์ด ์กด์ฌํ๋์ง ๊ทธ๋ฆฌ๊ณ ํด๋น ๋ชจ๋์ ์์ฒด์ธ ๋ฑ์ฌ๋ฉํ์ ์ฒ๋ฆฌ๋ฅผ ์ ์ ์ ๋ฐํ ์์์ ๋ณํ๋ฅผ ํ์ํ์๋ค. ์์ ์ฒ์ ํ์ 107๋ช
์ ๋ถ๋ฉธํ๋ ๋ฆผํ๋ชจ์ธํฌ ์ธํฌ์ฃผ์ ์ฑ์ธ์ฒ์ ํ์ 29๋ช
์ ๋ง์ดํ์ก ๋จํต๊ตฌ์์ ์ ์ ์ ๋ฐํ ์์์ ๋ถ์ํ์๋ค. ์ฒ์ ๊ธ์ฑ์
ํ๋ ์ ์ ์คํ
๋ก์ด๋๋ฅผ 3์ผ์ด์ ๋ณต์ฉํ๊ฑฐ๋ ์ฒ์์ผ๋ก ์ธํด ์๊ธ ๋ฐฉ๋ฌธ ๋๋ ์
์์ผ๋ก ์ ์ํ์๋ค. ์์์ฒ์ ํ์๊ตฐ๊ณผ ์ฑ์ธ์ฒ์ ํ์๊ตฐ์์ ๊ณตํต์ ์ผ๋ก ๊ด์ฐฐ๋๋ ์ด 77๊ฐ์ ์ ์ ์๋ก ๊ตฌ์ฑ๋ ๊ธ์ฑ์
ํ๊ณผ ๊ด๋ จ๋ ์ ์ ์ฒด ๋ชจ๋์ ์ฐพ์๋ค. ํด๋น ๋ชจ๋์ EIF2AK2 ์ ์ ์ฒด์ NOL11 ์ ์ ์ฒด๋ ๋ฑ์ฌ๋ฉํ์ ์ฒ๋ฆฌ์ ์์ ์ฒ์ํ์๊ตฐ๊ณผ ์ฑ์ธ์ฒ์ ํ์๊ตฐ ๋ชจ๋์์ ์ ์ ์ฒด ๋ฐํ์์ด ์ ์ํ๊ฒ ๊ฐ์ํ์๋ค. ํด๋น ๋ชจ๋ ์ค 64๊ฐ์ ์ ์ ์ฒด๋ ๋ฑ์ฌ๋ฉํ์ ์ฒ๋ฆฌ์ ์ ์ ์ ๋ฐํ์์ด ์ ์ํ๊ฒ ๋ณํ์ง ์์๋๋ฐ, ์ด๋ค ์ ์ ์๋ค์ ๋จ๋ฐฑ์ง ์๋ฆฌ ๊ฒฝ๋ก (protein repair pathway) ๋ฑ๊ณผ ๊ด๋ จ์ฑ์ด ์์๋ค. ๋จ๋ฐฑ์ง ์๋ฆฌ ๊ฒฝ๋ก์ ๊ด๋ จ๋ ์ ์ ์ ์ค์์ MSRA์ MSRB2์ ์ค์ํ ์ญํ ์ ์ฐํ ์คํธ๋ ์ค๋ฅผ ์กฐ์ ํ๋ ๊ฒ์ผ๋ก ์๋ ค์ ธ ์๋ค. ๋ณธ ์ฐ๊ตฌ์ ๋๋ฒ์งธ ํํธ๋ ์ ์ ์ ์กฐ์ ๋คํธ์ํฌ๋ฅผ ํตํด ์ฑ์ธ ์ฒ์ํ์์์ ํก์
์ฉ ์คํ
๋ก์ด๋์ ๋ํ ๋ฐ์์ฑ์ ์ํฅ์ ๋ฏธ์น๋ ์์ธ๋ค์ ํ์ํ์๋ค. ํก์
์ฉ ์คํ
๋ก์ด๋์ ๋ํ ์น๋ฃ ํจ๊ณผ๊ฐ ์์๋ ํ์๊ตฐ๊ณผ ์น๋ฃ ํจ๊ณผ๊ฐ ์์๋ ํ์๊ตฐ์์ ์์ฒด์ธ ๋ฑ์ฌ๋ฉํ์ ์ฒ๋ฆฌ์ ์ ์ฌ์ธ์ ์ฐจ๋ณ๋ฐํ์ ๋ณด์๋ ์์ 5๊ฐ์ ์ ์ฌ์ธ์ํจ๊ณผ๋ GATA1, JUN, NFKB1, SPl1 ๊ทธ๋ฆฌ๊ณ RELA์๋ค. ์ด๋ค ์ ์ฌ์ธ์๋ ํก์
์ฉ ์คํ
๋ก์ด๋์ ๋ฐ์์ด ์์๋ ํ์๊ตฐ๊ณผ ์์๋ ํ์๊ตฐ์์ ์๋ก ๋ค๋ฅธ ์ ์ ์๋ค๊ณผ ๋ค์ํ ์๋ฌผํ์ ๊ฒฝ๋ก์์ ์ฐ๊ฒฐ๋์ด ์์๋ค. TBX4 ์ ์ ์๋ ํก์
์ฉ ์คํ
๋ก์ด๋์ ์ข์ ์น๋ฃํจ๊ณผ๋ฅผ ๋ณด์๋ ํ์๊ตฐ์์ ์ผ์ฆ๋ฐ์๊ณผ ๊ด๋ จ๋ NFKB1 ์ ์ฌ์ธ์์ ์ฐ๊ฒฐ๋์ด ์์๋ค.
๋ณธ ์ฐ๊ตฌ๋ฅผ ํตํด ๊ท๋ช
๋ ์๋ก์ด ์ ์ ์ ๋ฐ ์๋ฌผํ์ ๊ฒฝ๋ก ํ์์ ํตํด ์คํ
๋ก์ด๋ ์ ๋ฐ์์ฑ๊ณผ ๊ด๋ จ๋ ์ ์ ์ ํน์ง์ ์ดํดํ๋๋ฐ ๋์์ด ๋์๊ณ , ์ด๋ ์ฒ์์ ๋ค์ํ ๋ณํ์๋ฆฌ์ ๊ธฐ๋ฐํ ์๋ก์ด ์น๋ฃ์ ๋๋ ์๋ฌผ์งํ๋ฅผ ๊ฐ๋ฐํ๋๋ฐ ์ด๋ฐ์งํ ์ ์์ ๊ฒ์ด๋ค.Asthma is a chronic inflammatory airway disease characterized by bronchial hyperresponsiveness and reversible airway obstruction. Corticosteroids are known to the most effective treatment for asthma. However, there is substantial variability in response to corticosteroids in asthma patients. Ineffective response to corticosteroids may result in exacerbation of asthma. Although many genetic studies have been conducted, the mechanisms of asthma pathogenesis and steroid insensitivity in asthma have not been fully elucidated. Gene expression profile represents the complete set of RNA transcripts that are produced by the genome under specific circumstances or in a specific cell. High-throughput methods such as microarray, and recent advances in biostatistics based on network-based approaches provide a quick and effective way of identifying novel genes and pathways related to asthma. This study aimed to understand the pathogenesis and steroid insensitivity in asthma using gene expression profiles of blood cells from asthma patients. To obtain a comprehensive picture of the gene expression in these cells, we used network-based approaches. The study was divided into two separate parts. In the first part of the study, important genetic signatures of acute