The main goal of our research is to uncover evolutionary-conserved mechanisms contributing to organismal development, cell identity and differentiation.
The overall aim of our research is to understand fundamental processes controlling cell identity and fate. We are interested in deciphering the role of histone methylation in these processes by studying the catalytic functions of enzymes (histone methyltransferases and demethylases) regulating histone methylation levels. To achieve our aims, we use genetic analyses combined with biochemical approaches.
Our Model System: C. elegans
C. elegans (Figure 1) is our favorite model system for several reasons. First, C. elegans is a simple multicellular organism and therefore provides an opportunity to study tissue-/organ-specific proteins without the complexity of higher eukaryotes. Second, it is a well-established system for genetic studies. Third, its life cycle is of few days, allowing rapid analyses over several generations. Finally, in C. elegans most of the chromatin regulating factors are conserved and gene families are often represented by single genes, allowing biological analyses in absence of functional redundancy.
C. elegans is an excellent system to study many aspects of neuronal development, including some that for their complexity are understudied in mammals, like axon guidance and neuronal cell body migration. Several genes involved specifically in H3K4 methylation regulation are mutated in Neurodevelopmental Disorders. Our recent results (Mariani et al, 2016, Riveiro et al, 2017, Abay-Nørgaard et al, 2020) indicate that H3K4 regulatory genes found mutated in Neurodevelopmental Disorders invariantly control axon guidance in nematode, pointing to a potential role of this neuronal developmental aspect in the etiology of the diseases.
Germ cell protection and integrity
With the aim to identify modulators of histone lysine methylation that play relevant roles in germline integrity, screens have been performed using a variety of stressors, including IR, UV and agents interfering with DNA replication. We recently discover a role for KDM8/JMJD-5, a regulator of H3K36me2, in germline protection after irradiation (Amendola et al, 2017). Similarly, we identified KDM7/JMJD-1.2, a regulator for the heterochromatic modifications H3K9/23/27me2, as a molecule protecting the genome from DNA replication stress (Myers et al, 2018) (Figure 3). We also identified H3K23 methylation as a novel histone modification located in heterochromatin (Vandamme et al, 2015).
We are mainly interested in studying the role of histone post-translation modifications, in particular methylation, in transcription regulation. Our major interests focus in neuronal development, germ cell identity and integrity. We are also exploring transgenerational effects of external environment and the possible contribution of chromatin factors in transmitting epigenetic information across generations. We are currently:
- investigating the causative/correlative role of H3K4 methylation in regulating transcription.
- studying the function of H3K36 demethylases in germ cell identity and fate.
- exploring the transmission of epigenetic landscapes over generations and the effects of external conditions.
Regulators of H3K4 methylation mutated in neurodevelopmental disorders control axon guidance in Caenorhabditis elegans. Abay-Nørgaard S, Attianese B, Boreggio L, Salcini AE. Development. 2020 Aug 7;147(15):dev190637. doi: 10.1242/dev.190637. PMID: 32675280
JMJD-1.2 controls multiple histone post-translational modifications in germ cells and protects the genome from replication stress. Myers TR, Amendola PG, Lussi YC, Salcini AE. Sci Rep. 2018 Feb 28;8(1):3765. doi: 10.1038/s41598-018-21914-9. PMID: 29491442
JMJD-5/KDM8 regulates H3K36me2 and is required for late steps of homologous recombination and genome integrity. Amendola PG, Zaghet N, Ramalho JJ, Vilstrup Johansen J, Boxem M, Salcini AE. PLoS Genet. 2017 Feb 16;13(2):e1006632. doi: 10.1371/journal.pgen.1006632. eCollection 2017 Feb. PMID: 28207814
JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling. Riveiro AR, Mariani L, Malmberg E, Amendola PG, Peltonen J, Wong G, Salcini AE. Development. 2017 Mar 1;144(5):856-865. doi: 10.1242/dev.142695. Epub 2017 Jan 26. PMID: 28126843
The H3K4me3/2 histone demethylase RBR-2 controls axon guidance by repressing the actin-remodeling gene wsp-1. Mariani L, Lussi YC, Vandamme J, Riveiro A, Salcini AE. Development. 2016 Mar 1;143(5):851-63. doi: 10.1242/dev.132985. Epub 2016 Jan 25. PMID: 26811384
H3K23me2 is a new heterochromatic mark in Caenorhabditis elegans. Vandamme J, Sidoli S, Mariani L, Friis C, Christensen J, Helin K, Jensen ON, Salcini AE. Nucleic Acids Res. 2015 Nov 16;43(20):9694-710. doi: 10.1093/nar/gkv1063. Epub 2015 Oct 17. PMID: 26476455