Biology subjects

Liechti, A.

Publications and source records attributed to Liechti, A..

5 recordsLinked to original sources

bioRxiv2026

Allele-specific expression is associated with lower translational efficiency in mouse embryos and stem cells

An mRNA's cytoplasmic fate can be shaped by its transcriptional history, its modifications and associated protein complexes. Allele-specific expression (ASE), in which a gene's two alleles are transcribed unequally, provides a natural experiment given that the alleles can differ in sequence or chromatin state, yet their transcripts share the same cytoplasm. We previously found lower translational efficiency (TE) among genes with ASE in early mouse embryos. Because that observation came from one cross direction and from preimplantation stages only, sequence-dependent and parent-of-origin-dependent ASE could not be separated, and whether the association held in other cell types remained unknown. Here we addressed both by generating RNA sequencing and ribosome profiling data from reciprocal-cross mouse 8-cell embryos, individual embryonic stem cell clones, neural progenitor cells, and adult tissues. In 8-cell embryos, both sequence-dependent and parent-of-origin-dependent ASE were associated with lower TE. Genes with ASE at the 8-cell stage also had lower protein abundance at the subsequent morula stage. Ribo-ITP, which enables ribosome profiling from single clones, allowed assessing the relationship between ASE and TE in individual embryonic stem cell clones. We found that TE was lower wherever a gene was allelically imbalanced, and the reduction was larger where that imbalance was consistent across clones. The same association held in neural progenitors, and when ASE was defined from independent published datasets, but was not detected in adult tissues. Allelic imbalance in transcription is therefore accompanied by reduced translation of the resulting mRNAs, though the intermediate carrying allelic information to the translation machinery remains unidentified.

molecular biology↗

bioRxiv2025

The 18S rRNA methyltransferase, BUD23, is required for appropriate lipid and mitochondrial metabolism

Efficient energy metabolism is essential for health and its dysregulation drives cardiometabolic disease. Delivery of regulatory control through translation and ribosome function is emerging as important. Here, we identify the rRNA methyltransferase BUD23 as a potent regulator of cellular and systemic energy homeostasis. Adipocyte-specific deletion of BUD23 in mice regulates lipid and mitochondrial metabolism resulting in a pronounced lean phenotype and resistance to diet-induced obesity. Mechanistically, BUD23 modulates translation initiation and efficiency of mRNAs with specific features - including short 5 UTR length and GC-rich post-initiation codon usage - characteristic of mitochondrial and lipogenic proteins. Genetic analyses and Mendelian randomisation support a role for BUD23 in human cardiometabolic traits and disease burden. Together, our findings uncover a conserved translational control mechanism that regulates energy state, from cellular metabolism through to human cardiometabolic health.

cell biology↗

bioRxiv2023

Diurnal control of iron responsive element (IRE)-containing mRNAs through iron regular proteins IRP1 and IRP2 is mediated by feeding rhythms

BackgroundCellular iron homeostasis is regulated by iron regulatory proteins (IRP1 and IRP2) that sense iron levels (and other metabolic cues) and modulate mRNA translation or stability via interaction with iron regulatory elements (IREs). IRP2 is viewed as the primary regulator in liver, yet our previous datasets showing diurnal rhythms for certain IRE-containing mRNAs suggest a nuanced temporal control mechanism. The purpose of this study is to gain insights into the daily regulatory dynamics across IRE-bearing mRNAs, specific IRP involvement, and underlying systemic and cellular rhythmicity cues in mouse liver. ResultsWe uncover high-amplitude diurnal oscillations in the regulation of key IRE containing transcripts in liver, compatible with maximal IRP activity at the onset of the dark phase. Although IRP2 protein levels also exhibit some diurnal variations and peak at the light-dark transition, ribosome profiling in IRP2-deficient mice reveals that maximal repression of target mRNAs at this time-point still occurs. We further find that diurnal regulation of IRE-containing mRNAs can continue in the absence of a functional circadian clock as long as feeding is rhythmic. ConclusionsOur findings suggest temporally controlled redundancy in IRP activities, with IRP2 mediating regulation of IRE-containing transcripts in the light phase and redundancy, conceivably with IRP1, at dark onset. Moreover, we highlight the significance of feeding-associated signals in driving rhythmicity. Our work highlights the dynamic nature and regulatory complexity in a metabolic pathway that had previously been considered well-understood.

molecular biology↗

bioRxiv2022

A novel Smg6 mouse model reveals regulation of circadian period and daily CRY2 accumulation through the nonsense-mediated mRNA decay pathway

Nonsense-mediated mRNA decay (NMD) has been intensively studied as a surveillance pathway that degrades erroneous transcripts arising from mutations or RNA processing errors. While additional roles in controlling regular mRNA stability have emerged, possible functions in mammalian physiology in vivo have remained unclear. Here, we report a novel conditional mouse allele that allows converting the NMD effector nuclease SMG6 from wild-type to nuclease domain-mutant protein. We analyzed how NMD downregulation affects the function of the circadian clock, a system known to require rapid mRNA turnover. We uncover strong lengthening of free-running circadian periods for liver and fibroblast clocks, and direct NMD regulation of Cry2 mRNA, encoding a key transcriptional repressor within the rhythm-generating feedback loop. In the entrained livers of Smg6 mutant animals we reveal transcriptome-wide alterations in daily mRNA accumulation patterns, altogether expanding the known scope of NMD regulation in mammalian gene expression and physiology.

genetics↗

bioRxiv2018

Functional repurposing of regulatory element activity during mammalian evolution

The spatiotemporal control of gene expression exerted by promoters and enhancers is central for organismal development, physiology and behaviour. These two types of regulatory elements have long been distinguished from each other based on their function, but recent work highlighted common architectural and functional features. It also suggested that inheritable alterations in the epigenetic and sequence context of regulatory elements might underlie evolutionary changes of their principal activity, which could result in changes in the transcriptional profile of genes under their control or even facilitate the birth of new genes. Here, based on integrated cross-mammalian analyses of DNase hypersensitivity, chromatin modification and transcriptional data, we provide support for this hypothesis by detecting 449 regulatory elements with signatures of activity turnover in sister species from the primate and rodent lineages (termed \"P/E\" elements). Through the comparison with outgroup species, we defined the directionality of turnover events, which revealed that most instances represent transformations of ancestral enhancers into promoters, leading to the emergence of species-specific transcribed loci or 5 exons. Notably, P/E elements have distinct GC sequence compositions and stabilizing 5 splicing (U1) regulatory motif patterns, which may predispose them to functional repurposing during evolution. Moreover, we trace changes in the U1 and polyadenylation signal densities and distributions that accompanied and likely drove the evolutionary activity switches. Overall, our work suggests rather widespread evolutionary remodelling of regulatory element functions. Functional repurposing thus represents a notable mechanism that likely facilitated regulatory innovation and the origination of new genes and exons during mammalian evolution.

genomics↗