exacerbation (AE) in asthma were identified using weighted gene co-expression network analysis (WGCNA) in peripheral blood mononuclear cells (PBMCs) from 29 adult asthma patients and lymphoblastoid cell lines (LCLs) from 107 childhood asthma patients. An AE-associated gene module composed of 77 genes was identified from childhood asthma patients and the conservation of this gene module structure was validated in adult asthma patients. The identified module was found to be conserved in terms of the gene expression profile and associated with AE in both childhood and adult asthma patients, and thus it was defined as an AE-associated common gene module. Changes in the expression of genes in the AE-associated common gene module following in vitro dexamethasone (Dex) treatment were examined, to better understand the mechanisms associated with steroid insensitivity. The differential gene expression profiles were classified into two classes according to Dex-induced changes in childhood asthma patients. Thirteen genes showed significant Dex-induced differential expression and were categorized as the A gene set. Sixty-four genes were not significantly altered by Dex were categorized as the B gene set. In the A gene set, the expression of eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) showed significant Dex-induced differential expression in adult asthma patients as well. In addition, the basal expression of EIF2AK2 (pre-Dex) were significantly higher in asthma patients with AE compared to those without AE in both childhood and adult asthma. In the B gene set, based on a pathway-based approach, the protein repair pathway was found to be significantly enriched. Among the genes that belong to this pathway, the basal expression of methionine sulfoxide reductase A (MSRA) and methionine sulfoxide reductase B2 (MSRB2) were significantly lower in asthma patients with AE compared to those without AE in both childhood and adult asthma. These findings suggest that alternate treatment options, apart from corticosteroids, may be needed to prevent AE in asthma. Expression of EIF2AK2, MSRA, and MSRB2 in blood cells may help us to identify AE-susceptible asthma patients and adjust treatments to prevent AE events. In the second study, gene regulatory networks identified gene expression profiles of PBMCs from 23 adult asthma patients were assessed to elucidate the differences in responsiveness to inhaled corticosteroids (ICSs). Among these the top five (top-5) transcriptional factors (TFs; Top-5 TFs: GATA1, JUN, NFฮบB1, SPl1, and RELA) showing differential connections between good-responders (GRs) and poor-responders (PRs) were identified. Interestingly, GATA1 and JUN also showed differential connections in the gene regulatory networks identified gene expression