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Leppek Group

Group leader

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Prof. Dr. rer. nat. Kathrin Leppek



Phone (Office): +49 228 287-51158
Phone (Lab): +49 228 287-51172
Fax: +49 228 287-16094

North Zone, Building B12
Ground Floor, Room EG-412

CV

Regulation of gene expression, the decision which proteins to make from an identical genome, is essential to specify cell types and tissues. Our lab focuses on how such regulation is executed through the ribosome and mRNA interactions and what the decisive molecular players are, particularly in context of the innate immune response.

The ribosome, one of life’s most ancient molecular machines, has recently been revealed to be an active regulator of gene expression. Ribosomes are not all identical in composition and do not translate all mRNAs equally: “specialized” ribosomes preferentially translate certain transcripts to diversify gene expression. It is poorly understood how ribosome components, proteins and ribosomal RNA (rRNA), mediate such selectivity. The regulatory capacity of rRNA in translation, one of the oldest molecules on earth, has long remained unexplored.

Our lab studies a fundamentally new mode of gene regulation by which rRNA regions exposed on the outer shell of the ribosome called rRNA expansion segments directly bind to selective transcripts to control mRNA- and species-specific translation (Leppek et al., 2020; Leppek, Byeon et al., 2021) and how rRNA-mRNA recognition patterns thereby diversify the proteome. Ribosomes have thereby evolved the ability to discriminate which proteins are made in a cell through selective translation via rRNA. We combine innovative RNA biochemistry and RNA-based technology development with model systems ranging from yeast to macrophages. Through this, our lab aims to decipher how rRNA-directed specialized translation – how ribosomes recognize, bind and translate selective mRNAs – shapes gene expression to understand the role of rRNA expansion segments on ribosomes in innate immune responses where customized translation may underlie dynamic cellular specification.

Regulation of gene expression, the decision which proteins to make from an identical genome, is essential to specify cell types and tissues. Our lab focuses on how such regulation is executed through the ribosome and mRNA interactions and what the decisive molecular players are, particularly in context of the innate immune response.

The ribosome, one of life’s most ancient molecular machines, has recently been revealed to be an active regulator of gene expression. Ribosomes are not all identical in composition and do not translate all mRNAs equally: “specialized” ribosomes preferentially translate certain transcripts to diversify gene expression. It is poorly understood how ribosome components, proteins and ribosomal RNA (rRNA), mediate such selectivity. The regulatory capacity of rRNA in translation, one of the oldest molecules on earth, has long remained unexplored.

Our lab studies a fundamentally new mode of gene regulation by which rRNA regions exposed on the outer shell of the ribosome called rRNA expansion segments directly bind to selective transcripts to control mRNA- and species-specific translation (Leppek et al., 2020; Leppek, Byeon et al., 2021) and how rRNA-mRNA recognition patterns thereby diversify the proteome. Ribosomes have thereby evolved the ability to discriminate which proteins are made in a cell through selective translation via rRNA. We combine innovative RNA biochemistry and RNA-based technology development with model systems ranging from yeast to macrophages. Through this, our lab aims to decipher how rRNA-directed specialized translation – how ribosomes recognize, bind and translate selective mRNAs – shapes gene expression to understand the role of rRNA expansion segments on ribosomes in innate immune responses where customized translation may underlie dynamic cellular specification.

Translation regulation through ribosomal RNA

Ribosomes have dramatically increased in size across eukaryotic evolution, due in part to less conserved sequence insertions called rRNA expansion segments (ESs) that “expand” rRNA on the outer ribosome shell. rRNA ESs neither contribute to nor interfere with rRNA’s essential role in peptide-bond formation, so why do they exist? And what do they do?

Since the 1970s, rRNA-directed binding of transcripts to start translation in prokaryotes has been a classic paradigm, but no such evidence exists in eukaryotes. Kathrin’s postdoc work revealed a so far undescribed mode of gene regulation by which rRNAs, particularly the enigmatic, exposed rRNA ESs, directly bind to specific transcripts to control their translation. Thereby, rRNA itself is a critical regulator of gene expression where rRNA ESs on the outer ribosome act as rRNA “tentacles” that precisely and directly recruit subsets of mRNAs for translation – a first direct regulatory role in translation identified for any rRNA region. The eukaryotic ribosome contains a multitude of distinct, unexplored ESs that all have different sequence and structure. Thus, there are many open questions about what other potential functions rRNA ESs on ribosomes may have in gene regulation. In addition, we view ribosome-regulation through the lens of the innate immune response of macrophages.

Development of versatile RNA-centric technologies and ribosome engineering

We continue to develop and use tailored RNA-based technologies such as RNA aptamer-based affinity purification (4xS1m) to understand RNA-protein interactions (Leppek, Stoecklin, 2014; Leppek et al., 2013). We are also advancing our recent VELCRO-IP (variable expansion segment-ligand chimeric ribosome-IP) method, a ribosome purification and mRNA-interaction strategy that harnesses the interspecies evolutionary change in rRNA ES sequence to engineer chimeric ribosomes. This allows us to comprehensively define classes of mRNAs that bind to a species-specific rRNA region on the ribosome (Leppek, Byeon, 2021). Beyond, we strive to design and employ ribosome- and RNA-focused technologies to ask hard biological questions and with applications in basic science as well as RNA therapeutics (Leppek, Byeon, Kladwang, Wayment-Steele, Kerr et al., 2022).

 

Group Members

Martin Haimann, Master Student

Phone: +49 228 287-51172

Alina Niedzwetzki, Lab technician

Phone: +49 228 287-51172

Jobs available at the Leppek Group

PhD positions (m/f/d)

Contact:

We are always interested in recruiting highly motivated students and postdocs and thus encourage applications from prospective candidates at any time. Our lab is a growing, exciting, creative and inclusive place to mentor the next generation of scientists.

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