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"McKean, David"
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Rare genetic variation at transcription factor binding sites modulates local DNA methylation profiles
Although DNA methylation is the best characterized epigenetic mark, the mechanism by which it is targeted to specific regions in the genome remains unclear. Recent studies have revealed that local DNA methylation profiles might be dictated by cis- regulatory DNA sequences that mainly operate via DNA-binding factors. Consistent with this finding, we have recently shown that disruption of CTCF-binding sites by rare single nucleotide variants (SNVs) can underlie cis -linked DNA methylation changes in patients with congenital anomalies. These data raise the hypothesis that rare genetic variation at transcription factor binding sites (TFBSs) might contribute to local DNA methylation patterning. In this work, by combining blood genome-wide DNA methylation profiles, whole genome sequencing-derived SNVs from 247 unrelated individuals along with 133 predicted TFBS motifs derived from ENCODE ChIP-Seq data, we observed an association between the disruption of binding sites for multiple TFs by rare SNVs and extreme DNA methylation values at both local and, to a lesser extent, distant CpGs. While the majority of these changes affected only single CpGs, 24% were associated with multiple outlier CpGs within ±1kb of the disrupted TFBS. Interestingly, disruption of functionally constrained sites within TF motifs lead to larger DNA methylation changes at nearby CpG sites. Altogether, these findings suggest that rare SNVs at TFBS negatively influence TF-DNA binding, which can lead to an altered local DNA methylation profile. Furthermore, subsequent integration of DNA methylation and RNA-Seq profiles from cardiac tissues enabled us to observe an association between rare SNV-directed DNA methylation and outlier expression of nearby genes. In conclusion, our findings not only provide insights into the effect of rare genetic variation at TFBS on shaping local DNA methylation and its consequences on genome regulation, but also provide a rationale to incorporate DNA methylation data to interpret the functional role of rare variants.
Journal Article
Expression of cilium-associated genes defines novel molecular subtypes of idiopathic pulmonary fibrosis
Background Idiopathic pulmonary fibrosis (IPF) is an untreatable lung disease with a median survival of only 3–5 years that is diagnosed using a combination of clinical, radiographic and pathologic criteria. Histologically, IPF is characterised by usual interstitial pneumonia (UIP), a fibrosing interstitial pneumonia with a pattern of heterogeneous, subpleural regions of fibrotic and remodelled lung. We hypothesised that gene expression profiles of lung tissue may identify molecular subtypes of disease that could classify subtypes of IPF/UIP that have clinical implications. Methods and findings We collected transcriptional profiles on lung tissue from 119 patients with IPF/UIP and 50 non-diseased controls. Differential expression of individual transcripts was identified using an analysis of covariance (ANCOVA) model incorporating the clinical diagnosis of each patient as well as age, gender and smoking status. Validation was performed in an independent cohort of 111 IPF/UIP and 39 non-diseased controls. Our analysis identified two subtypes of IPF/UIP based on a strong molecular signature associated with expression of genes previously associated with fibrosis (matrix metalloproteinases, osteopontin, keratins), cilium genes and genes with unknown function. We demonstrate that elevated expression of cilium genes is associated with more extensive microscopic honeycombing and higher expression of both the airway mucin gene MUC5B and the metalloproteinase MMP7, a gene recently implicated in attenuating ciliated cell differentiation during wound repair. Conclusions Expression of cilium genes appears to identify two unique molecular phenotypes of IPF/UIP. The different molecular profiles may be relevant to therapeutic responsiveness in patients with IPF/UIP.
Journal Article
Mouse, bird, snake, wolf
Using sticks, leaves, and clay, Little Ben makes a mouse, Sue, a bird, and Harry, a snake, but when they create a terrifying wolf that turns on them, Little Ben must summon the courage to save them.
Book
Rare Variants in RTEL1 Are Associated with Familial Interstitial Pneumonia
Abstract
Rationale
Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families.
Objectives
To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis.
Methods
Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds.
Measurements and Main Results
We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (<10% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function.
Conclusions
Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.
Journal Article
Joe Quinn's poltergeist
\"Joe Quinn tells everyone about the poltergeist in his house, but no one believes him. No one that is, except for Davie. He's felt the inexplicable presence in the rooms, he's seen random objects fly through the air. And there's something else--a memory of his beloved sister, and a feeling deep down that somehow it might be possible for ghosts to exist.\"--Provided by publisher.
Book
Genomic, transcriptomic, and immunogenomic landscape of over 1300 sarcomas of diverse histology subtypes
Given their rarity and diversity, a fundamental understanding of the genomic underpinnings for many sarcoma subtypes is still lacking. To better define the molecular landscape of this group of diseases, we perform matched whole exome sequencing and RNA sequencing on a cohort of 1340 sarcoma tumor specimens. We identify recurrent somatic mutations and observe an increased mutational burden in metastatic vs. primary samples (
p
< 0.001). We observe frequent copy number alterations including whole genome doubling, with this feature being more common in metastatic tumors (p = 0.026). Estimation of immune cell abundances followed by hierarchical clustering identifies five immune subtypes ranging from low to high and we observe inferior overall survival in immune deplete clusters compared to immune enriched (
p <
0.01). Interestingly, GIST predominantly form a distinct “immune intermediate” cluster that is marked by a specific enrichment for NK cells (FDR < 0.01).
Sarcoma is a highly heterogeneous disease, which can be caused by a large variety of mutations. Here, the authors utilise multi-omics to characterise a cohort of 1,340 sarcoma tissue specimens to identify key somatic mutations and identify immune subtypes.
Journal Article
A common genetic variant within SCN10A modulates cardiac SCN5A expression
Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.
Journal Article
Loss of RNA expression and allele-specific expression associated with congenital heart disease
Congenital heart disease (CHD), a prevalent birth defect occurring in 1% of newborns, likely results from aberrant expression of cardiac developmental genes. Mutations in a variety of cardiac transcription factors, developmental signalling molecules and molecules that modify chromatin cause at least 20% of disease, but most CHD remains unexplained. We employ RNAseq analyses to assess allele-specific expression (ASE) and biallelic loss-of-expression (LOE) in 172 tissue samples from 144 surgically repaired CHD subjects. Here we show that only 5% of known imprinted genes with paternal allele silencing are monoallelic versus 56% with paternal allele expression—this cardiac-specific phenomenon seems unrelated to CHD. Further, compared with control subjects, CHD subjects have a significant burden of both LOE genes and ASE events associated with altered gene expression. These studies identify
FGFBP2
,
LBH
,
RBFOX2
,
SGSM1
and
ZBTB16
as candidate CHD genes because of significantly altered transcriptional expression.
Congenital heart disease (CHD) is a disorder that occurs in ∼1% of live births. Here the authors describe a genome-wide allele-specific expression analyses in CHD patients, identifying five new genes involved in CHD and showing that paternally-expressed imprinted genes are monoallelic, while maternally-expressed imprinted genes are biallelic.
Journal Article