B lymphocytes in treatment-naive paediatric patients with lupus are epigenetically distinct from healthy children
Background SLE is likely triggered by gene–environment interactions. We have shown that most SLE-associated haplotypes encompass genomic regions enriched for epigenetic marks associated with enhancer function in lymphocytes, suggesting genetic risk is exerted through altered gene regulation. Data re...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-01-01
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| Series: | Lupus Science and Medicine |
| Online Access: | https://lupus.bmj.com/content/10/1/e000921.full |
| _version_ | 1797771752192868352 |
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| author | Betty Diamond Joyce Hui-Yuen Kaiyu Jiang Susan Malkiel Barbara Anne Eberhard Heather Walters James Jarvis |
| author_facet | Betty Diamond Joyce Hui-Yuen Kaiyu Jiang Susan Malkiel Barbara Anne Eberhard Heather Walters James Jarvis |
| author_sort | Betty Diamond |
| collection | DOAJ |
| description | Background SLE is likely triggered by gene–environment interactions. We have shown that most SLE-associated haplotypes encompass genomic regions enriched for epigenetic marks associated with enhancer function in lymphocytes, suggesting genetic risk is exerted through altered gene regulation. Data remain scarce on how epigenetic variance contributes to disease risk in paediatric SLE (pSLE). We aim to identify differences in epigenetically regulated chromatin architecture in treatment-naive patients with pSLE compared with healthy children.Methods Using the assay for transposase-accessible chromatin with sequencing (ATACseq), we surveyed open chromatin in 10 treatment-naive patients with pSLE, with at least moderate disease severity, and 5 healthy children. We investigated whether regions of open chromatin unique to patients with pSLE demonstrate enrichment for specific transcriptional regulators, using standard computational approaches to identify unique peaks and a false discovery rate of <0.05. Further analyses for histone modification enrichment and variant calling were performed using bioinformatics packages in R and Linux.Results We identified 30 139 differentially accessible regions (DAR) unique to pSLE B cells; 64.3% are more accessible in pSLE than healthy children. Many DAR are found in distal, intergenic regions and enriched for enhancer histone marks (p=0.027). B cells from adult patients with SLE contain more regions of inaccessible chromatin than those in pSLE. In pSLE B cells, 65.2% of the DAR are located within or near known SLE haplotypes. Further analysis revealed enrichment of transcription factor binding motifs within these DAR that may regulate genes involved in pro-inflammatory responses and cellular adhesion.Conclusions We demonstrate an epigenetically distinct profile in pSLE B cells when compared with healthy children and adults with lupus, indicating that pSLE B cells are predisposed for disease onset/development. Increased chromatin accessibility in non-coding genomic regions controlling activation of inflammation suggest that transcriptional dysregulation by regulatory elements controlling B cell activation plays an important role in pSLE pathogenesis. |
| first_indexed | 2024-03-12T21:42:11Z |
| format | Article |
| id | doaj.art-3be5afe2e0424205b0d85301fa2463fe |
| institution | Directory Open Access Journal |
| issn | 2053-8790 |
| language | English |
| last_indexed | 2024-03-12T21:42:11Z |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Lupus Science and Medicine |
| spelling | doaj.art-3be5afe2e0424205b0d85301fa2463fe2023-07-26T16:45:07ZengBMJ Publishing GroupLupus Science and Medicine2053-87902023-01-0110110.1136/lupus-2023-000921B lymphocytes in treatment-naive paediatric patients with lupus are epigenetically distinct from healthy childrenBetty Diamond0Joyce Hui-Yuen1Kaiyu Jiang2Susan Malkiel3Barbara Anne Eberhard4Heather Walters5James Jarvis6Institute of Molecule Medicine, The Feinstein Institutes for Medical Research, Manhasset, New York, USAPediatric Rheumatology, Northwell Health, Lake Success, New York, USAPediatrics, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York, USACenter for Autoimmune, Musculoskeletal, and Hematopoietic Diseases Research, The Feinstein Institutes for Medical Research, Manhasset, New York, USAPediatric Rheumatology, Northwell Health, Lake Success, New York, USAPediatric Rheumatology, Northwell Health, Lake Success, New York, USAPediatrics, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York, USABackground SLE is likely triggered by gene–environment interactions. We have shown that most SLE-associated haplotypes encompass genomic regions enriched for epigenetic marks associated with enhancer function in lymphocytes, suggesting genetic risk is exerted through altered gene regulation. Data remain scarce on how epigenetic variance contributes to disease risk in paediatric SLE (pSLE). We aim to identify differences in epigenetically regulated chromatin architecture in treatment-naive patients with pSLE compared with healthy children.Methods Using the assay for transposase-accessible chromatin with sequencing (ATACseq), we surveyed open chromatin in 10 treatment-naive patients with pSLE, with at least moderate disease severity, and 5 healthy children. We investigated whether regions of open chromatin unique to patients with pSLE demonstrate enrichment for specific transcriptional regulators, using standard computational approaches to identify unique peaks and a false discovery rate of <0.05. Further analyses for histone modification enrichment and variant calling were performed using bioinformatics packages in R and Linux.Results We identified 30 139 differentially accessible regions (DAR) unique to pSLE B cells; 64.3% are more accessible in pSLE than healthy children. Many DAR are found in distal, intergenic regions and enriched for enhancer histone marks (p=0.027). B cells from adult patients with SLE contain more regions of inaccessible chromatin than those in pSLE. In pSLE B cells, 65.2% of the DAR are located within or near known SLE haplotypes. Further analysis revealed enrichment of transcription factor binding motifs within these DAR that may regulate genes involved in pro-inflammatory responses and cellular adhesion.Conclusions We demonstrate an epigenetically distinct profile in pSLE B cells when compared with healthy children and adults with lupus, indicating that pSLE B cells are predisposed for disease onset/development. Increased chromatin accessibility in non-coding genomic regions controlling activation of inflammation suggest that transcriptional dysregulation by regulatory elements controlling B cell activation plays an important role in pSLE pathogenesis.https://lupus.bmj.com/content/10/1/e000921.full |
| spellingShingle | Betty Diamond Joyce Hui-Yuen Kaiyu Jiang Susan Malkiel Barbara Anne Eberhard Heather Walters James Jarvis B lymphocytes in treatment-naive paediatric patients with lupus are epigenetically distinct from healthy children Lupus Science and Medicine |
| title | B lymphocytes in treatment-naive paediatric patients with lupus are epigenetically distinct from healthy children |
| title_full | B lymphocytes in treatment-naive paediatric patients with lupus are epigenetically distinct from healthy children |
| title_fullStr | B lymphocytes in treatment-naive paediatric patients with lupus are epigenetically distinct from healthy children |
| title_full_unstemmed | B lymphocytes in treatment-naive paediatric patients with lupus are epigenetically distinct from healthy children |
| title_short | B lymphocytes in treatment-naive paediatric patients with lupus are epigenetically distinct from healthy children |
| title_sort | b lymphocytes in treatment naive paediatric patients with lupus are epigenetically distinct from healthy children |
| url | https://lupus.bmj.com/content/10/1/e000921.full |
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