Recent research has highlighted a role for a specific type of RNA molecule in the epigenetic control of cardiac mesoderm differentiation.
In a recent study published in Developmental Cell, a collaboration of researchers from the Max Planck Institute for Molecular Genetics (Berlin, Germany), the Massachusetts Institute of Technology (MA, USA) and the Broad Institute (MA, USA) have demonstrated that a specific type of RNA molecule is involved in the epigenetic modification of gene promoters, and therefore implicated in the healthy development of the heart.
During embryonic development, a variety of processes function to determine the progression of pluripotent stem cells into the defined tissues and organs of the body. Many of these processes are known to be controlled by transcription factors and are well characterized. In this study, the team has highlighted a role for RNA molecules in the process of stem cell commitment into cardiac tissue.
PRC2 and TrxG/MLL are histone-modifying complexes with a known role in the control of genes determining pluripotency, cell lineage commitment and differentiation. These complexes can be bound and modulated by lncRNAs. lncRNAs are RNA molecules that are longer than 300 nucleotides and do not display protein-coding reading frames.
The team knocked down a gene for the lateral mesoderm-specific lncRNA, Fendrr, in mouse embryos. This proved to be lethal for the embryos as the development of the heart and the body wall was severely impaired. The team observed an upregulation of the transcription factors known to control cardiac mesoderm differentiation, and a dramatic reduction in PRC2 occupancy in the embryos deficient in Fendrr. Fendrr can also bind to the PRC2 and TrxG/MLL complexes, suggesting that it acts, via chromatin modification, to control the activation state of transcription factors responsible for cardiac development.
The researchers claim to have demonstrated for the first time that lncRNAs may be vital in development. The results suggest that these molecules can exert epigenetic control over important transcription factors via histone-modifying protein complexes. Fendrr is likely one of many of these molecules to be active in the epigenetic control of embryonic development. The next step for the team will be to try and locate additional lncRNAs involved in both cardiogenesis and embryonic development in general.
Source: Grote P, Wittler L, Hendrix D. The tissue-specific lncRNA fendrr is an essential regulator of heart and body wall development in the mouse. Developmental Cell 24(2), 206–214 (2013).
New research has demonstrated evidence for the mechanism by which genes and their regulatory tags may integrate to promote rheumatoid arthritis.
In a recent study published in Nature Biotechnology, researchers from Johns Hopkins (MD, USA) and the Karolinska Institute (Solna, Sweden) have conducted one of the first genome-wide studies to screen both genes and epigenetic tags in patients suffering from a common disease.
Rheumatoid arthritis (RA) is a disease that is prevalent in the population, affecting an estimated 1.5 million American adults. It is thought to be an autoimmune disease, where the body‘s own immune system (predominantly the white blood cells) damages its own tissues. There are several known DNA mutations associated with risk of RA, but research has shown that there are likely to be some epigenetic systems in place that are also associated. These involve chemical tags that regulate the expression of certain genes.
The aim of the study was to distinguish between tagging events that occurred as a result of RA from those which may have been involved in causing it. The team analyzed white blood cell samples from 354 subjects with anticitrullinated protein antibody-associated RA and 337 control subjects using Illumina HumanMethylation450 arrays. By eliminating epigenetic tags that appeared on the same DNA sequence in cells from subjects both with and without RA, the researchers highlighted the RA-relevant tags. They then focused on the tags associated with the DNA sequences that were more prevalent in cells from patients with RA in order to determine those sequences associated with altered tagging patterns in RA cells. Ten DNA sites demonstrated altered tagging in RA patients. Nine of these sites were located in a region of the genome that had previously been demonstrated to be involved in autoimmune disease; for example, the team identified two clusters in the major histocompatibility complex region with differential methylation. When speaking to Epigenomics, Andrew Feinberg, director of the Center for Epigenetics at the Johns Hopkins University School of Medicine‘s Institute for Basic Biomedical Sciences, stated “our findings address two general challenges for epigenetics, the cellular heterogeneity of sample material, and the relationship between genetic and epigenetic variation. They show how DNA methylation can mediate genetic effects in a common human disease”.
Currently, treatments for autoimmune diseases involve the suppression of the whole immune system. These results suggest that it may be possible to target specific genes or epigenetic tags. It is likely that this method may be applied to predict risk factors for other common diseases, such as Type II diabetes, by predicting which tagging sites are most important in the pathophysiology of that disease and how epigenetic mechanisms integrate genetic and environmental causes of disease. Feinberg commented that “even though this work focused on the role of genetic risk factors on epigenetics, it also provides us with an approach that can be applied to study the role of environmental/life factors, such as smoking, in rheumatoid arthritis. By understanding the role of genetic and epigenetic susceptibility, as well as their interactions with environmental and lifestyle exposures, this new knowledge will greatly help us towards development of new predictive, preventive and therapeutic strategies in rheumatoid arthritis”.
Source: Liu Y, Aryee MJ, Padyukov L. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat. Biotechnol. 31, 142–147 (2013).
New research has highlighted two proteins that contribute to the epigenetic control of embryonic stem cell pluripotency and differentiation.
Researchers from the Center for Genomic Regulation (Barcelona, Spain) have discovered a role for two proteins that are indispensible in the process of commitment from embryonic stem cell to defined tissue. The two proteins, RYBP and CBX7, were reported in a recent issue of Cell Reports to confer distinct functions in the control of stem cell fate.
There are many processes involved in the process of commitment and development of stem cells into differentiated tissues, and relatively little is known about many of the underlying mechanisms. PRC1 is a complex necessary for stem cell fate decisions that acts as an epigenetic regulator. There are two variations of the PRC1 complex, each having a different protein incorporated; one with CBX7 and the other with RYBP. It was not previously understood whether these subtypes conferred different functions. When speaking to Epigenomics, lead investigator Luis Morey from the research group of Luciano Di Croce at the Center for Genomic Regulation, stated that the team “aimed to understand whether the canonical and noncanonical PRC1 complexes in ESC have the same target genes, which are the biological functions of these two complexes, and finally, whether there is a recruitment interdependency of these complexes”.
The team analyzed 2.64 billion DNA nucleotides from mouse embryonic stem cells and compared the regions controlled by PRC1z-CBX7 with those controlled by PRC1-RYBP. Some functions were shared, but it was observed that the two subtypes also carried out distinct functions. Cbx7 was necessary for the recruitment of Ring1B to chromatin, thereby regulating the early lineage commitment decisions of embryonic stem cells. RYBP was demonstrated to enhance PRC1 enzymatic activity and lower levels of RingB1 recruitment were observed. This protein was therefore primarily associated with the regulation of metabolism. Morey stated that the team “showed that these two complexes are recruited independently to chromatin. Specifically, Cbx7 is necessary for the recruitment of the canonical PRC1 into chromatin, while RYBP it is not a recruiting factor for the noncanonical PRC1 complex, yet it is important for its enzymatic activity”.
These results demonstrate a complex pattern of gene expression, regulated by different PRC1 subtypes, acting to determine stem cell behavior. More research is now required in order to understand the extent of the influence of these PRC1 subtypes on stem cell fate in order to potentially harness these mechanisms for therapeutic applications.
Source: Morey L, Aloia L, Cozzuto L. RYBP and Cbx7 define specific biological functions of polycomb complexes in mouse embryonic stem cells. Cell Rep. 3(1), 60–69 (2012).
––All stories written by Caroline Telfer
A recent study has demonstrated that epigenetic changes may affect the mechanism used to repair dsDNA breaks and affect a cell‘s response to chemotherapy.
Researchers at the University of Pennsylvania (PA, USA) have uncovered a key determinant in the control of DNA repair machinery. The research, published recently in the journal Nature Structural & Molecular Biology has demonstrated a mechanism to explain how epigenetic mechanisms can be a key factor in cancer progression and response to chemotherapy.
DNA double-stranded breaks are a common occurrence. Cells have two complex mechanisms by which they can repair these breaks: nonhomologous end-joining and homologous recombination. Many proteins are involved in the regulation of these processes and if they are disrupted, cancer may occur.
BRCA1 and 53BP1 are proteins that act to determine which of these two repair mechanisms are utilized. Breast and ovarian cancers are associated with a disruption in the repair systems associated with these proteins.
The team aimed to understand the signals responsible for the prevalence of BRCA1 or 53BP1 at a DNA break site. It appears that the acetylation of histone H4 controls this balance. If histone H4 is acetylated at a particular point (or under conditions of HDAC inhibition) then 53BP1 binding is reduced near the dsDNA break. BRCA1 then takes over, promoting the homologous recombination repair system. Conversely, a reduction in acetylation (due to TIP60 acetyltransferase deficiency) caused 53BP1 to outcompete BRCA1 at a double-stranded break, thereby initiating nonhomologous end-joining.
These results may help to explain why both humans and mice with BRCA1 mutations have resistance to PARP inhibition chemotherapy. Previous results from other groups have shown that, in the absence of BRCA1 and 53BP1, the homologous recombination system is activated and BRCA1-mutant cells develop a resistance to PARP inhibitors.
This raises the possibility of improving a patient‘s response to PARP inhibitors by hyperactivating 53BP1 binding to breaks in cancers where BRCA1 is mutated. These results also suggest that the levels of acetylation at histone H4 may act as a biomarker to predict a patient‘s response to PARP inhibitors. This mechanism, and others which are possibly involved in DNA repair, now need to be investigated to determine potential therapeutic targets.
Source: Tang J, Cho N, Cui G. Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination. Nat. Struct. Mol. Biol. 20(3), 317–325 (2013).