Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease
Abstract
Nearly all human genetic disorders result from a limited repertoire of mutations in an associated gene or its regulatory elements. We recently described an individual with an inherited form of anemia (alpha-thalassemia) who has a deletion that results in a truncated, widely expressed gene (LUC7L) becoming juxtaposed to a structurally normal alpha-globin gene (HBA2). Although it retains all of its local and remote cis-regulatory elements, expression of HBA2 is silenced and its CpG island becomes completely methylated early during development. Here we show that in the affected individual, in a transgenic model and in differentiating embryonic stem cells, transcription of antisense RNA mediates silencing and methylation of the associated CpG island. These findings identify a new mechanism underlying human genetic disease.
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As a consequence, transcription from this gene extended into the gene under investigation, causing abnormal promoter methylation and gene silencing.
“As a consequence, transcription from this gene extended into the gene under investigation, causing abnormal promoter methylation and gene silencing.”
From A critical view on transgenerational epigenetic inheritance in humans (2018) · cites this paper as [14]
In these cases, the abnormal DNA methylation of the gene under investigation was linked to a mutation in a neighboring gene that removed the transcription termination signal.
“In these cases, the abnormal DNA methylation of the gene under investigation was linked to a mutation in a neighboring gene that removed the transcription termination signal (Fig. 1b).”
From A critical view on transgenerational epigenetic inheritance in humans (2018) · cites this paper as [14]
Several studies including Guéant et al. have reported the co-segregation of an abnormal DNA methylation pattern (epimutation) with a rare disease in two or more generations of certain families.
“Several studies14–16 including a recent study by Guéant et al.18 in this journal, have reported the co-segregation of an abnormal DNA methylation pattern (called “epimutation”) with a rare disease in two or more generations of certain families.”
From A critical view on transgenerational epigenetic inheritance in humans (2018) · cites this paper as [14]
Most cases of segregation of abnormal DNA methylation patterns in families with rare diseases turned out to be caused by an underlying genetic variant.
“Most cases of segregation of abnormal DNA methylation patterns in families with rare diseases, however, turned out to be caused by an underlying genetic variant14–16 (see below).”
From A critical view on transgenerational epigenetic inheritance in humans (2018) · cites this paper as [14]
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Self-citation
- Authors
- Tufarelli, C., Stanley, J. A. S., Garrick, D., Sharpe, J. A., Ayyub, H., Wood, W. G., & Higgs, D. R.
- Affiliations
- John Radcliffe Hospital (GB)
- Corresponding author
- Higgs, Douglas R
- Venue
- Nature Genetics
- Published
- 2003-05-05
- Volume
- 34
- Issue
- 2
- Pages
- 157-165
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2048447535
- Cited by
- 547
- References
- 40
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 6 · 2023: 7 · 2022: 11 · 2021: 16 · 2020: 16 · 2019: 20 · 2018: 20 · 2017: 21 · 2016: 27 · 2015: 18 · 2014: 19 · 2013: 30 · 2012: 31
- FWCI
- 13.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Keywords
- gene silencing, DNA methylation, CpG island methylation, alpha-thalassemia, HbA2, alpha-globin gene, gene deletion, cis-regulatory elements, embryonic stem cells, transgenic mouse model, inherited anemia, epigenetic inheritance
- MeSH terms
- Animals, Base Sequence, Cell Line, Chromosomes, Human, Pair 16, DNA, Globins, Humans, Mice, Transgenic, Models, Genetic, Promoter Regions, Genetic, Transcription, Genetic, RNA, Antisense, alpha-Thalassemia, CpG Islands, DNA Methylation, Gene Silencing, Mice
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