Example Of Epigenetic Regulation Research Articles

BRD9 regulates normal human hematopoietic stem cell function and lineage differentiation

Bromodomain containing protein 9 (BRD9), a member of the non-canonical BRG1/BRM-associated factor (ncBAF) chromatin remodeling complex, has been implicated as a synthetic lethal target in AML but its function in normal human hematopoiesis is unknown. In hematopoietic stem and progenitor cells (HSPC) genomic or chemical inhibition of BRD9 led to a proliferative disadvantage and loss of stem cells in vitro. Human HSPCs with reduced BRD9 protein levels produced lower numbers of immature mixed multipotent GEMM colonies in semi-solid media. In lineage-promoting culture conditions, cells with reduced BRD9 levels failed to differentiate into the megakaryocytic lineage and showed delayed differentiation into erythroid cells but enhanced terminal myeloid differentiation. HSPCs with BRD9 knock down (KD) had reduced long-term multilineage engraftment in a xenotransplantation assay. An increased number of downregulated genes in RNAseq analysis after BRD9 KD coupled with a gain in chromatin accessibility at the promoters of several repressive transcription factors (TF) suggest that BRD9 functions in the maintenance of active transcription during HSC differentiation. In particular, the hematopoietic master regulator GATA1 was identified as one of the core TFs regulating the gene networks modulated by BRD9 loss in HSPCs. BRD9 inhibition reduced a GATA1-luciferase reporter signal, further suggesting a role for BRD9 in regulating GATA1 activity. BRD9 is therefore an additional example of epigenetic regulation of human hematopoiesis.

Koala methylomes reveal divergent and conserved DNA methylation signatures of X chromosome regulation.

X chromosome inactivation (XCI) mediated by differential DNA methylation between sexes is an iconic example of epigenetic regulation. Although XCI is shared between eutherians and marsupials, the role of DNA methylation in marsupial XCI remains contested. Here, we examine genome-wide signatures of DNA methylation across fives tissues from a male and female koala (Phascolarctos cinereus), and present the first whole-genome, multi-tissue marsupial ‘methylome atlas’. Using these novel data, we elucidate divergent versus common features of representative marsupial and eutherian DNA methylation. First, tissue-specific differential DNA methylation in koalas primarily occurs in gene bodies. Second, females show significant global reduction (hypomethylation) of X chromosome DNA methylation compared to males. We show that this pattern is also observed in eutherians. Third, on average, promoter DNA methylation shows little difference between male and female koala X chromosomes, a pattern distinct from that of eutherians. Fourth, the sex-specific DNA methylation landscape upstream of Rsx, the primary lncRNA associated with marsupial XCI, is consistent with the epigenetic regulation of female-specific (and presumably inactive X chromosome-specific) expression. Finally, we use the prominent female X chromosome hypomethylation and classify 98 previously unplaced scaffolds as X-linked, contributing an additional 14.6 Mb (21.5%) to genomic data annotated as the koala X chromosome. Our work demonstrates evolutionarily divergent pathways leading to functionally conserved patterns of XCI in two deep branches of mammals.

Epigenetic regulator Stuxnet modulates octopamine effect on sleep through a Stuxnet-Polycomb-Octβ2R cascade.

Sleep homeostasis is crucial for sleep regulation. The role of epigenetic regulation in sleep homeostasis is unestablished. Previous studies showed that octopamine is important for sleep homeostasis. However, the regulatory mechanism of octopamine reception in sleep is unknown. In this study, we identify an epigenetic regulatory cascade (Stuxnet-Polycomb-Octβ2R) that modulates the octopamine receptor in Drosophila. We demonstrate that stuxnet positively regulates Octβ2R through repression of Polycomb in the ellipsoid body of the adult fly brain and that Octβ2R is one of the major receptors mediating octopamine function in sleep homeostasis. In response to octopamine, Octβ2R transcription is inhibited as a result of stuxnet downregulation. This feedback through the Stuxnet-Polycomb-Octβ2R cascade is crucial for sleep homeostasis regulation. This study demonstrates a Stuxnet-Polycomb-Octβ2R-mediated epigenetic regulatory mechanism for octopamine reception, thus providing an example of epigenetic regulation of sleep homeostasis.

Minireview: The Epigenetic Modulation of KISS1 in Reproduction and Cancer.

Epigenetics describes how both lifestyle and environment may affect human health through the modulation of genome functions and without any change to the DNA nucleotide sequence. The discovery of several epigenetic mechanisms and the possibility to deliver epigenetic marks in cells, gametes, and biological fluids has opened up new perspectives in the prevention, diagnosis, and treatment of human diseases. In this respect, the depth of knowledge of epigenetic mechanisms is fundamental to preserving health status and to developing targeted interventions. In this minireview, we summarize the epigenetic modulation of the KISS1 gene in order to provide an example of epigenetic regulation in health and disease.

