Our main focus is to characterize the role of RNA-based mechanisms of epigenetic inheritance during animal development and upon environmental changes.
One of the paradox in developmental biology is the observation that a multicellular organism is composed of many different cell types all having an identical genome. Similarly, the adaptation of genetically identical organisms to different environmental conditions imply that the genetic information alone is not sufficient to explain these fundamental biological processes. Indeed, in eukaryotes, the genetic information is highly organized in the nucleus in the form of chromatin, which can be modified by hundreds of chemical modifications without alteration in DNA sequence. This may constitute an additional layer of information,
called epigenetic information. Therefore, from one given genome different configurations of the chromatin may occur, and this will lead to the existence of multiple epigenomes.
The mechanisms responsible for the specific modification of chromatin, also known as epigenetic mechanisms, are considered to be central to the development of multicellular organisms. Extensive research over the past two decades has been focused on the characterization of the molecular mechanisms responsible for epigenetic chromatin modifications in different cells types and organisms and on studying their roles in regulating gene expression. Yet, the molecular mechanisms regulating how epigenetic traits can be inherited during cell division or across generations are not fully understood. However, in recent years, it is becoming apparent that RNAs also play a fundamental role in epigenetic processes. Therefore, RNAs are the appealing candidate molecules to propagate epigenetic information.
RNA play important roles in epigenetic regulation, and many RNAs are nuclear and chromatin-associated
The protein-coding portion of the genome represents only a small fraction of it (in humans less than 3%), but most of the genome produce RNAs
Among many different kinds of non-coding RNAs (ncRNAs), small interfering RNAs (siRNAs) play a major role in regulating gene activity and are heritable and act in a sequence-specific manner
Argonaute proteins and their associated siRNAs also localize in the nucleus
In our lab we are investigating the role of small interfering RNAs (siRNAs) and RNA interference (RNAi) in epigenetic inheritance.
The initial discovery of RNAi in the nematode Caenorhabditis elegans, as well as the characterization of different classes of small RNAs, has radically changed the way we think about the role of RNA in gene regulation in eukaryotes. All RNAi-related small RNAs exist in complexes with conserved proteins of the Argonaute family. The molecular function of small RNAs is in providing sequence-specific recognition of target RNAs, which is followed by a silencing step. Indeed, most of the Argonaute proteins and their small RNA co-factors are mainly known to inhibit gene expression by a variety of mechanisms, which include inhibition of mRNA translation, mRNA or pre-mRNA degradation, and inhibition of transcription by promoting heterochromatin assembly. Surprisingly, nuclear Argonaute proteins also localize on active euchromatic regions of metazoan genomes, including humans, and their functions on these active loci still remain largely unknown (for a review click here).
mRNA target recognition
- Transcriptional regulation?
- Chromatin organization? - Epigenetic inheritance?
We have recently revealed that euchromatin-associated Argonaute protein and its bound small RNAs participate in global transcriptional regulation and chromatin organization, and contribute to the inheritance of the proper epigenetic landscape (you can read the paper here). This unprecedented observation opened up a new class of molecular mechanisms by which Argonaute proteins and their bound small RNAs may actively contribute to epigenetic inheritance of euchromatic regions in animals.
We are currently testing the hypotesis that small RNAs and euchromatin-associated Argonaute proteins constitue an RNA-based system for propagating the memory of transcriptionally active genes across generations. We plan to integrate genetic, biochemical, and molecular biology tools with high-throughput genomic and proteomic approaches to achieve a deep mechanistic understanding of the role of Argonaute-bound small RNAs in epigenetic inheritance in animals, using C. elegans as a model system.
Further reading on RNAi, Argonaute proteins, and small RNAs: