Herrmann, J. C. | bioRxiv Science

bioRxiv2024

Deciphering cis-regulatory elements using REgulamentary

With the boom in Genome-Wide Association Studies (GWAS), it has become apparent that many disease-associated genetic variants lie in the non-coding regions of the genome. In order to prioritise these variants and disentangle their functional significance, it is important to be able to accurately classify cis-regulatory elements within these non-coding regions of the genome. Historically, the classification of cis-regulatory elements relied purely on the presence of characteristic histone marks, with recent advancements in their classification using more sophisticated Hidden Markov Model (HMM)-based approaches. The limitation of the HMM-based approaches is that the output of these models is an arbitrary chromatin state, which then requires the user to manually assign these states to a particular class of cis-regulatory elements. Here we present a new tool, REgulamentary, which enables de novo genome-wide annotation of cis-regulatory elements in a cell-type specific manner. We benchmarked REgulamentary against GenoSTAN, the most popular existing published chromatin annotation and regulatory element identification tool, to demonstrate the advancements REgulamentary can provide in assigning chromatin states. Finally, as an example of REgulamentarys utility in solving complex disease trait loci, we applied REgulamentary to published GWAS data to demonstrate how this tool can be used to prioritise likely causal variants.

bioinformatics↗

bioRxiv2023

A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

The frequent acquisition of genomic abnormalities in human preimplantation embryos is a leading cause of pregnancy loss, but does not necessarily prohibit healthy offspring. However, the impact of genomic abnormalities on cellular states and development of the early human embryo remains largely unclear. Here, we characterise aneuploidy and reconstruct gene regulatory networks in human preimplantation embryos, and investigate gene expression and developmental perturbations instigated by aneuploidy using single-cell genome-and-transcriptome sequencing (G&T-seq). At the genomic level, we show that acquired numerical and structural chromosomal aberrations are frequent across all stages of early embryogenesis and in all cell lineages. At the transcriptome level, we identify regulators of cell identity and uncover a network of 248 transcription factors from 10 major gene regulatory modules that characterise the distinct lineages of human preimplantation embryos. By integrating single-cell DNA-with RNA-information, we unveil how expression levels are affected by losses or gains of the corresponding genes in embryonic cells across human preimplantation development, as well as how copy-number aberrant transcription factor genes perturb the expression of their cognate target genes in euploid regions. Furthermore, we reveal a majority of aneuploid cells show a developmental delay and reduced fitness, indicating cell competition within the mosaic diploid-aneuploid embryo, which may contribute to selection against aneuploid cells and the birth of healthy offspring from mosaic diploid-aneuploid embryos. In summary, our multi-modal analyses provide unprecedented insights into early human embryo development.

developmental biology↗