Biology subjects

Bernhart, S. H.

Publications and source records attributed to Bernhart, S. H..

4 recordsLinked to original sources

bioRxiv2021

Spatio-temporal Coordination of Transcription During the Cell Growth Cycle in Budding Yeast.

Metabolic oscillations are characterized by alternating phases of high and low respiratory activity, associated with transcription of genes involved in biosynthetic pathways and growth, and in catabolism and stress response. However, the functional consequences of transcriptome oscillations remain unclear, since most proteins are too stable to be affected by oscillatory transcript abundances. In this work, we investigate a transcriptome time series during an unstable state of the oscillation. Our analyses confirm previous suggestions that the relative times spent in the alternative transcription states are coupled to growth rate. This pulse-width modulation of transcription provides a simple mechanism for the long-standing question of how cells adjust their ribosome content and growth rate to environmental conditions. A mathematical model of this idea reproduces both the almost linear relation of transcript and protein abundances and the non-linear relation of oscillation periods to growth rate.

cell biology↗

bioRxiv2021

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

Despite its prominence, the mechanisms through which the tumor suppressor p53 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three distinct cell systems reveals that RFX7 directly controls multiple established tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the missing link for their activation in response to p53 and stress. RFX7 target gene expression correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work establishes RFX7s role as a ubiquitous regulator of cell growth and fate determination and a key node in the p53 transcriptional program.

genomics↗

bioRxiv2020

The failure of B cells to induce non-canonical MYD88 splice variants correlates with lymphomagenesis via sustained NF-κB signaling

Gain-of-function mutations of the TLR adaptor and oncoprotein MyD88 drive B cell lymphomagenesis via sustained NF-{kappa}B activation. In myeloid cells, sustained TLR activation and NF-{kappa}B activation lead to the induction of inhibitory MYD88 splice variants that restrain prolonged NF-{kappa}B activation. We therefore sought to investigate whether such a negative feedback loop exists in B cells. Analyzing MYD88 splice variants in normal B cells and different primary B cell malignancies, we observed that MYD88 splice variants in transformed B cells are dominated by the canonical, strongly NF-{kappa}B-activating isoform of MYD88 and contain at least three novel, so far uncharacterized signaling-competent splice isoforms. TLR stimulation in B cells unexpectedly reinforces splicing of NF-{kappa}B-promoting, canonical isoforms rather than the MyD88s, a negative regulatory isoform that is typically induced by TLRs in myeloid cells. This suggests that an essential negative feedback loop restricting TLR signaling in myeloid cells at the level of alternative splicing, is missing in B cells, rendering B cells vulnerable to sustained NF-{kappa}B activation and eventual lymphomagenesis. Our results uncover MYD88 alternative splicing as an unappreciated promoter of B cell lymphomagenesis and provide a rationale why oncogenic MYD88 mutations are exclusively found in B cells.

cancer biology↗

bioRxiv2019

Unbiased Map of Transcription Termination Sites in Haloferax volcanii reveals manifold termination patterns

Archaeal genomes are densely packed; thus, correct transcription termination is an important factor for orchestrated gene expression. A systematic analysis of RNA 3 termini, to identify transcription termination sites (TTS) using RNAseq data has hitherto only been performed in two archaea. In this study, only part of the genome had been investigated. Here, we developed a novel algorithm that allows an unbiased, genome-wide identification of RNA 3 termini independent of annotation. In an RNA fraction enriched for primary transcripts by terminator exonuclease (TEX) treatment we identified 1,543 RNA 3 termini. A strong sequence signature consistent with known termination events at intergenic loci indicates a clear enrichment for native TTS among them. Using these data we determined distinct putative termination motifs for intergenic (a T stretch) and coding regions (AGATC). In vivo reporter gene tests of selected TTS confirmed termination at these sites, which exemplify the different motifs. For several genes, more than one termination site was detected, resulting in transcripts with different lengths of the 3 untranslated region.

molecular biology↗