Biology subjects

Bartlett, T. E.

Publications and source records attributed to Bartlett, T. E..

4 recordsLinked to original sources

bioRxiv2024

Inferring gene regulatory networks using DNA methylation data

We show improved accuracy in-silico of inference of gene-regulatory network (GRN) structure, resulting from the use of an epigenomic prior network. We demonstrate important use-cases of our proposed methodology by re-analysing 12 datasets from 12 different studies. These include data from cells from human embryos, healthy adult tissue, and cancer, and include single-cell mRNA sequencing data, DNA methylation (DNAme) data, chromatin accessibility data, and histone modification data. We find that DNAme data are very effective for inferring the epigenomic prior network, recapitulating known epigenomic network structure found previously from chromatin accessibility data. Furthermore, we find that inferring the epigenomic prior network from DNAme data reveals candidate TF cis-regulations for at least eight times as many genes, when compared with chromatin accessibility data. When our proposed methodology is applied to real datasets from human embryonic development and from women at risk of breast cancer, we find patterns of differential cis-regulation that are in line with expectations under appropriate biological models, and that may be used to propose hypotheses about pre-cancerous epigenomic changes.

genomics↗

bioRxiv2023

MICA: A multi-omics method to predict gene regulatory networks in early human embryos

Recent advances in single-cell-omics have been transformative to characterise cell types in challenging to study biological contexts. It is technically difficult to infer transcription factor-gene regulatory interactions from these datasets, especially in contexts with limited single-cell sample number such as the early human embryo. Here we systematically assessed the application of four different linear or non-linear gene regulatory network (GRN) prediction strategies to single-cell simulated and human embryo transcriptome datasets. We also compared how gene expression normalisation methods impact on regulatory network predictions, finding that TPM (transcripts per million reads) outperformed alternative methods. We identified more reproducible GRN inferences using a non-linear method based on mutual information (MI) applied to single-cell transcriptome datasets refined with chromatin accessibility (CA) (called MICA), compared to alternative network prediction methods tested. MICA captures complex non-monotonic dependencies and feedback loops. Using MICA, we generated the first GRN inferences in early human development. MICA predicted co-localisation of the AP-1 transcription factor subunit proto-oncogene JUND and the TFAP2C transcription factor AP-2{psi} in human preimplantation embryos. These interactions were supported by previous findings in other developmental and stem cell contexts. Overall, our comparative analysis of gene regulatory network prediction methods defines a pipeline that can be applied to single-cell multi-omics datasets in especially challenging contexts to infer interactions between transcription factor expression and target gene regulation.

developmental biology↗

bioRxiv2021

Fusion of single-cell transcriptome and DNA-binding data, for genomic network inference in cortical development

BackgroundNetwork models are well-established as very useful computational-statistical tools in cell biology. However, a genomic network model based only on gene expression data can, by definition, only infer gene co-expression networks. Hence, in order to infer gene regulatory patterns, it is necessary to also include data related to binding of regulatory factors to DNA. ResultsWe propose a new dynamic genomic network model, for inferring patterns of genomic regulatory influence in dynamic processes such as development. Our model fuses experiment-specific gene expression data with publicly available DNA-binding data. The method we propose is computationally efficient, and can be applied to genome-wide data with tens of thousands of transcripts. Thus, our method is well suited for use as an exploratory tool for genome-wide data. We apply our method to data from human fetal cortical development, and our findings confirm genomic regulatory patterns which are recognised as being fundamental to neuronal development. ConclusionsOur method provides a mathematical/computational toolbox which, when coupled with targeted experiments, will reveal and confirm important new functional genomic regulatory processes in mammalian development.

bioinformatics↗

bioRxiv2021

Inference of tissue relative proportions of the breast epithelial cell types luminal progenitor, basal, and luminal mature

Single-Cell Analysis has revolutionised genomic science in recent years. However, due to cost and other practical considerations, single-cell analyses are impossible for studies based on medium or large patient cohorts. For example, a single-cell analysis usually costs thousands of euros for one tissue sample from one volunteer, meaning that typical studies using single-cell analyses are based on very few individuals. While single-cell genomic data can be used to examine the phenotype of individual cells, cell-type deconvolution methods are required to track the quantities of these cells in bulk-tissue genomic data. Hormone receptor negative breast cancers are highly aggressive, and are thought to originate from a subtype of epithelial cells called the luminal progenitor. In this paper, we show how to quantify the number of luminal progenitor cells as well as other epithelial subtypes in breast tissue samples using DNA and RNA based measurements. We find elevated levels of cells which resemble these hormone receptor negative luminal progenitor cells in breast tumour biopsies of hormone receptor negative cancers, as well as in healthy breast tissue samples from BRCA1 (FANCS) mutation carriers. We also find that breast tumours from carriers of heterozygous mutations in non-BRCA Fanconi Anaemia pathway genes are much more likely to be hormone receptor negative. These findings have implications for understanding hormone receptor negative breast cancers, and for breast cancer screening in carriers of heterozygous mutations of Fanconi Anaemia pathway genes.

bioinformatics↗