profiles of LCLs from 107 childhood asthma patients in a previous study. The top-5 TFs and their connected genes were significantly enriched in distinct biological pathways associated with asthma. Among the genes connected to the top-5 TFs, the expression of TBX4, which is regulated by the TF, NFฮบB1, may be helpful in identifying GRs to ICS treatment. In conclusion, the novel genes and biological pathways identified in this study may deepen our understanding of asthma pathophysiology and steroid insensitivity in asthma.Table of Contents
Chapter 1 Introduction 1
Chapter 2 Part I 10
2.1 Introduction 10
2.2 Methods 12
2.3 Results 23
2.4 Discussion 43
Chapter 3 Part II 48
3.1 Introduction 48
3.2 Methods 50
3.3 Results 53
3.4 Discussion 79
Chapter 4 Conclusions 84
Bibliography 86
Abstract in korean 101
List of Tables
Table 1 26
Table 2 27
Table 3 29
Table 4 34
Table 5 55
Table 6 56
Table 7 57
Table 8 59
List of Figures
Figure 1 14
Figure 2 35
Figure 3 36
Figure 4 37
Figure 5 38
Figure 6 39
Figure 7 40
Figure 8 41
Figure 9 42
Figure 10 77
Figure 11 78Docto
Network Medicine in the Age of Biomedical Big Data
Network medicine is an emerging area of research dealing with molecular and genetic interactions, network biomarkers of disease, and therapeutic target discovery. Large-scale biomedical data generation offers a unique opportunity to assess the effect and impact of cellular heterogeneity and environmental perturbations on the observed phenotype. Marrying the two, network medicine with biomedical data provides a framework to build meaningful models and extract impactful results at a network level. In this review, we survey existing network types and biomedical data sources. More importantly, we delve into ways in which the network medicine approach, aided by phenotype-specific biomedical data, can be gainfully applied. We provide three paradigms, mainly dealing with three major biological network archetypes: protein-protein interaction, expression-based, and gene regulatory networks. For each of these paradigms, we discuss a broad overview of philosophies under which various network methods work. We also provide a few examples in each paradigm as a test case of its successful application. Finally, we delineate several opportunities and challenges in the field of network medicine. We hope this review provides a lexicon for researchers from biological sciences and network theory to come on the same page to work on research areas that require interdisciplinary expertise. Taken together, the understanding gained from combining biomedical data with networks can be useful for characterizing disease etiologies and identifying therapeutic targets, which, in turn, will lead to better preventive medicine with translational impact on personalized healthcare