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Biology subjects

Oser, M.

Publications and source records attributed to Oser, M..

2 recordsLinked to original sources

Regulation of Neuroendocrine Plasticity by the RNA-Binding Protein ZFP36L1

Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 inhibitors are thought to induce their anti-proliferative effects by blocking neuroendocrine differentiation, but the mechanisms by which LSD1 controls the SCLC neuroendocrine phenotype are not well understood. To identify genes required for LSD1 inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss of function screen and found that ZFP36L1, an mRNA-binding protein that destabilizes mRNAs, is required for LSD1 inhibitor sensitivity. LSD1 binds and represses ZFP36L1 and upon LSD1 inhibition, ZFP36L1 expression is restored, which is sufficient to block the SCLC neuroendocrine differentiation phenotype and induce a non-neuroendocrine "inflammatory" phenotype. Mechanistically, ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs, two transcription factors that are required for SCLC neuroendocrine differentiation. This work identifies ZFP36L1 as an LSD1 target gene that controls the SCLC neuroendocrine phenotype and demonstrates that modulating mRNA stability of lineage transcription factors controls neuroendocrine to non-neuroendocrine plasticity.

cancer biology↗

Variation in genome context and predatory phenotypes between Bdellovibrio sp. NC01 isolated from soil and B. bacteriovorus type strain HD100

The range of naturally occurring variation in the ability of Bdellovibrio strains to attack and kill Gram-negative bacteria is not well understood. Defining phenotypic and associated genotypic variation among Bdellovibrio will clarify how divergent lineages within this genus impact microbial communities and will inform development of predatory bacteria as biocontrol agents to combat bacterial infections. We isolated Bdellovibrio sp. NC01 from soil and compared its genome and predatory phenotypes to B. bacteriovorus type strain HD100. Based on analysis of 16S rRNA gene sequences and average amino acid identity, NC01 belongs to a different species than HD100. Genome-wide comparisons and individual gene analyses indicated that eight NC01 genome regions were likely acquired by horizontal gene transfer (HGT), further supporting an important role for HGT in Bdellovibrio genome evolution. Within these regions, multiple protein-coding sequences were assigned predicted functions related to transcriptional regulation and transport; however, most were annotated as hypothetical proteins. Compared to HD100, NC01 has a limited prey range and kills E. coli ML35 less efficiently. Whereas HD100 drastically reduces the ML35 population and then maintains low prey population density, NC01 causes a smaller reduction in ML35, after which the prey population recovers, accompanied by a decrease in NC01. In addition, NC01 forms turbid plaques on lawns of ML35, in contrast to clear plaques formed by HD100. Characterizing variation in interactions between Bdellovibrio and Gram-negative bacteria, such as observed with NC01 and HD100, is important for understanding the ecological significance of predatory bacteria and evaluating their effectiveness in clinical applications. ImportanceBdellovibrio attack and kill Gram-negative bacteria; however, not all Bdellovibrio strains are equally efficient at killing the same Gram-negative bacteria. Defining how Bdellovibrio vary in predatory phenotypes and how this phenotypic variation relates to differences in genotype is important for understanding the ecological significance of predatory bacteria and evaluating their effectiveness in biocontrol of bacterial infections. We determined variation in genome content and predatory phenotypes, including prey range and predation efficiency, between Bdellovibrio sp. NC01 isolated from soil and B. bacteriovorus type strain HD100. NC01 is phylogenetically divergent from HD100, with eight regions of unique gene content likely acquired by horizontal gene transfer. Compared to HD100, the prey range of NC01 is limited, and it was less efficient at killing a strain of E. coli. These differences may have important implications for how each strain impacts microbial communities in different environments and for the effectiveness of each in clinical applications.

microbiology↗