Novel parent-of-origin-specific differentially methylated loci on chromosome 16
Abstract Background Congenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-cau...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-04-01
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| Series: | Clinical Epigenetics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13148-019-0655-8 |
| _version_ | 1818977974062415872 |
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| author | Katharina V. Schulze Przemyslaw Szafranski Harry Lesmana Robert J. Hopkin Aaron Hamvas Jennifer A. Wambach Marwan Shinawi Gladys Zapata Claudia M. B. Carvalho Qian Liu Justyna A. Karolak James R. Lupski Neil A. Hanchard Paweł Stankiewicz |
| author_facet | Katharina V. Schulze Przemyslaw Szafranski Harry Lesmana Robert J. Hopkin Aaron Hamvas Jennifer A. Wambach Marwan Shinawi Gladys Zapata Claudia M. B. Carvalho Qian Liu Justyna A. Karolak James R. Lupski Neil A. Hanchard Paweł Stankiewicz |
| author_sort | Katharina V. Schulze |
| collection | DOAJ |
| description | Abstract Background Congenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-causative deletions, involving FOXF1 or its lung-specific upstream enhancer at 16q24.1, arise almost exclusively on the maternally inherited chromosome 16. Given the phenotypic similarities between upd(16)mat and ACDMPV, together with parental allelic bias in ACDMPV, we hypothesized that there may be unknown imprinted loci mapping to chromosome 16 that become functionally unmasked by chromosomal structural variants. Results To identify parent-of-origin biased DNA methylation, we performed high-resolution bisulfite sequencing of chromosome 16 on peripheral blood and cultured skin fibroblasts from individuals with maternal or paternal upd(16) as well as lung tissue from patients with ACDMPV-causative 16q24.1 deletions and a normal control. We identified 22 differentially methylated regions (DMRs) with ≥ 5 consecutive CpG methylation sites and varying tissue-specificity, including the known DMRs associated with the established imprinted gene ZNF597 and DMRs supporting maternal methylation of PRR25, thought to be paternally expressed in lymphoblastoid cells. Lastly, we found evidence of paternal methylation on 16q24.1 near LINC01082 mapping to the FOXF1 enhancer. Conclusions Using high-resolution bisulfite sequencing to evaluate DNA methylation across chromosome 16, we found evidence for novel candidate imprinted loci on chromosome 16 that would not be evident in array-based assays and could contribute to the birth defects observed in patients with upd(16)mat or in ACDMPV. |
| first_indexed | 2024-12-20T16:36:15Z |
| format | Article |
| id | doaj.art-bf6be8c5ff914536b4d51e4548e033c3 |
| institution | Directory Open Access Journal |
| issn | 1868-7075 1868-7083 |
| language | English |
| last_indexed | 2024-12-20T16:36:15Z |
| publishDate | 2019-04-01 |
| publisher | BMC |
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| series | Clinical Epigenetics |
| spelling | doaj.art-bf6be8c5ff914536b4d51e4548e033c32022-12-21T19:33:08ZengBMCClinical Epigenetics1868-70751868-70832019-04-0111111010.1186/s13148-019-0655-8Novel parent-of-origin-specific differentially methylated loci on chromosome 16Katharina V. Schulze0Przemyslaw Szafranski1Harry Lesmana2Robert J. Hopkin3Aaron Hamvas4Jennifer A. Wambach5Marwan Shinawi6Gladys Zapata7Claudia M. B. Carvalho8Qian Liu9Justyna A. Karolak10James R. Lupski11Neil A. Hanchard12Paweł Stankiewicz13Department of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDivision of Human Genetics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of MedicineDivision of Human Genetics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of MedicinePediatrics, Northwestern University Feinberg School of MedicineDivision of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of MedicineDivision of Genetics and Genomic Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of MedicineDepartment of Pediatrics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Molecular and Human Genetics, Baylor College of MedicineAbstract Background Congenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-causative deletions, involving FOXF1 or its lung-specific upstream enhancer at 16q24.1, arise almost exclusively on the maternally inherited chromosome 16. Given the phenotypic similarities between upd(16)mat and ACDMPV, together with parental allelic bias in ACDMPV, we hypothesized that there may be unknown imprinted loci mapping to chromosome 16 that become functionally unmasked by chromosomal structural variants. Results To identify parent-of-origin biased DNA methylation, we performed high-resolution bisulfite sequencing of chromosome 16 on peripheral blood and cultured skin fibroblasts from individuals with maternal or paternal upd(16) as well as lung tissue from patients with ACDMPV-causative 16q24.1 deletions and a normal control. We identified 22 differentially methylated regions (DMRs) with ≥ 5 consecutive CpG methylation sites and varying tissue-specificity, including the known DMRs associated with the established imprinted gene ZNF597 and DMRs supporting maternal methylation of PRR25, thought to be paternally expressed in lymphoblastoid cells. Lastly, we found evidence of paternal methylation on 16q24.1 near LINC01082 mapping to the FOXF1 enhancer. Conclusions Using high-resolution bisulfite sequencing to evaluate DNA methylation across chromosome 16, we found evidence for novel candidate imprinted loci on chromosome 16 that would not be evident in array-based assays and could contribute to the birth defects observed in patients with upd(16)mat or in ACDMPV.http://link.springer.com/article/10.1186/s13148-019-0655-8ImprintingCpGTrisomy 16Uniparental disomy 16ACDMPV |
| spellingShingle | Katharina V. Schulze Przemyslaw Szafranski Harry Lesmana Robert J. Hopkin Aaron Hamvas Jennifer A. Wambach Marwan Shinawi Gladys Zapata Claudia M. B. Carvalho Qian Liu Justyna A. Karolak James R. Lupski Neil A. Hanchard Paweł Stankiewicz Novel parent-of-origin-specific differentially methylated loci on chromosome 16 Clinical Epigenetics Imprinting CpG Trisomy 16 Uniparental disomy 16 ACDMPV |
| title | Novel parent-of-origin-specific differentially methylated loci on chromosome 16 |
| title_full | Novel parent-of-origin-specific differentially methylated loci on chromosome 16 |
| title_fullStr | Novel parent-of-origin-specific differentially methylated loci on chromosome 16 |
| title_full_unstemmed | Novel parent-of-origin-specific differentially methylated loci on chromosome 16 |
| title_short | Novel parent-of-origin-specific differentially methylated loci on chromosome 16 |
| title_sort | novel parent of origin specific differentially methylated loci on chromosome 16 |
| topic | Imprinting CpG Trisomy 16 Uniparental disomy 16 ACDMPV |
| url | http://link.springer.com/article/10.1186/s13148-019-0655-8 |
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