- Post Doctoral Fellow, Cold Spring Harbor Laboratory, 2007-2015
- Graduate Student, Friedrich Miescher Institute for Biomedical Research, 2002-2007
- Ph.D., University of Basel, Switzerland, 2007
- M.D., University of Vienna, Austria, 2002
We aim to understand how small non-coding RNAs guard genomic integrity.
Small non-coding RNAs play crucial roles in development and disease. Globally referred to as RNA interference (RNAi), conserved small RNA pathways operate from yeast to human. They regulate gene expression, defend against viruses and control repetitive genetic elements. Additionally, their elegant mechanisms are widely harnessed for biotechnology and targeted therapy.
Our group studies a particular class of small RNAs that represses transposon activity in the germline. The ability of transposons to mobilize and insert into new genomic locations threatens genomic integrity and must be suppressed. Integrity of genomic information is particularly important in germ cells that determine the genetic make-up of a species. Therefore germ cells employ specialized small RNA pathways -PIWI proteins and PIWI-interacting RNAs (piRNAs)- to silence transposons and thus ensure genomic stability and fertility in animals. Mature piRNAs guide their associated PIWI complexes to silence transposons at transcriptional or post-transcriptional levels, directing chromatin modifications or promoting RNA decay.
We aim to elucidate molecular mechanisms of piRNA silencing through an integrated approach combining Drosophila genetics, biochemistry and next-generation sequencing. While recent advances have provided a framework for what resembles a small RNA-based immune system, further studies are required to elucidate the many molecular innovations that enable discrimination of transposons from host genes and efficient selective silencing of genetic mobility. Successfully meeting our goals will bolster our understanding of fundamental mechanisms that survey and guard genomic integrity.
Applying our Research
Genome integrity is essential for cellular and organismal fitness and is lost in various diseases including cancer. Insights into the molecular mechanisms of small RNA-guided genome defense will further our understanding of genome surveillance, and will inspire novel biomedical approaches to combat genomic instability in diseases. Additionally, mechanisms of RNA interference have been successfully harnessed for biotechnology and targeted therapy over the past years, and novel insights into piRNA pathways will enlarge our molecular repertoire.
Need for Further Study
Small regulatory RNAs have been discovered in all branches of life but we are just beginning to understand their diverse functions in gene regulation and genome surveillance. Further studies are required to characterize these regulatory pathways and to elucidate their molecular mechanisms.
- Aberrant expression of select piRNA-pathway genes does not reactivate piRNA silencing in cancer cells.
- Genzor P, Cordts SC, Bokil NV, Haase AD.
- Proc Natl Acad Sci U S A (2019 Jun 4) 116:11111-11112. Abstract/Full Text
- Decoding the 5' nucleotide bias of PIWI-interacting RNAs.
- Stein CB, Genzor P, Mitra S, Elchert AR, Ipsaro JJ, Benner L, Sobti S, Su Y, Hammell M, Joshua-Tor L, Haase AD.
- Nat Commun (2019 Feb 19) 10:828. Abstract/Full Text
Research in Plain Language
Genomes are massive databases that tell the body how to create cells, tissues, and organs. It is important to protect these databases and make sure that the genes within them keep their integrity. This is essential for fertility in animals and the survival of each species. Additionally, loss of genomic integrity has been observed in many diseases including cancer.
To protect these databases, the body uses various kinds of molecular guards. Our group studies a particular class of molecular guards that protect germ cells. Little is known about their elaborate surveillance system and defense strategies. We aim to generate valuable knowledge of how these databases are maintained.