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PubMed1998

Autoregulation of eukaryotic transcription factors.

The structures of several promoters regulating the expression of eukaryotic transcription factors have in recent years been examined. In many cases there is good evidence for autoregulation, in which a given factor binds to its own promoter and either activates or represses transcription. Autoregulation occurs in all eukaryotes and is an important component in controlling expression of basal, cell cycle specific, inducible response and cell type-specific factors. The basal factors are autoregulatory, being strictly necessary for their own expression, and as such must be epigenetically inherited. Autoregulation of stimulus response factors typically serves to amplify cellular signals transiently and also to attenuate the response whether or not a given inducer remains. Cell cycle-specific transcription factors are positively and negatively autoregulatory, but this frequently depends on interlocking circuits among family members. Autoregulation of cell type-specific factors results in a form of cellular memory that can contribute, or define, a determined state. Autoregulation of transcription factors provides a simple circuitry, useful in many cellular circumstances, that does not require the involvement of additional factors, which, in turn, would need to be subject to another hierarchy of regulation. Autoregulation additionally can provide a direct means to sense and control the cellular conce]ntration of a given factor. However, autoregulatory loops are often dependent on cellular pathways that create the circumstances under which autoregulation occurs.

Animals↗

PubMed2003

From flour to flower: how Polycomb group proteins influence multiple aspects of plant development.

Cell identity and differentiation are determined by patterns of regulatory gene expression. Spatially and temporally regulated homeotic gene expression defines segment identities along the anterior-posterior axis of animal embryos. Polycomb group (PcG) proteins form a cellular memory system that maintains the repressed state of homeotic gene expression. Conserved PcG proteins control multiple aspects of Arabidopsis development and maintain homeotic gene repression. In animals, PcG proteins repress their target genes by modifying histone tails through deacetylation and methylation, generating a PcG-specific histone code that recruits other chromatin remodeling proteins to establish a stable, heritable mechanism of epigenetic expression control. Plant PcG proteins might function through a similar biochemical mechanism owing to their conserved structural and functional relationship to animal PcG proteins.

Arabidopsis↗

PubMed2001

Exploring the biology of socialization.

How will the social sciences take advantage of the revolution that has taken place in biology during the past two decades? Over the last fifteen years, neuroimaging has allowed the study of human cognition and emotion within psychology to achieve close alliances with biology through the development of cognitive and affective neuroscience. There is little doubt that a similar alliance between psychology and biology will occur in the domain of human brain development. In principle, understanding how the human brain is organized by experience (epigenetic rules) and how societies instruct their young could produce a link between natural and social science. The late David C. McClelland sought methods to base the social sciences on psychological ideas. McClelland sought to connect the values of achievement and power as coded from children's readers and popular ballads to societal economic growth and conflict. These efforts lacked knowledge of brain mechanisms of memory and attention and an understanding of the role of experience in organizing brain circuitry. Understanding of cognitive and brain systems related to knowledge and action may allow a new approach to forging connections between individual minds and social behavior.

Biology↗

PubMed1999

1998 Runme Shaw Memorial Lecture: somatic evolution of cancer.

The interpretation of cancer as a somatic evolutionary process involving genetic mutation followed by selection, traces its origins to the early years this century. The dramatic developments in molecular genetics have substantiated these early ideas. Through the application of positional cloning and genomic analysis, many mutations in particular genes, both dominant oncogenes and tumour suppressor genes have now been found in a wide variety of tumours. Other genetic events such as non-disjunction leading to haploid expression of a gene and so reduced gene dosage, or epigenetic changes following, for example, changes in methylation patterns leading to reduced or increased gene expression, may also play critical roles in the progression of a cancer. The analysis of mutations at different stages of colorectal cancer provides a good model for following the initiation and progression of a cancer. Mutations in the APC gene, which explain familial adenomatous polyposis, occur in a high proportion of sporadic colorectal carcinomas and appear to be the earliest known changes. Patterns of mutation in the gene suggest dominant negative or gain of function effects, and also reveal important low penetrance subpolymorphic missense mutations that nevertheless may have a very significant impact on the genetic contribution to colorectal cancer susceptibility. Mutations are also found in related genes in the APC pathway, such as beta-catenin and E-cadherin. Mutations in mismatch repair genes (hMLH1 and hMSH2) have also been shown to occur, as well as reduced expression due to methylation changes, in 10% to 20% of sporadic colorectal carcinomas. In addition, mutations in the well known oncogenes p53 and ras are commonly found. The growth of a cancer is a balance between the rate of cell division and the rate of cell death or apoptosis. Thus, genetic changes which reduce the probability of apoptosis, such as p53 and probably hMLH1, are as important a feature of the evolution of a cancer as those which enhance the independence (APC) and rate of cell division (growth factors). Simple models for the evolution of a cancer that take into account these two processes, show that cancers evolve initially by a series of finite increases in cell population size, following which there may be long periods of cell turnover during which there is an opportunity for further mutation and selection. This explains the long lag periods between the initiation and subsequent progression of most cancers. Our rapidly developing understanding of cancers at the fundamental genetic level provides new opportunities for developing targeted treatments, as well as novel approaches to prevention and early detection.

