Biology subjects

Schneider-Lunitz, V.

Publications and source records attributed to Schneider-Lunitz, V..

2 recordsLinked to original sources

bioRxiv2020

Trans control of cardiac mRNA translation in a protein length-dependent fashion

Little is known about the impact of naturally occurring genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate how genetic influences on mRNA translational efficiency are associated with complex disease phenotypes using a panel of rat recombinant inbred lines. We identify a locus for cardiac hypertrophy that is associated with a translatome-wide and protein length-dependent shift in translational efficiency. This master regulator primarily affects the translation of very short and very long protein-coding sequences, altering the physiological stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus points to altered ribosome assembly, characterized by accumulation of polysome half-mers, changed ribosomal configurations and misregulation of the small nucleolar RNA SNORA48. We postulate that this locus enhances a pre-existing negative correlation between protein length and translation initiation in diseased hearts. Our work shows that a single genomic locus can trigger a complex, translation-driven molecular mechanism that contributes to phenotypic variability between individuals. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/133298v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@e46986org.highwire.dtl.DTLVardef@1cc0b08org.highwire.dtl.DTLVardef@e86011org.highwire.dtl.DTLVardef@1fb3706_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIGenetic variability impacts protein synthesis rates in a rat model for cardiac hypertrophy C_LIO_LIA trans locus affects stoichiometric translation rates of cardiac sarcomeric proteins C_LIO_LIThis master regulator locus induces a global, protein length-dependent shift in translation C_LIO_LIDysregulated ribosome assembly induces half-mer formation and affects translation initiation rate C_LI

genetics↗

bioRxiv2020

A functional screen of translated pancreatic lncRNAs identifies a microprotein-independent role for LINC00261 in endocrine cell differentiation

Long noncoding RNAs (lncRNAs) are a heterogenous group of RNAs, which can encode small proteins. The extent to which developmentally regulated lncRNAs are translated and whether the produced microproteins are relevant for human development is unknown. Here, we show that many lncRNAs in direct vicinity of lineage-determining transcription factors (TFs) are dynamically regulated, predominantly cytosolic, and highly translated during pancreas development. We genetically ablated ten such lncRNAs, most of them translated, and found that nine are dispensable for endocrine cell differentiation. However, deletion of LINC00261 diminishes generation of insulin+ endocrine cells, in a manner independent of the nearby TF FOXA2. Systematic deletion of each of LINC00261s seven poorly conserved microproteins shows that the RNA, rather than the microproteins, is required for endocrine development. Our work highlights extensive translation of lncRNAs into recently evolved microproteins during human pancreas development and provides a blueprint for dissection of their coding and noncoding roles. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/062679v1_ufig1.gif" ALT="Figure 1"> View larger version (96K): org.highwire.dtl.DTLVardef@10715caorg.highwire.dtl.DTLVardef@27af76org.highwire.dtl.DTLVardef@17083a6org.highwire.dtl.DTLVardef@1d31f9f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIExtensive lncRNA translation and microprotein production during human pancreas development C_LIO_LIA small-scale loss-of-function screen shows most translated lncRNAs are dispensable C_LIO_LILINC00261 is highly translated and regulates endocrine cell differentiation C_LIO_LIDeleting LINC00261s evolutionary young microproteins reveals no essential roles C_LI

developmental biology↗