Epigenetics knocks on synthetic biology's door.

Epigenetics is the study of heritable changes in gene expression without concomitant changes in DNA sequence. Due to its relevance in development, differentiation and human health, epigenetics has recently become an emerging area of science with regard to eukaryotic organisms and has shown enormous potential in synthetic biology. However, significant examples of epigenetic regulation in bacterial synthetic biology have not yet been reported. In the current study, we present the first model of such an epigenetic circuit. We termed the circuit the alternator circuit because parental cells carrying this circuit and their progeny alternate between distinct and heritable cellular fates without undergoing changes in genome sequence. Furthermore, we demonstrated that the alternator circuit exhibits hysteresis because its output depends not only on its present state but also on its previous states.

Evidence of Epigenetic Mechanisms Affecting Carotenoids.

Epigenetic mechanisms are able to regulate plant development by generating non-Mendelian allelic interactions. An example of these are the responses to environmenal stimuli that result in phenotypic variability and transgression amongst important crop traits. The need to predict phenotypes from genotypes to understand the molecular basis of the genotype-by-environment interaction is a research priority. Today, with the recent discoveries in the field of epigenetics, this challenge goes beyond analyzing how DNA sequences change. Here we review examples of epigenetic regulation of genes involved in carotenoid synthesis and degradation, cases in which histone- and/or DNA-methylation, and RNA silencing at the posttranscriptional level affect carotenoids in plants.

Modulation of Chromatin by Noncoding RNA.

Noncoding RNAs (ncRNAs) are remarkably powerful, flexible, and pervasive cellular regulators. The involvement of these molecules in virtually all aspects of eukaryotic chromatin function is notable. Long and short ncRNAs play broadly complementary roles in these processes. Short ncRNAs underlie a programmable system of chromatin modification that silences mobile elements, identifies boundaries, and initiates the formation of constitutive heterochromatin in yeast. In contrast, long noncoding RNAs (lncRNAs) enforce developmentally appropriate expression and switch gene expression programs. lncRNAs accomplish this through diverse mechanisms, but often by modulating the activity or localization of chromatin regulatory complexes. Both long and short ncRNAs play key roles in organization of complex genomes of higher eukaryotes, and their coordinated actions appear to underlie some of the more dramatic examples of epigenetic regulation. This review contrasts well-studied examples of chromatin regulation by RNA and introduces examples of coordination between these systems.

Different Mechanisms of Epigenetic Regulation of Gene Expression

In our days it becomes clear that not only the genetic information encoded in the sequence of DNA is responsible for gene expression profile but the epigenetic signature encoded in the pattern of modifications of histones that associate with DNA in chromosomes also plays a very important role in the determination of gene expression. Octomere of histones (H3/H4 and H2A/H2B) and a segment of DNA surrounding histone proteins compose a nucleosome, a basic unit of chromatin that in turn is the first level of chromosome organization. Besides the hypermethylation of CpG islands of DNA that leads to gene repression multiple modifications of histones also influence gene expression either activating or inhibiting it. These histone modifications altogether are called a “histone code” and include such diverse covalent modifications of Lys, Arg, Ser residues of histones as acetylation, methylation, phosphorylation, ADP-ribosylation, ubiquitination that are usually reversible. While acetylation of histones is an activating mark, methylation of histones at particular residues could be either repressive or activating modification. Although changes in histone modification pattern already lead to changes in gene expression, the data were accumulated indicating that complete replacement of whole nucleosome or nucleosome arrays with newly synthesized and modified nucleosomes could induce gene activation or repression. In this review the data on different epigenetic mechanisms of gene expression regulation will be presented. Regulation of interferon-beta gene expression will be described in more details as comprehensively studied example of epigenetic regulation of gene expression.

Distinct contributions of MSL complex subunits to the transcriptional enhancement responsible for dosage compensation in Drosophila

The regulatory mechanism of dosage compensation is the paramount example of epigenetic regulation at the chromosomal level. In Drosophila, this mechanism, designed to compensate for the difference in the dosage of X-linked genes between the sexes, depends on the MSL complex that enhances the transcription of the single dose of these genes in males. We have investigated the function of various subunits of the complex in mediating dosage compensation. Our results confirm that the highly enriched specific acetylation of histone H4 at lysine 16 of compensated genes by the histone acetyl transferase subunit MOF induces a more disorganized state of their chromatin. We have determined that the association of the MSL complex reduces the level of negative supercoiling of the deoxyribonucleic acid of compensated genes, and we have defined the role that the other subunits of the complex play in this topological modification. Lastly, we have analyzed the potential contribution of ISWI-containing remodeling complexes to the architecture of compensated chromatin, and we suggest a role for this remodeling factor in dosage compensation.

