Biology subjects

Altorfer, M.

Publications and source records attributed to Altorfer, M..

4 recordsLinked to original sources

bioRxiv2025

Specificity and exon target space of splicing modifying compounds

Modulation of splicing has become an established therapeutic strategy, with proven clinical applications and continued potential to target specific exons to influence gene expression. Recent advancements led to the identification of small molecule splicing modifiers such as Risdiplam and Branaplam. These compounds induce the inclusion of exons that are typically skipped due to their weak 5' splice site. While Risdiplam has a preference to induce exons with a N-3G-2A-1 sequence at the 3' exon end, Branaplam has a proclivity towards introducing A-3G-2A-1 -ending exons. However, the variables that determine the selectivity and specificity of splicing modulators are still not completely understood, as evidenced by the hundreds of unaffected N-3G-2A-1 -ending exons present in the human genome. In this study, we delve into the molecular mechanisms governing the specificity of splicing-modifying compounds, focusing on their interactions with RNA structures at splice sites. Using biochemical assays, whole transcriptome analyses, and genetic perturbation approaches, our findings reveal contributions of primary sequence codependencies that help determine the required secondary structural conformation, thus governing responsiveness to splicing modulator induction. Based on these learnings, we were able to reprogram the specificity of splicing modulators by genetic manipulation of the U1 snRNA component of the spliceosome. Our findings further the understanding of splicing modulators and might help to identify new targets and compounds.

molecular biology↗

bioRxiv2025

Exercise-Induced Myostimulin Enhances Muscle Function in Health and Disease

Musculoskeletal diseases are a leading contributor to years lived with disability worldwide1,2. While exercise offers significant benefits for people with these conditions, many individuals do not engage in adequate physical activity3. Consequently, there is growing interest in pharmacological interventions that can emulate essential health-promoting effects of exercise4,5. By integrating transcriptomics data of exercised skeletal muscle, we identified C1orf54/C1ORF54 as a novel exercise-responsive gene in mice and humans. We demonstrate that removal of the first sixteen N-terminal amino acids of C1ORF54 gives rise to a previously uncharacterized protein that stimulates the proliferation of muscle precursor cells and which we named myostimulin. Intriguingly, repeated intermittent treatment of mice with recombinant myostimulin boosts maximal isometric strength in mice within a week. Moreover, we have engineered a variant with improved biophysical properties, increased biological activity in vitro and enhanced efficacy in vivo. This variant even accelerates the recovery of muscle strength from axonotmesis, a condition associated with pronounced muscle weakness. Our data ascribe to myostimulin a role for enhancing the regenerative capacity of skeletal muscle and mediating functional adaptations characteristic of sustained resistance training. Therefore, myostimulin could be an innovative, fast acting therapeutic for certain human musculoskeletal diseases, injuries and other disorders that improve with exercise.

physiology↗

bioRxiv2024

The transcription factor ZNF469 regulates collagen production in liver fibrosis

Non-alcoholic fatty liver disease (NAFLD) - characterized by excess accumulation of fat in the liver - now affects one third of the worlds population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis.

molecular biology↗

bioRxiv2023

Genome assembly of the bearded iris Iris pallida Lam.

Irises are perennial plants, representing a large genus with hundreds of species. While cultivated extensively for their ornamental value, commercial interest in irises lies in the secondary metabolites present in their rhizomes. The Dalmatian Iris (Iris pallida Lam.) is an ornamental plant that also produces secondary metabolites with potential value to the fragrance and pharmaceutical industries. In addition to providing base notes for the fragrance industry, iris tissues and extracts possess anti-oxidant, anti- inflammatory, and immunomodulatory effects. However, study of these secondary metabolites has been hampered by a lack of genomic information, instead requiring difficult extraction and analysis techniques. Here, we report the genome sequence of Iris pallida Lam., generated with Pacific Bioscience long-read sequencing, resulting in a 10.04 Gbp assembly with a scaffold N50 of 14.34 Mbp and 91.8% complete BUSCOs. This reference genome will allow researchers to study the biosynthesis of these secondary metabolites in much greater detail, opening new avenues of investigation for drug discovery and fragrance formulations. Research area: Genetics and Genomics; Botany; Plant Genetics

plant biology↗