Characterizing the molecular impact of KMT2D variants on the epigenetic and transcriptional landscapes in Kabuki syndrome
| العنوان: | Characterizing the molecular impact of KMT2D variants on the epigenetic and transcriptional landscapes in Kabuki syndrome |
|---|---|
| المؤلفون: | Youngsook L Jung, Christina Hung, Jaejoon Choi, Eunjung A Lee, Olaf Bodamer |
| المصدر: | Human Molecular Genetics. |
| بيانات النشر: | Oxford University Press (OUP), 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Genetics, General Medicine, Molecular Biology, Genetics (clinical) |
| الوصف: | Kabuki syndrome (KS) is a rare, multisystem disorder with a variable clinical phenotype. The majority of KS is caused by dominant loss-of-function mutations in KMT2D (lysine methyltransferase 2D). KMT2D mediates chromatin accessibility by adding methyl groups to lysine residue 4 of histone 3, which plays a critical role in cell differentiation and homeostasis. The molecular underpinnings of KS remain elusive partly because of a lack of histone modification data from human samples. Consequently, we profiled and characterized alterations in histone modification and gene transcription in peripheral blood mononuclear cells (PBMCs) from 33 patients with KMT2D mutations and 36 unaffected healthy controls. Our analysis identified unique enhancer signatures in H3K4me1 and H3K4me2 in KS compared with controls. Reduced enhancer signals were present for promoter-distal sites of immune-related genes for which co-binding of PBMC-specific transcription factors was predicted; 31% of super-enhancers of normal blood cells overlapped with disrupted enhancers in KS, supporting an association of reduced enhancer activity of immune-related genes with immune deficiency phenotypes. In contrast, increased enhancer signals were observed for promoter-proximal regions of metabolic genes enriched with EGR1 and E2F2 motifs, whose transcriptional levels were significantly increased in KS. Additionally, we identified ~100 de novo enhancers in genes, such as in MYO1F and AGAP2. Together, our results underscore the effect of KMT2D haploinsufficiency on dysregulation of enhancer states and gene transcription and provide a framework for the identification of therapeutic targets and biomarkers in preparation for clinical trial readiness. |
| تدمد: | 1460-2083 0964-6906 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::58a0a066075b425a4224a40fbc49ce31 https://doi.org/10.1093/hmg/ddad059 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi...........58a0a066075b425a4224a40fbc49ce31 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
|---|