Sustained and coordinate gene transcription of the 12 CC chemokine gene clustered on chromosome 11 are necessary for inflammatory cell influx in asthma and controls disease severity. The long term goal of this R21 application is to investigate the mechanisms through which histone modifications (termed """"""""epigenetic"""""""") modulate chemokine expression and airway inflammation. The disruption of histone modifications contribute to disease. I identified the transcription factor;ATF3, as a negative regulator of proinflammatory gene transcription via a histone modification mechanism. ATF3 plays a dominant role in the formation of specific chromatin structure, thereby controlling gene expression. Preliminary studies in a murine asthma model with ATF3-null mice show overwhelming inflammatory cell influx and overinduction of 8 CC chemokine genes in alveolar macrophages, providing strong evidence that ATF3 plays a critical role in asthma. To explore this further we will determine the asthmatic profiles of ATF3 and histone modifications in wild-type mice. We will then compare the profiles generated from ATF3-null mice to determine the epigenetic differences that lead to chemokine overinduction in the following specific aims.
Aim1. Determine the CC chemokine expression profile in alveolar macrophages in asthma and determine the ATF3 DNA-binding profile within the CC chemokine cluster using chromatin-immunoprecipitation combined with promoter array (ChIP-to-chip).
Aim2. Identify chromatin structure of this loci focusing on histone acetylation using ChIP-to-chip.
Aim3. Determine novel transcriptional complexes involved in asthma using bioinformatic analyses. This study will define the histone profile that leads to overexpression of CC chemokines in asthma, and delineate the histone-modifying role of ATF3. In addition, genome-wide analysis of this dataset will reveal further genes whose expression is modulated by histone modification events and the extent of these changes leading to the progression of allergic asthma. The data can be used to define epigenetic """"""""fingerprints"""""""" of asthma for further study in humans. We anticipate that this will lead to a better understanding of the role of histone modifications in asthma pathogenesis, and ultimately better strategies for diagnosis, treatment and prevention.
Allergic asthma is a major public health problem, and the morbidity and motility of asthma have increased significantly in the last two decades, particularly in children. Data generated from this proposal will define novel mechanisms that control the inflammation that is linked to disease severity. This information can lead to the discovery and development of novel diagnostic markers as well as new targets for therapeutic intervention in this disease.
|Hertz, Angie L; Bender, Andrew T; Smith, Kimberly C et al. (2009) Elevated cyclic AMP and PDE4 inhibition induce chemokine expression in human monocyte-derived macrophages. Proc Natl Acad Sci U S A 106:21978-83|