Epigenetic and genetic disturbance of the imprinted 11p15 region in Beckwith–Wiedemann and Silver–Russell syndromes

Genomic imprinting is a particularly attractive example of epigenetic regulation leading to the parental-origin-specific expression of genes. In several ways, the 11p15 imprinted region is an exemplary model for regulation of genomic imprinting. The two imprinted domains are controlled by imprinting control regions (ICRs) which carry opposite germ line imprints and they are regulated by two major mechanisms of imprinting control. Dysregulation of 11p15 genomic imprinting results in two fetal growth disorders [Silver-Russell (SRS) and Beckwith-Wiedemann (BWS) syndromes], with opposite growth phenotypes. BWS and SRS result from abnormal imprinting involving either, both domains or only one of them, with ICR1 and ICR2 more often involved in SRS and BWS respectively. DNA methylation defects affecting ICR1 or ICR2 account for approximately 60% of SRS and BWS patients. Recent studies have identified new cis-acting regulatory elements, as well as new trans-acting factors involved in the regulation of 11p15 imprinting, therefore establishing new mechanisms of BWS and SRS. Those studies also showed that, apart of CTCF, other transcription factors, including factors of the pluripotency network, play a crucial role in the regulation of 11p15 genomic imprinting. Those new findings have direct consequences in molecular testing, risk assessment and genetic counseling of BWS and SRS patients.

Polycomb proteins regulate the quantitative induction of VERNALIZATION INSENSITIVE 3 in response to low temperatures

Vernalization, the promotion of flowering in response to low temperatures, is one of the best characterized examples of epigenetic regulation in plants. The promotion of flowering is proportional to the duration of the cold period, but the mechanism by which plants measure time at low temperatures has been a long-standing mystery. We show that the quantitative induction of the first gene in the Arabidopsis vernalization pathway, VERNALIZATION INSENSITIVE 3 (VIN3), is regulated by the components of Polycomb Response Complex 2, which trimethylates histone H3 lysine 27 (H3K27me3). In differentiated animal cells, H3K27me3 is mostly associated with long-term gene repression, whereas, in pluripotent embyonic stem cells, many cell lineage-specific genes are inactive but exist in bivalent chromatin that carries both active (H3K4me3) and repressive (H3K27me3) marks on the same molecule. During differentiation, bivalent domains are generally resolved to an active or silent state. We found that H3K27me3 maintains VIN3 in a repressed state prior to cold exposure; this mark is not removed during VIN3 induction. Instead, active VIN3 is associated with bivalently marked chromatin. The continued presence of H3K27me3 ensures that induction of VIN3 is proportional to the duration of the cold, and that plants require prolonged cold to promote the transition to flowering. The observation that Polycomb proteins control VIN3 activity defines a new role for Polycomb proteins in regulating the rate of gene induction.

Genomic imprinting and human disease

In many epigenetic phenomena, covalent modifications on DNA and chromatin mediate somatically heritable patterns of gene expression. Genomic imprinting is a classical example of epigenetic regulation in mammals. To date, more than 100 imprinted genes have been identified in humans and mice. Many of these are involved in foetal growth and deve lopment, others control behaviour. Mono-allelic expression of imprinted genes depends on whether the gene is inherited from the mother or the father. This remarkable pattern of expression is controlled by specialized sequence elements called ICRs (imprinting control regions). ICRs are marked by DNA methylation on one of the two parental alleles. These allelic marks originate from either the maternal or the paternal germ line. Perturbation of the allelic DNA methylation at ICRs is causally involved in several human diseases, including the Beckwith-Wiedemann and Silver-Russell syndromes, associated with aberrant foetal growth. Perturbed imprinted gene expression is also implicated in the neuro-developmental disorders Prader-Willi syndrome and Angelman syndrome. Embryo culture and human-assisted reproduction procedures can increase the occurrence of imprinting-related disorders. Recent research shows that, besides DNA methylation, covalent histone modifications and non-histone proteins also contribute to imprinting regulation. The involvement of imprinting in specific human pathologies (and in cancer) emphasizes the need to further explore the underlying molecular mechanisms.

Transcriptional Memory: Mothers SET the Table for Daughters

Eukaryotic gene transcription within individual cells of a population is often associated with heterogeneous pulses of gene activity. A recent study, however, shows that mothers and their daughters share similar transcriptional frequencies, and inheritance of mother's transcriptional tendencies requires methylation of histone H3 by a Set1 methyltransferase.

