Publications
9 results found
Jobbins AM, Yu S, Paterson HAB, et al., 2023, Pre-RNA splicing in metabolic homeostasis and liver disease, Trends in Endocrinology and Metabolism, Vol: 34, Pages: 823-837, ISSN: 1043-2760
The liver plays a key role in sensing nutritional and hormonal inputs to maintain metabolic homeostasis. Recent studies into pre-mRNA splicing and alternative splicing (AS) and their effects on gene expression have revealed considerable transcriptional complexity in the liver, both in health and disease. While the contribution of these mechanisms to cell and tissue identity is widely accepted, their role in physiological and pathological contexts within tissues is just beginning to be appreciated. In this review, we showcase recent studies on the splicing and AS of key genes in metabolic pathways in the liver, the effect of metabolic signals on the spliceosome, and therapeutic intervention points based on RNA splicing.
Nagy D, Maude H, Birdsey GM, et al., 2023, Liver sinusoidal endothelial transcription factors in metabolic homeostasis and disease, Journal of Molecular Endocrinology, Vol: 71, Pages: 1-20, ISSN: 0952-5041
Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that form the liver microvasculature. LSECs maintain liver homeostasis, scavenging bloodborne molecules, regulating immune response, and actively promoting hepatic stellate cell quiescence. These diverse functions are underpinned by a suite of unique phenotypical attributes distinct from other blood vessels. In recent years, studies have begun to reveal the specific contributions of LSECs to liver metabolic homeostasis and how LSEC dysfunction associates with disease aetiology. This has been particularly evident in the context of non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, which is associated with loss of key LSEC phenotypical characteristics and molecular identity. Comparative transcriptome studies of LSECs and other endothelial cells, together with rodent knockout models, have revealed that loss of LSEC identity through disruption of core transcription factor activity leads to impaired metabolic homeostasis and to hallmarks of liver disease. This review explores the current knowledge of LSEC transcription factors, covering their roles in LSEC development and maintenance of key phenotypic features, which, when disturbed, lead to loss of liver metabolic homeostasis and promote features of chronic liver diseases, such as non-alcoholic liver disease.
Maude H, Cebola I, 2023, Zooming into process-specific risk., Nature Metabolism, Vol: 5, Pages: 730-731, ISSN: 2522-5812
Dixon PH, Levine AP, Cebola I, et al., 2022, GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements, Nature Communications, Vol: 13, ISSN: 2041-1723
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1,138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility.
Maude H, Lau W, Maniatis N, et al., 2021, New Insights Into Mitochondrial Dysfunction at Disease Susceptibility Loci in the Development of Type 2 Diabetes, Frontiers in Endocrinology, Vol: 12, ISSN: 1664-2392
This study investigated the potential genetic mechanisms which underlie adipose tissue mitochondrial dysfunction in Type 2 diabetes (T2D), by systematically identifying nuclear-encoded mitochondrial genes (NEMGs) among the genes regulated by T2D-associated genetic loci. The target genes of these ‘disease loci’ were identified by mapping genetic loci associated with both disease and gene expression levels (expression quantitative trait loci, eQTL) using high resolution genetic maps, with independent estimates co-locating to within a small genetic distance. These co-locating signals were defined as T2D-eQTL and the target genes as T2D cis-genes. In total, 763 cis-genes were associated with T2D-eQTL, of which 50 were NEMGs. Independent gene expression datasets for T2D and insulin resistant cases and controls confirmed that the cis-genes and cis-NEMGs were enriched for differential expression in cases, providing independent validation that genetic maps can identify informative functional genes. Two additional results were consistent with a potential role of T2D-eQTL in regulating the 50 identified cis-NEMGs in the context of T2D risk: (1) the 50 cis-NEMGs showed greater differential expression compared to other NEMGs and (2) other NEMGs showed a trend towards significantly decreased expression if their expression levels correlated more highly with the subset of 50 cis-NEMGs. These 50 cis-NEMGs, which are differentially expressed and associated with mapped T2D disease loci, encode proteins acting within key mitochondrial pathways, including some of current therapeutic interest such as the metabolism of branched-chain amino acids, GABA and biotin.
Maude H, Sanchez Cabanillas C, Cebola I, 2021, Epigenetics of hepatic insulin resistance, Frontiers in Endocrinology, Vol: 12, Pages: 1-24, ISSN: 1664-2392
Insulin resistance (IR) is largely recognized as a unifying feature that underlies metabolic dysfunction. Both lifestyle and genetic factors contribute to IR. Work from recent years has demonstrated that the epigenome may constitute an interface where different signals may converge to promote IR gene expression programs. Here, we review the current knowledge of the role of epigenetics in hepatic IR, focusing on the roles of DNA methylation and histone post-translational modifications. We discuss the broad epigenetic changes observed in the insulin resistant liver and its associated pathophysiological states and leverage on the wealth of ‘omics’ studies performed to discuss efforts in pinpointing specific loci that are disrupted by these changes. We envision that future studies, with increased genomic resolution and larger cohorts, will further the identification of biomarkers of early onset hepatic IR and assist the development of targeted interventions. Furthermore, there is growing evidence to suggest that persistent epigenetic marks may be acquired over prolonged exposure to disease or deleterious exposures, highlighting the need for preventative medicine and long-term lifestyle adjustments to avoid irreversible or long-term alterations in gene expression.
