Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis
Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterized by enthesitis of the spine and sacroiliac joints. Genome-wide association studies (GWASs) have revealed more than 100 genetic associations whose functional effects remain largely unresolved. Here, we prese...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2023
|
| _version_ | 1826310719042224128 |
|---|---|
| author | Brown, AC Cohen, CJ Mielczarek, O Migliorini, G Costantino, F Allcock, A Davidson, C Elliott, KS Fang, H Lledó Lara, A Martin, AC Osgood, JA Sanniti, A Scozzafava, G Vecellio, M Zhang, P Black, MH Li, S Truong, D Molineros, J Howe, T Wordsworth, BP Bowness, P Knight, JC |
| author_facet | Brown, AC Cohen, CJ Mielczarek, O Migliorini, G Costantino, F Allcock, A Davidson, C Elliott, KS Fang, H Lledó Lara, A Martin, AC Osgood, JA Sanniti, A Scozzafava, G Vecellio, M Zhang, P Black, MH Li, S Truong, D Molineros, J Howe, T Wordsworth, BP Bowness, P Knight, JC |
| author_sort | Brown, AC |
| collection | OXFORD |
| description | Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterized by enthesitis of the spine and sacroiliac joints. Genome-wide association studies (GWASs) have revealed more than 100 genetic associations whose functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We find that, while CD14+ monocytes and CD4+ and CD8+ T cells show disease-specific differences at the RNA level, epigenomic differences are only apparent upon multi-omics integration. The latter reveals enrichment at disease-associated loci in monocytes. We link putative functional SNPs to genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1, and show how disease-specific functional genomic data can be integrated with GWASs to enhance therapeutic target discovery. This study combines epigenetic and transcriptional analysis with GWASs to identify disease-relevant cell types and gene regulation of likely pathogenic relevance and prioritize drug targets. |
| first_indexed | 2024-03-07T07:56:08Z |
| format | Journal article |
| id | oxford-uuid:823d1f05-cbe9-42c1-8a6d-dfeb8d3bf539 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:56:08Z |
| publishDate | 2023 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:823d1f05-cbe9-42c1-8a6d-dfeb8d3bf5392023-08-17T11:54:16ZComprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:823d1f05-cbe9-42c1-8a6d-dfeb8d3bf539EnglishSymplectic ElementsCell Press2023Brown, ACCohen, CJMielczarek, OMigliorini, GCostantino, FAllcock, ADavidson, CElliott, KSFang, HLledó Lara, AMartin, ACOsgood, JASanniti, AScozzafava, GVecellio, MZhang, PBlack, MHLi, STruong, DMolineros, JHowe, TWordsworth, BPBowness, PKnight, JCAnkylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterized by enthesitis of the spine and sacroiliac joints. Genome-wide association studies (GWASs) have revealed more than 100 genetic associations whose functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We find that, while CD14+ monocytes and CD4+ and CD8+ T cells show disease-specific differences at the RNA level, epigenomic differences are only apparent upon multi-omics integration. The latter reveals enrichment at disease-associated loci in monocytes. We link putative functional SNPs to genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1, and show how disease-specific functional genomic data can be integrated with GWASs to enhance therapeutic target discovery. This study combines epigenetic and transcriptional analysis with GWASs to identify disease-relevant cell types and gene regulation of likely pathogenic relevance and prioritize drug targets. |
| spellingShingle | Brown, AC Cohen, CJ Mielczarek, O Migliorini, G Costantino, F Allcock, A Davidson, C Elliott, KS Fang, H Lledó Lara, A Martin, AC Osgood, JA Sanniti, A Scozzafava, G Vecellio, M Zhang, P Black, MH Li, S Truong, D Molineros, J Howe, T Wordsworth, BP Bowness, P Knight, JC Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis |
| title | Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis |
| title_full | Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis |
| title_fullStr | Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis |
| title_full_unstemmed | Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis |
| title_short | Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis |
| title_sort | comprehensive epigenomic profiling reveals the extent of disease specific chromatin states and informs target discovery in ankylosing spondylitis |
| work_keys_str_mv | AT brownac comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT cohencj comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT mielczareko comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT migliorinig comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT costantinof comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT allcocka comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT davidsonc comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT elliottks comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT fangh comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT lledolaraa comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT martinac comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT osgoodja comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT sannitia comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT scozzafavag comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT vecelliom comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT zhangp comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT blackmh comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT lis comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT truongd comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT molinerosj comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT howet comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT wordsworthbp comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT bownessp comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis AT knightjc comprehensiveepigenomicprofilingrevealstheextentofdiseasespecificchromatinstatesandinformstargetdiscoveryinankylosingspondylitis |