Biology subjects

Lars M Steinmetz

Publications and source records attributed to Lars M Steinmetz.

3 recordsLinked to original sources

bioRxiv2016

Principles for RNA metabolism and alternative transcription initiation within closely spaced promoters

Mammalian transcriptomes are complex and formed by extensive promoter activity. In addition, gene promoters are largely divergent and initiate transcription of reverse-oriented promoter upstream transcripts (PROMPTs). Although PROMPTs are commonly terminated early, influenced by polyadenylation sites, promoters often cluster so that the divergent activity of one might impact another. Here, we find that the distance between promoters strongly correlates with the expression, stability and length of their associated PROMPTs. Adjacent promoters driving divergent mRNA transcription support PROMPT formation, but due to polyadenylation site constraints, these transcripts tend to spread into the neighboring mRNA on the same strand. This mechanism to derive new alternative mRNA transcription start sites (TSSs) is also evident at closely spaced promoters supporting convergent mRNA transcription. We suggest that basic building blocks of divergently transcribed core promoter pairs, in combination with the wealth of TSSs in mammalian genomes, provides a framework with which evolution shapes transcriptomes.

Genomics↗

bioRxiv2015

Meiotic interactors of a mitotic gene TAO3 revealed by functional analysis of its rare variant

Studying the molecular consequences of rare genetic variants has the potential of identifying novel and hereto uncharacterized pathways causally contributing to phenotypic variation. Here we characterize the functional consequences of a rare coding variant of TAO3, previously reported to significantly contribute to sporulation efficiency variation in Saccharomyces cerevisiae. During mitosis TAO3 interacts with CBK1, a conserved NDR kinase and a component of RAM network. The RAM network genes are involved in regulation cell separation and polarization. We demonstrate that the role of the rare allele TAO3(4477C) in meiosis is distinct from its role in mitosis by being independent of ACE2, which is a RAM network target gene. By quantitatively measuring cell morphological dynamics and conditionally expressing TAO3(4477C) allele during sporulation, we show that TAO3 has an early role in meiosis. This early role of TAO3 coincides with entry of cells into meiotic division. Time-resolved transcriptome analyses during early sporulation phase identified regulators of carbon and lipid metabolic pathways as candidate mediators. We experimentally show that during sporulation the TAO3 allele genetically interacts with ERT1 and PIP2, the regulators of tricarboxylic acid cycle and gluconeogenic enzymes, respectively. We thus uncover meiotic functions of TAO3, a mitotic gene and propose ERT1 and PIP2 as novel regulators of sporulation efficiency. Our results demonstrate that study of causal effects of genetic variation on the underlying molecular network has the potential to provide more extensive comprehension of the pathways driving a complex trait. This can help identify prospective personalized targets for intervention in complex diseases.

Genetics↗

bioRxiv2013

Mutated SF3B1 is associated with transcript isoform changes of the genes UQCC and RPL31 both in CLLs and uveal melanomas

BackgroundGenome sequencing studies of chronic lympoid leukemia (CLL) have provided a comprehensive overview of recurrent somatic mutations in coding genes. One of the most intriguing discoveries has been the prevalence of mutations in the HEAT-repeat domain of the splicing factor SF3B1. A frequently observed variant is predicted to cause the substitution of a lysine with a glutamic acid at position 700 of the protein (K700E). However, the molecular consequences of the mutations are largely unknown.\n\nResultsTo start exploring this question, we sequenced the transcriptomes of six samples: four samples of CLL tumour cells, of which two contained the K700E mutation in SF3B1, and CD19 positive cells from two healthy donors. We identified 41 genes that showed differential usage of exons statistically associated with the mutated status of SF3B1 (false discovery rate of 10%). These genes were enriched in pathways related to interferon signaling and mRNA splicing.\n\nAmong these genes, we found UQCC and RPL31; notably, a similar effect on these genes was described in a previously published study of uveal melanoma. In addition, while this manuscript was under revision, another study independently reported the common splicing signature of the gene UQCC in different tumour types with mutations in SF3B1.\n\nConclusionsOur results suggest common effects of isoform deregulation in the genes UQCC and RPL31 upon mutations in SF3B1. Additionally, our data provide a candidate list of potential isoform consequences of the SF3B1 (K700E) mutation in CLL, some of which might contribute to the tumourigenesis.\n\nValidation studies on larger cohorts and model systems are required to extend these findings.

Cancer Biology↗