Maude H, Davidson M, Charitakis N, et al., 2019, NUMT confounding biases mitochondrial heteroplasmy calls in favor of the reference allele, Frontiers in Cell and Developmental Biology, Vol: 7, ISSN: 2296-634X
Homology between mitochondrial DNA (mtDNA) and nuclear DNA of mitochondrial origin (nuMTs) causes confounding when aligning short sequence reads to the reference human genome, as the true sequence origin cannot be determined. Using a systematic in silico approach, we here report the impact of all potential mitochondrial variants on alignment accuracy and variant calling. A total of 49,707 possible mutations were introduced across the 16,569bp reference mitochondrial genome (16,569 x 3 alternative alleles), one variant at-at-time. The resulting in silico fragmentation and alignment to the entire reference genome (GRCh38) revealed preferential mapping of mutated mitochondrial fragments to nuclear loci, as variants increased loci similarity to nuMTs, for a total of 807, 362 and 41 variants at 333, 144 and 27 positions when using 100bp, 150bp and 300bp single end fragments. We subsequently modelled these affected variants at 50% heteroplasmy and carried out variant calling, observing bias in the reported allele frequencies in favor of the reference allele. Four variants (chrM:6023A, chrM:4456T, chrM:5147A and chrM:7521A) including a possible hypertension factor, chrM:4456T, caused 100% loss of coverage at the mutated position (with all 100bp single-end fragments aligning to homologous, nuclear positions instead of chrM), rendering these variants undetectable when aligning to the entire reference genome. Furthermore, four mitochondrial variants reported to be pathogenic were found to cause significant loss of coverage and select Haplogroup-defining SNPs were shown to exacerbate the loss of coverage caused by surrounding variants. Increased fragment length and use of paired-end reads both improved alignment accuracy.
Dalmia A, Dib M-J, Maude H, et al., 2019, A genetic epidemiological study in British adults and older adults shows a high heritability of the combined indicator of vitamin B12 status (cB12) and connects B12 status with utilization of mitochondrial substrates and energy metabolism, The Journal of Nutritional Biochemistry, Vol: 70, Pages: 156-163, ISSN: 0955-2863
Vitamin B12 deficiency is common among older adults. However, the most commonly used marker of deficiency, total serum vitamin B12 (B12), is not sensitive enough to diagnose true deficiency in a significant proportion of the population. The combined indicator of B12 status (cB12), formulated as a composite score of various biomarkers of vitamin B12 status (which also accounts for low folate status and age) has been shown to offer a more robust and powerful test to diagnose B12 deficiency.There are no epidemiological studies of cB12 variability in older adults. We carried out a twin study to characterize the relative contribution of heritable (h2) and environmental factors to the observed variability in cB12 score in an adult and older adult population (n=378). Furthermore, we tested for association between variability in cB12 and candidate polymorphisms and genes previously associated with B12 biomarker levels characterized in silico the mechanism linking the genetic variants and cB12 variability.We found the variability in cB12 and its constituents to be highly heritable (h2=55%–64%). The single nucleotide polymorphism rs291466 in HIBCH, previously associated with variation in MMA, was significantly associated with cB12 (R2=5%, P=5E-04). Furthermore, variants in MTRR, MMAB and MUT, underlying inborn errors of B12 metabolism, were nominally associated with variation in cB12. Pathway accompanied by expression quantitative trait loci analysis revealed that HIBCH rs291466 influences the concentration of MMA via the valine degradation pathway.Our study provides etiological insight into how B12 deficiency can manifest into impaired mitochondrial function through perturbations in mitochondrial “fuel” usage.
Coelho MB, Ascher DB, Gooding C, et al., 2016, Functional interactions between polypyrimidine tract binding protein and PRI peptide ligand containing proteins, Biochemical Society Transactions, Vol: 44, Pages: 1058-1065, ISSN: 0300-5127
<jats:p>Polypyrimidine tract binding protein (PTBP1) is a heterogeneous nuclear ribonucleoprotein (hnRNP) that plays roles in most stages of the life-cycle of pre-mRNA and mRNAs in the nucleus and cytoplasm. PTBP1 has four RNA binding domains of the RNA recognition motif (RRM) family, each of which can bind to pyrimidine motifs. In addition, RRM2 can interact via its dorsal surface with proteins containing short peptide ligands known as PTB RRM2 interacting (PRI) motifs, originally found in the protein Raver1. Here we review our recent progress in understanding the interactions of PTB with RNA and with various proteins containing PRI ligands.</jats:p>
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