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-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. Electronic supplementary material The online version of this article (10.1186/s13148-019-0655-8) contains supplementary material, which is available to authorized users.

Genome wide DNA methylation analysis of alveolar capillary dysplasia lung tissue reveals aberrant methylation of genes involved in development including the FOXF1 locus

“…And thus, the absence of DMRs in comparison indicates that the methylation pattern of the unaffected paternal allele is similar to the combined methylation patterns of both alleles in control samples. In line with previous studies, these results indicate that if the FOXF1 enhancer is imprinted through DNA methylation, this involves the paternal allele (Additional file 4: Figure S 2A, right panel) [4,6,9,16]. Although MeD-seq revealed multiple regions within the 60 kb enhancer that are methylated on the paternal allele of ACD-del samples, additional methylation studies and analyses are needed to define if these regions are paternally imprinted.…”

“…However, they did not study allele specific methylation and therefore could not exclude allele specific imprinting through DNA methylation at the maternal allele. If the 60 kb FOXF1 enhancer normally contains regions that are specifically methylated on the maternal allele, these would be lost in the ACDdel samples studied by us, resulting in significant DMRs between ACD-del and control samples (Additional [16]. Since our ACD-del and control samples carried an intact paternal allele, we investigated whether this region was methylated in our samples.…”

“…Furthermore, although very unlikely, parental imprinting of the FOXF1 enhancer on the maternal allele has never been excluded either. Up to now, studies investigating allele specific methylation in the 60 kb enhancer are limited and mainly use DNA isolated from blood or skin tissue which might not be representative for methylation patterns in lung tissue [15,16].…”

Identification of differentially methylated genes in first-trimester placentas with trisomy 16

“…Mosaic forms of trisomy 16 are associated with a high probability of fetal death, preterm birth, intrauterine growth retardation, fetal abnormalities, and preeclampsia 6 . These malformations likely occur due to the aberrant expression of imprinted genes located on chromosome 16 7 , 8 .…”

IncRNAs and circRNAs provide insight into discoid lupus pathogenesis and progression

“…ETV6, an important TF for blood cell development, has been found to be associated with multiple hematologic malignancies such as primarily acute lymphoblastic lymphoma (24). The function of TF ZNF597, has not yet been elucidated (25). These findings suggest that lncRNA may have transregulatory function and predispose to DLE by altering the transcription of various protein-coding genes.…”