Biology subjects

Morley, M.

Publications and source records attributed to Morley, M..

5 recordsLinked to original sources

bioRxiv2025

Investigating the role of long non-coding RNA in hypertrophic cardiomyopathy

Long non-coding RNA (lncRNA) are transcripts that do not typically code for protein but have essential roles in the regulation of transcription and translation in health and disease. The objective of this study was to identify potential lncRNAs that could play a role in the pathophysiology of hypertrophic cardiomyopathy (HCM). We analyzed RNA-Seq data for lncRNA expression from a mouse model of HCM and cross-referenced transcripts to a published human HCM tissue dataset. We identified a total of 9,140 lncRNA transcripts in the mouse dataset, of which 35 were differentially expressed between transgenic TNNT2 {Delta}160 mice (TG) and non-transgenic mice (nTG, p-adj < 0.05). Of these, 13 had a human ortholog as predicted by ortho2align. We used the computational tools MiPepid, AlphaFold, and PhyloCSF to predict potential micropeptides that could be coded for by these 13 mouse lncRNAs. We found that predicted micropeptides from 3 of these lncRNAs-G730003C15Rik, 9830004L10Rik, and Gm45012-have higher AlphaFold folding confidence metrics than random peptides or truly non-coding lncRNA negative controls (p < 0.05). Another 2 of these lncRNAs, 6330403L08Rik and 2900072N19Rik, have positive PhyloCSF scores, also indicating micropeptide coding potential. In summary, we developed a computational workflow to identify differentially expressed lncRNAs in a mouse model of HCM that can be prioritized for future experimental studies based on their cross-species conservation and micropeptide coding potential. NEW & NOTEWORTHYThis is the first analysis of RNA-Seq data for lncRNA expression in an HCM mouse model and the first cross-species analysis of HCM lncRNA RNA-Seq data. Additionally, this study demonstrated a novel computational pipeline that combines several tools-RNA-Seq, MiPepid, AlphaFold, and PhyloCSF-to identify potential lncRNAs of interest from RNA-Seq data.

bioinformatics↗

bioRxiv2021

Circadian regulation of lung repair and regeneration

Optimal lung repair and regeneration is essential for recovery from viral infections such as that induced by influenza A virus (IAV). We have previously demonstrated that lung inflammation induced by IAV is under circadian control. However, it is not known if the circadian clock exerts its influence on lung repair and regenerative processes independent of acute inflammation from IAV. Here, we demonstrate for the first time that lung organoids have a functional clock as they mature and that the absence of an intact circadian clock impairs regenerative capacity. Using several models of circadian disruption, we show that with the absence of an intact clock lung proliferation is disrupted. Further, we find that the circadian clock acts through direct control of the Wnt/{beta}-catenin pathway. We speculate, that adding the circadian dimension to the critical process of lung repair and regeneration will lead to novel therapies and improve outcomes. Finally, we use data from UK Biobank to demonstrate at the population level, the role of poor circadian rhythms in mediating negative outcomes following lung infection.

cell biology↗

bioRxiv2021

Microstructured hydrogels to guide self-assembly and function of lung alveolospheres

Epithelial cell organoids have increased opportunities to probe questions on tissue development and disease in vitro and for therapeutic cell transplantation. Despite their potential, current protocols to grow these organoids almost exclusively depend on culture within three-dimensional (3D) Matrigel, which limits defined culture conditions, introduces animal components, and results in heterogenous organoids (i.e., shape, size, composition). Here, we describe a method that relies on polymeric hydrogel substrates for the generation and expansion of lung alveolar organoids (alveolospheres). Using synthetic hydrogels with defined chemical and physical properties, human induced pluripotent stem cell (iPSC)-derived alveolar type 2 cells (iAT2s) self-assemble into alveolospheres and propagate in Matrigel-free conditions. By engineering pre-defined microcavities within these hydrogels, the heterogeneity of alveolosphere size and structure was reduced when compared to 3D culture while maintaining alveolar type 2 cell fate of human iAT2 and primary mouse tissue-derived progenitor cells. This hydrogel system is a facile and accessible culture system for the culture of primary and iPSC-derived lung progenitors and the method could be expanded to the culture of other epithelial progenitor and stem cell aggregates.

bioengineering↗

bioRxiv2021

Metabolic and Proteomic Defects in Human Hypertrophic Cardiomyopathy

RationaleImpaired cardiac energetics in hypertrophic cardiomyopathy (HCM) is thought to result from increased ATP utilization at the sarcomere and is believed to be central to pathophysiology. However, the precise defects in cardiac metabolism and substrate availability in human HCM have not been defined. ObjectiveThe purpose of this study is to define major disease pathways and determine the pool sizes of intermediary metabolites in human HCM. Methods and ResultsWe conducted paired proteomic and metabolomic analyses of septal myectomy samples from patients with HCM and compared results to non-failing control human hearts. Increased abundance of extracellular matrix and intermediate filament / Z-disc proteins, and decreased abundance of proteins involved in fatty acid oxidation and cardiac energetics was evident in HCM compared to controls. Acyl carnitines, byproducts of fatty acid oxidation, were markedly depleted in HCM samples. Conversely, the ketone body 3-hydroxybutyrate, lactate, and the 3 branched chain amino acids, were all significantly increased in HCM hearts, suggesting that they may serve as alternate fuel sources for the production of ATP. ATP, nicotinamide adenine dinucleotide (NADH), NADP and NADPH, and acetyl CoA were also severely depleted in HCM hearts. Based on measurements from human skinned muscle fibers, the magnitude of observed reduction in ATP content in the HCM hearts would be expected to decrease the rate of cross-bridge detachment, implying a direct effect of energy depletion on myofilament function that could contribute to diastolic dysfunction. ConclusionsHCM hearts display profound deficits in cardiac energetics, marked by depletion of fatty acid derivatives and compensatory increases in other metabolites that could serve as alternate fuel sources. These results lend support to the paradigm that energy depletion contributes to the pathophysiology of HCM and also have important therapeutic implications for the future design of metabolic modulators to treat HCM.

physiology↗

bioRxiv2019

Disease and phenotype relevant genetic variants identified from histone acetylomes in human hearts

Identifying genetic markers for heterogeneous complex diseases such as heart failure has been challenging, and may require prohibitively large cohort sizes in genome-wide association studies (GWAS) in order to demonstrate statistical significance1. On the other hand, chromatin quantitative trait loci (QTL), elucidated by direct epigenetic profiling of specific human tissues, may contribute towards prioritising variants for disease-association. Here, we captured non-coding genetic variants by performing enhancer H3K27ac ChIP-seq in 70 human control and end-stage failing hearts, mapping out a comprehensive catalogue of 47,321 putative human heart enhancers. 3,897 differential acetylation peaks (FDR < 0.05) pointed to recognizable pathways altered in heart failure (HF). To identify cardiac histone acetylation QTLs (haQTLs), we regressed out confounding factors including HF disease status, and employed the G-SCI test2 to call out 1,680 haQTLs (FDR < 0.1). A subset of these showed significant association to gene expression, either in cis (180), or through long range interactions (81), identified by Hi-C and Hi-ChIP performed on a subset of hearts. Furthermore, a concordant relationship was found between the gain or disruption of specific transcription factor (TF) binding motifs, inferred from alternative alleles at the haQTLs, associated with altered H3K27ac peak heights. Finally, colocalisation of our haQTLs with heart-related GWAS datasets allowed us to identify 62 unique loci. Disease-association for these new loci may indeed be mediated through modification of H3K27-acetylation enrichment and their corresponding gene expression differences.

genomics↗