Role of RNAi-mediated epigenetic mechanisms in early embryonic development
Epigenetic functions of RNAi.
In addition to their role in gene regulation, nuclear Argonaute proteins and their associated short RNAs may also have epigenetic functions. In fission yeast, a well-known nuclear function of RNAi is to promote the epigenetic inheritance of heterochromatic regions of the genome . Therefore, an exciting possibility is that euchromatin-localized Argonaute proteins and their associated short RNAs might play a role in propagating the epigenetic information associated with transcriptionally active genomic regions. In C. elegans, silent (H3K27me3) and active (H3K36me3) chromatin modifications are precisely defined across the genome (see figure below) and are epigenetically propagated in the embryo . We have shown that CSR-1 restricts the activity of Pol II to active genomic regions to avoid ectopic initiation of transcription of silent chromatin domains (3). Remarkably, the distinction between silent and active chromatin domains is lost in CSR-1 mutant embryos . Based on these observations, we proposed a model whereby CSR-1 22G-RNAs produced from the active locations of the genome reinforce germline transcription and help to propagate the distinction between active and silent chromatin domains during cell division.
from Cecere et al., 2014
Epigenetic functions of siRNAs at the beginning of life.
One exciting possibility is that the zygote inherits not only the genetic information but also a pre-organized epigenetic structure of the genome (epigenome), which might help the differentiation process at the beginning of life.
In C. elegans, embryonic transcription starts as early as the 4-cell stage embryo [4, 6], and the transcriptional status of the somatic and germline blastomeres is already defined at this early stage of embryogenesis [5, 6]. Although some transcriptional repressors are known to be involved in this process, little is known about the contribution of epigenetic factors in the regulation of early zygotic transcription.
We are currently testing the hypothesis that heritable siRNAs play a key role in the inheritance and propagation of the genome wide Pol II localisation and chromatin modifications in somatic and germline blastomeres.
New Hypothesis and directions:
- Multiple epigenomes contribute to the differential transcriptional status of the somatic and germline blastomeres at 4-cell stage of embryogenesis.
- Short RNAs act as an RNA-based epigenetic system for propagating the memory of active transcription during early embryonic development.
1. Buhler, M.; S.M. Gasser, EMBO J, 2009
2. Kelly, W.G., Epigenetics Chromatin, 2014
3. Cecere, G., et al., Nat Struct Mol Biol, 2014
4. Seydoux, G.; M.A. Dunn, Development, 1997
5. Seydoux, G.; A. Fire, Development, 1994
6. Seydoux, G., et al., Nature, 1996