Biology subjects

Fink, S.

Publications and source records attributed to Fink, S..

3 recordsLinked to original sources

bioRxiv2025

Combinatorial effects of multiple genes contribute to beneficial aneuploidy phenotypes

Aneuploidy is one of the most common adaptive mechanisms to environmental selection in cells, yet its advantages over other genomic alterations remain unclear. We used budding yeast to determine if beneficial aneuploidy phenotypes are driven primarily by combinatorial expression changes of multiple genes. To determine the impact of complex aneuploidy on cellular fitness and drug resistance, we generated yeast collections with nearly every combination of two chromosome gains or losses. Additionally, we genetically dissected aneuploid chromosomes using partial deletions to identify chromosomal regions contributing to aneuploidy-driven drug resistance. Strong resistance phenotypes consistently came from combinations of chromosomes or chromosomal regions, with up to five regions on a chromosome contributing to resistance to a single drug. Gene ontology terms had limited predictive power in identifying the genes contributing to resistance phenotypes, as the combinatorial effects from different aneuploid regions act through multiple resistance pathways. The strongest phenotypes came from synergistic effects between copy number changes of different chromosomes or chromosomal regions, demonstrating how subtle gene expression changes of many genes combine to greatly impact cell survival.

genetics↗

bioRxiv2024

Identification of small molecule agonists of fetal hemoglobin expression for the treatment of sickle cell disease

Induction of fetal hemoglobin (HbF) has been shown to be a viable therapeutic approach to treating sickle cell disease and potentially other {beta}-hemoglobinopathies. To identify targets and target-modulating small molecules that enhance HbF expression, we engineered a human umbilical-derived erythroid progenitor reporter cell line (HUDEP2_HBG1_HiBiT) by genetically tagging a HiBiT peptide to the carboxyl (C)-terminus of the endogenous HBG1 gene locus, which codes for {gamma}-globin protein, a component of HbF. Employing this reporter cell line, we performed a chemogenomic screen of approximately 5000 compounds annotated with known targets or mechanisms that have achieved clinical stage or approval by the US Food and Drug Administration (FDA). Among them, 10 compounds were confirmed for their ability to induce HbF in the HUDEP2 cell line. These include several known HbF inducers, such as pomalidomide, lenalidomide, decitabine, idoxuridine, and azacytidine, which validate the translational nature of this screening platform. We identified avadomide, autophinib, triciribine, and R574 as novel HbF inducers from these screens. We orthogonally confirmed HbF induction activities of the top hits in both parental HUDEP2 cells as well as in human primary CD34+ hematopoietic stem and progenitor cells (HSPCs). Further, we demonstrated that pomalidomide and avadomide, but not idoxuridine, induced HbF expression through downregulation of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. These studies demonstrate a robust phenotypic screening workflow that can be applied to large-scale small molecule profiling campaigns for the discovery of targets and pathways, as well as novel therapeutics of sickle cell disease and other {beta}-hemoglobinopathies. Key PointsO_LIEstablished a robust HbF luciferase reporter cell line to monitor endogenous {gamma}-globin expression for a chemogenomic screen of compounds for the treatment of sickle cell disease. C_LIO_LILead hit compounds were mechanistically confirmed for their ability to decrease expression of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. C_LI Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/601536v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@7f86f6org.highwire.dtl.DTLVardef@75b613org.highwire.dtl.DTLVardef@49fc9org.highwire.dtl.DTLVardef@196472e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Lithic bacterial communities: ecological aspects focusing on Tintenstrich communities

Tintenstrich communities (TC) are mainly composed by Cyanobacteria developing on the rock substrate and forming physical structures strictly connected to the rock itself. Endolithic and epilithic bacterial communities are important because they contribute to nutrients release within run-off waters flowing on the rock surface. Despite them being ubiquitous, little information about their ecology and main characteristics is available. In this paper, we characterized the bacterial communities of rock surfaces of TC in Switzerland through Illumina sequencing and investigated their bacterial community composition on two substrate types (silicious and limestone rocks) through multivariate models. Our results show that Cyanobacteria and Proteobacteria are the predominant phyla in this environment. Bacterial alpha diversity was higher on limestone than on siliceous rock, and beta diversity of siliceous rock varied with changes in rock surface structure. Here we provide novel insights into the bacterial community composition of TC, their differences from other lithic communities, and the effects of the rock substrate and structure.

microbiology↗