Evidence of Xist RNA-independent initiation of mouse imprinted X-chromosome inactivation

SummaryXX female mammals undergo transcriptional silencing of most genes on one of their two X-chromosomes to equalize X-linked gene dosage with XY males in a process referred to as X-chromosome inactivation (XCI). XCI is a paradigm of epigenetic regulation1. Once enacted in individual cells of the early female embryo, XCI is stably transmitted such that most descendant cells maintain silencing of that X-chromosome2. In eutherian mammals, XCI is thought to be triggered by the expression of the non-coding Xist RNA from the future inactive-X (Xi)3,4,5; Xist RNA in turn is proposed to recruit protein complexes that bring about heterochromatinization of the Xi6,7. Here we test whether imprinted XCI, which results in preferential inactivation of the paternal X-chromosome (Xp), occurs in mouse embryos inheriting an Xp lacking Xist. We find that silencing of Xp-linked genes can initiate in the absence of paternal Xist; Xist is, however, required to stabilize silencing of the Xp. Xp-linked gene silencing associated with mouse imprinted XCI, therefore, can initiate in the embryo independently of Xist RNA.

Hypoxic incubation blunts the development of thermogenesis in chicken embryos and hatchlings

We asked to what extent sustained hypoxia during embryonic growth might interfere with the normal development of thermogenesis. White Leghorn chicken eggs were incubated at 38 degrees C either in normoxia (Nx, 21% O2) or in hypoxia [Hx, 15% O2, from embryonic day 5 (E5) until hatching]. The Hx embryos had lower body weight (W) throughout incubation, and hatching was delayed by about 10 h. For both groups, all measurements were conducted in normoxia. At embryonic day E11, the static temperature-oxygen consumption (ambient T-Vo2) curve was typically ectothermic (Q10 = 1.92-1.94) and similar between Nx and Hx. Toward the end of incubation (E20), the Q10 averaged 1.41 +/- 0.06 in Nx and 1.79 +/- 0.08 in Hx (P < 0.005), indicating that the onset of the thermogenic response in Hx lagged behind Nx. In the 1-day-old hatchlings (H1), body weight did not significantly differ between Nx and Hx. At H1, the T-Vo2 curves were endothermic-type, and more so in the older (>8 h old) than in the newly hatched (<8 h old) chicks, whether examined statically or dynamically as a function of time. In either case, the thermogenic responses of Hx were lower than those of Nx. In a 43-31 degrees C thermocline, the preferred T of the Hx hatchlings was around 37.3 degrees C, and similar to Nx, suggesting a similar setpoint for thermoregulation. We conclude that hypoxic incubation blunted the development of thermogenesis. This could be interpreted as an example of epigenetic regulation, in which an environmental perturbation during early development alters the phenotypic expression of a regulatory system.

Metabolic response to cooling temperatures in chicken embryos and hatchlings after cold incubation

We asked to what extent cold exposure during embryonic growth, and the accompanying hypometabolism, may interfere with the normal development of thermogenesis. White Leghorn chicken eggs were incubated in control conditions (38 degrees C) or at 36 or 35 degrees C. Embryos incubated at a lower temperature (34 degrees C) failed to hatch. The cold-incubated embryos had lower oxygen consumption (VO2) and body weight (W) throughout incubation, and hatching was delayed by about, respectively, 1 and 2 days. The W-VO2 relationship of the cold-incubated embryos was as in controls, indicating that cold-induced hypometabolism was at the expense of the growth, not the maintenance, component of VO2. At embryonic day E11, the metabolic response to changes in ambient temperature (T) over the 30-39 degrees C range was typically poikilothermic, with Q10 = 1.8-1.9, and similar among all sets of embryos. Toward the end of incubation (E20), the thermogenic responses of the cold-incubated embryos were significantly lower than in controls. This difference occurred also in the few-hour old hatchlings (H1), even though, at this time, W was similar among groups. Exposure to cold during only the last 3 days of incubation (from E18 to H1), i.e. during the developmental onset of the endothermic mechanisms, did not lower the thermogenic capacity of the hatchlings. In conclusion, sustained cold-induced hypometabolism throughout incubation blunted the rate of embryonic growth and the development of thermogenesis. This latter phenomenon could be an example of epigenetic regulation, i.e. of environmental factors exerting a long-term effect on gene expression.

Epigenetic regulation of gene expression: the effect of altered chromatin structure from yeast to mammals.

Epigenetic gene regulation refers to different states of phenotypic expression caused by differential effects of chromosome or chromatin packaging rather than by differences in DNA sequence. Examples of epigenetic regulation can be found in organisms as diverse as the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the fruit fly Drosophila melanogaster, the nematode Caenorhabditis elegans, and mammals. Three major types of epigenetic regulation are considered in this review: dosage compensation, imprinting and position effect variegation. While the specific details and mechanisms of each is quite different, they all involve either local or extensive alterations in chromatin structure. A number of genes implicated in epigenetic regulation have been isolated and their products identified as proteins or RNA molecules involved at various levels in DNA, chromatin or chromosome binding. While in general our understanding of mammalian epigenetic phenomena is not as advanced as that in model systems, the detailed molecular and genetic understanding of processes responsible for conditional gene silencing in invertebrate systems provides strong models for consideration of such effects in human and mouse genetics.