Biology subjects

Willi, M.

Publications and source records attributed to Willi, M..

3 recordsLinked to original sources

bioRxiv2023

Cell-specific and shared enhancers control a high-density multi-gene locus active in mammary and salivary glands

Regulation of high-density loci harboring genes with different cell-specificities remains a puzzle. Here we investigate a locus that evolved through gene duplication1 and contains eight genes and 20 candidate regulatory elements, including a super-enhancer. Five genes are expressed in mammary glands and account for 50% of all mRNAs during lactation, two are salivary-specific and one has dual specificity. We probed the function of eight candidate enhancers through experimental mouse genetics. Deletion of the super-enhancer led to a 98% reduced expression of Csn3 and Fdcsp in mammary and salivary glands, respectively, and Odam expression was abolished in both tissues. The other three casein genes were only marginally affected. Notably, super-enhancer activity requires the additional presence of a distal Csn3-specific enhancer. Our work identifies an evolutionary playground on which regulatory duality of a multigene locus was attained through an ancestral super-enhancer active in mammary and salivary tissue and gene-specific mammary enhancers.

genomics↗

bioRxiv2019

Cytosine but not adenine base editor generates mutations in mice

Deaminase base editing has emerged as a tool to install or correct point mutations in the genomes of living cells in a wide range of organisms and its ultimate success therapeutically depends on its accuracy. Here we have investigated the fidelity of cytosine base editor 4 (BE4) and adenine base editor (ABE) in mouse embryos using unbiased whole genome sequencing of a family-based trio cohort. We demonstrate that BE4-edited mice carry an excess of single-nucleotide variants and deletions compared to ABE-edited mice and controls.

genomics↗

bioRxiv2017

Assessing eRNAs associated with a cytokine-sensing mammary super-enhancer

Enhancers are transcription factor platforms that also bind RNA polymerase II and generate enhancer RNAs (eRNA). Although eRNAs have been suggested as predictors of enhancer activities and possibly key components facilitating transcription, there is little genetic evidence to support this. We address the biology of eRNAs in vivo and investigate eRNA patterns, expression levels and possible functions within a mammary-specific super-enhancer that is composed of three units with distinct transcriptional capacities. We show that eRNA levels do not correspond with the activities of their respective enhancer units. However, changes in eRNA expression upon deletion of individual enhancer units reflect the change in overall super-enhancer activity. These data provide genetic evidence that eRNA levels are not a reliable readout of individual enhancers, but they predict super-enhancer activity in the absence of constituent elements.

genetics↗