In this multi-PI proposal we will investigate the role of epigenetic mechanisms in driving severe asthma pathogenesis. The identification of molecular players/pathways that lead to pathogenic immune responses in asthma will be beneficial for the discovery of drug targets and development of new vaccine strategies to prevent asthma. Genome-wide enhancer profiling is a powerful new tool that has allowed investigators to precisely track genes and their cognate enhancers and thus capture molecular events involved in cellular development and differentiation. We have successfully micro-scaled this tool to enable large-scale human studies that have the potential to unravel novel molecular mechanisms underlying human diseases. In this proposal, we will define asthma-related epigenetic markers in ~100 patients with severe asthma, and correlate these with clinical phenotypes to obtain specific molecular markers for distinguishable disease states (i.e. severe asthma phenotypes). We will capitalize on three longitudinal asthma cohorts: (i) the Wessex AsThma CoHort of difficult asthma (WATCH), an observational clinical cohort with on-going active recruitment (~25 new cases/month) that currently consists of ~250 subjects with severe asthma, who are actively followed up by the treating physicians (PI Ramesh/Hasan, UK), (ii) The NIH-funded IOW, UK cohort of >100 well-phenotyped mild asthmatics; (iii) the La Jolla Institute (LJI) cohort of 40 subjects with mild-to-moderate asthma, who have provided blood samples every 6 months over two years.
In Aim 1, we will profile the enhancer landscape in immune cell types relevant to severe asthma pathogenesis (nave, TH2 memory T cell subsets and classical monocytes), isolated from longitudinally collected blood samples from 200 subjects with varying asthma severity. We will perform comparative bioinformatics analysis to identify the immune cell enhancers linked to severe asthma. We will also perform transcriptional profiling of blood and airway immune cells to precisely define the genes that are affected (influenced) by the enhancers identified in severe asthma.
In Aim 2, we will define the target genes of severe asthma associated enhancers and determine if genetics variants linked to asthma risk affect their function. We will then test the function of these genes in primary human T cells using optimized micro-scaled immunological assays. Overall, our discovery-based epigenetic studies and follow up functional studies will identify novel genes and pathways involved in severe asthma and corticosteroid insensitivity, and could open novel ways to treat severe asthma.

Public Health Relevance

Asthma can be a devastating illness for the 23 million Americans affected by this disease. The emerging field of epigenetics, which aims to define how genes are turned on and off in cells, has already shown great promise in finding new therapies for many human diseases, especially cancer. We have already identified epigenetic markers that are associated with pathogenic T cells in adults with mild-to-moderate asthma. In this proposal, we will extend our approach to investigate adults with severe asthma. Our findings should directly benefit human asthma research by identifying novel severe asthma-related genes that may be targets for new therapeutic drugs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL114093-08
Application #
9677177
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Gan, Weiniu
Project Start
2011-09-23
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Youhanna Jankeel, Diana; Cayford, Justin; Schmiedel, Benjamin Joachim et al. (2018) An Integrated and Semiautomated Microscaled Approach to Profile Cis-Regulatory Elements by Histone Modification ChIP-Seq for Large-Scale Epigenetic Studies. Methods Mol Biol 1799:303-326
Patil, Veena S; Madrigal, Ariel; Schmiedel, Benjamin J et al. (2018) Precursors of human CD4+ cytotoxic T lymphocytes identified by single-cell transcriptome analysis. Sci Immunol 3:
Engel, Isaac; Seumois, Grégory; Chavez, Lukas et al. (2016) Innate-like functions of natural killer T cell subsets result from highly divergent gene programs. Nat Immunol 17:728-39
Schmiedel, Benjamin Joachim; Seumois, Grégory; Samaniego-Castruita, Daniela et al. (2016) 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells. Nat Commun 7:13426
Seumois, Grégory; Zapardiel-Gonzalo, Jose; White, Brandie et al. (2016) Transcriptional Profiling of Th2 Cells Identifies Pathogenic Features Associated with Asthma. J Immunol 197:655-64
Yue, Xiaojing; Trifari, Sara; Äijö, Tarmo et al. (2016) Control of Foxp3 stability through modulation of TET activity. J Exp Med 213:377-97
Chang, Xing; Li, Bin; Rao, Anjana (2015) RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation. Proc Natl Acad Sci U S A 112:E1888-97
LaFlam, Taylor N; Seumois, Grégory; Miller, Corey N et al. (2015) Identification of a novel cis-regulatory element essential for immune tolerance. J Exp Med 212:1993-2002
Arlehamn, Cecilia Lindestam; Seumois, Gregory; Gerasimova, Anna et al. (2014) Transcriptional profile of tuberculosis antigen-specific T cells reveals novel multifunctional features. J Immunol 193:2931-40
Tsagaratou, Ageliki; Äijö, Tarmo; Lio, Chan-Wang J et al. (2014) Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation. Proc Natl Acad Sci U S A 111:E3306-15

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