Epigenetic refers to the study of heritable changes that occur without a modification in DNA sequence of the genes. It is caused mostly by histone modifications and DNA methylation upon gene expression.
Epigenetic defects have been found to be major factors in cancer, genetic disorders as well as in autoimmune diseases and aging.
Cells manage gene expression by wrapping DNA around clusters of globular histone proteins to form nucleosomes. These nucleosomes of DNA and histones are organized into chromatin. Changes to the structure of chromatin influence gene expression. For example, genes are inactivate when the chromatin is condensed, and they are expressed when chromatin is open. These chromatin states are controlled by DNA methylation and histone modifications.
A number of proteins involved in epigenetics interact with histone modifying enzymes like histone methyltransferases (HMTs) and histone deacetylases (HDACs). Disturbing their relationship will almost have severe consequences on the epigenome and chromatin organization. The histone N-terminal sequences are crucial to maintain chromatin stability and they are subject to numerous modifications. Most modifications such as acetylation, methylation and phosphorylation have some role to play in transcriptional regulation and have the potential to be oncogenic if result, for example, to loss of expression of a tumour suppressor gene.
The Laboratory now has projects related to biochemical and genetic characterization of the enzymes that catalyze arginine methylation.
The stability of the genome is essential for the proper function and survival of all organisms. DNA damage is very frequent and appears to be a fundamental problem for life. DNA damage can trigger the development of cancer, and accelerate aging. Most DNA damage is removed by DNA repair enzymes, but these repair processes are not completely efficient. DNA damage, if not repaired, causes errors during DNA synthesis leading to mutations that can give rise to cancer.
Cell cycle checkpoints are regulatory pathways that govern the order and timing of cell cycle transitions to ensure completion of one cellular event prior to another. Upon sensing DNA damage, cell cycle checkpoints are activated to arrest cell cycle progression to allow time for repair before the damage is passed on to the cells. In addition to checkpoint activation, the DNA damage response leads to induction of transcriptional programs, enhancement of DNA repair pathways, and when the level of damage is severe, to initiation of apoptosis.
The key regulators of the checkpoint pathways in the DNA damage response are the ATM (ataxia telangiectasia, mutated) and ATR (ATM and Rad3-related) protein kinases.
These proteins are central to the entire DNA damage response. Both of these proteins belong to an unique family of serine-threonine kinases characterized by a C-terminal catalytic motif containing a phosphatidylinositol 3-kinase domain. Although ATM and ATR appear to phosphorylate many of the same cellular substrates, they generally respond to distinct types of DNA damage. For example, ATM is the primary mediator of the response to DNA double strand breaks (DSBs) that can arise by exposure to ionizing radiation (IR). Cells lacking ATM have major problems in repairing DSBs and sustain major chromosome instability. On the other hand, ATR directs the principle response to UV damage. Downstream of these proteins are two families of checkpoint kinases (CHK), the Chk1 and Chk2 kinases, and their homologues. These kinases carry out subsets of the DNA damage response and are targets of regulation by ATM and ATR kinases.
Depending on the type of cells, amount, and location, DNA damage has been shown to be involved in a variety of disorders in aging, and in carcinogenesis. The development of cancer and the process of aging can be delayed by reducing the load of DNA.
The laboratory is currently studying projects that implicate protein methylation in the DNA damage response.
RNA binding proteins
Ribonucleic acids (RNAs) are derived from the DNA and program the cells to make proteins. There are many types of RNAs in the cells such as transfer RNAs (tRNAs), ribosomal RNAs ( rRNAs), and messenger RNAs (mRNAs). They all have their respective functions to carry on within the cells.
RNAs in cells are associated with RNA-binding proteins (RBPs) to form ribonucleoprotein (RNP) complexes. RBPs function in multiple cellular processes. For example, RBPs are involved in DNA replication, expression of histone genes, regulation of transcription, and translational control. Many RBPs have been identified as essential factors during the development of somatic tissues, including neurons and muscles. Genetic information stored in chromosomal DNA is translated into proteins through mRNAs. This allows for post-transcriptional control of gene expression conferring a crucial role to the mRNA-binding proteins in this regulation. Post-transcriptional control can occur at many different steps in RNA metabolism, including splicing, polyadenylation, mRNA stability, mRNA localization and translation.
RBPs contain one or, more often, multiple RNA-binding domains. Some well-characterized RBPs such as Sam68 contain a heterogeneous nuclear ribonucleoprotein K-homology (KH) domain in a larger RNA binding domain. Sam68 is a member of a family of proteins referred to as the STAR (signal transduction and activators of RNA metabolism) proteins.
RBPs are associated with a large number of human diseases including neurodegeneration and cancers. Proper functioning of these networks is essential for the coordination of post-transcriptional events, and their perturbation can lead to diseases.
The laboratory is currently studying projects that implicate Sam68 in cancer metabolism and the role of the QKI RNA binding proteins in oligodendrocyte differentiation and CNS myelination.