Adenomatous Polyposis Coli↗

PubMed2003

A neuronal isoform of the aplysia CPEB has prion-like properties.

Prion proteins have the unusual capacity to fold into two functionally distinct conformations, one of which is self-perpetuating. When yeast prion proteins switch state, they produce heritable phenotypes. We report prion-like properties in a neuronal member of the CPEB family (cytoplasmic polyadenylation element binding protein), which regulates mRNA translation. Compared to other CPEB family members, the neuronal protein has an N-terminal extension that shares characteristics of yeast prion-determinants: a high glutamine content and predicted conformational flexibility. When fused to a reporter protein in yeast, this region confers upon it the epigenetic changes in state that characterize yeast prions. Full-length CPEB undergoes similar changes, but surprisingly it is the dominant, self-perpetuating prion-like form that has the greatest capacity to stimulate translation of CPEB-regulated mRNA. We hypothesize that conversion of CPEB to a prion-like state in stimulated synapses helps to maintain long-term synaptic changes associated with memory storage.

Animals↗

PubMed2006

Cellular memory and hematopoietic stem cell aging.

Hematopoietic stem cells (HSCs) balance self-renewal and differentiation in order to sustain lifelong blood production and simultaneously maintain the HSC pool. However, there is clear evidence that HSCs are subject to quantitative and qualitative exhaustion. In this review, we briefly discuss several known aspects of the stem cell aging process, including DNA damage, telomere shortening, and oxidative stress. Besides these known players, there is increasing evidence that higher order chromatin structure, largely defined by the histone code and affecting transcriptional activity, is important. A model is suggested which describes how epigenetic regulation of gene transcription by modulation of the chromatin structure in stem cells can account for regulation of the aging program.

Animals↗

PubMed2000

Transcriptional silencing in fission yeast.

In eukaryotes, epigenetic events govern diverse processes, ranging from gene expression to other aspects of global chromosome architecture essential for preserving the integrity of the genome. Transcriptional silencing at the mating-type locus, centromeres, and telomeres of the fission yeast is regulated by epigenetic mechanisms. Epigenetic states are inherited in cis during mitosis and, remarkably, even through meiosis. Several trans-acting genes that affect silencing are found to encode either chromatin proteins such as chromodomain proteins Swi6 and Clr4 or the factors that affect chromatin assembly, including histone deacetylase homologs Clr3 and Clr6. A recent study showed that Swi6 is involved in imprinting at the mating-type locus and contributes to the cellular memory responsible for maintenance of the silenced state. The "gene" in this instance thus comprises DNA plus the associated Swi6-containing protein complex.

Centromere↗

PubMed2026

Co-regulation of HIV control and cytomegalovirus pp65-specific IL-1β and TNF-α responses by genetic variants in the MHC region.

The spontaneous control of HIV infection in the absence of antiretroviral therapy, termed HIV control, is associated with genetic variation in the Major Histocompatibility Complex (MHC) locus. These variants are known to influence the immune response to HIV itself. However, people living with HIV are often co-infected with other pathogens that can also elicit immune responses, which might also be regulated by these variants. Here, we assessed whether genetic variants associated with HIV control influence cytokine responses to various co-pathogens. HIV-control-associated single nucleotide polymorphisms (SNPs) were enriched among variants regulating TNF-α and IL-1β production upon CMV pp65 peptide pool stimulation. The top enriched SNPs, rs1128175-A and rs2853971-A, were linked to lower odds of HIV control and increased cytokine responses to CMV. These SNPs were in linkage disequilibrium (LD) with classical HLA alleles HLA-B*07:02 and HLA-C*07:02. Intracellular cytokine staining showed CMV serostatus-dependent production of TNF-α by monocytes and CD8 T cells. The rs1128175-A/rs2853971-A/HLA-B*07:02/HLA-C*07:02 haplotype was associated with increased IFN-γ production by CD8 T cells upon CMV pp65 peptide pool stimulation, indicating an effect on memory responses. Quantitative trait locus (QTL) mapping showed that rs1128175 and rs2853971 influence HLA-B and HLA-C expression, DNA methylation levels and cell-type-specific cis-effects on chromatin accessibility, as well as CD8 T cell subset abundance. These QTL associations suggest that variants associated with poor HIV control are linked to heightened pro-inflammatory responses to CMV pp65 through effects on antigen presentation, epigenetic modifications, gene expression and immune cell repertoire, potentially negatively affecting HIV control status.

Humans↗

PubMed2004

Advances in chromatin remodeling and human disease.

Epigenetic factors alter phenotype without changing genotype. A primary molecular mechanism underlying epigenetics is the alteration of chromatin structure by covalent DNA modifications, covalent histone modifications, and nucleosome reorganization. Remodeling of chromatin structure regulates DNA methylation, replication, recombination, and repair as well as gene expression. As these functions would predict, dysfunction of the proteins that remodel chromatin causes an array of multi-system disorders and neoplasias. Insights from these diseases suggest that during embryonic and fetal life, environmental distortions of chromatin remodeling encode a 'molecular memory' that predispose the individual to diseases in adulthood.

Acetylation↗

PubMed2026

Post-vaccination expansion of extrafollicular Th10 and regulatory Tfr cells distinguishes strong from weak influenza vaccine responses in older adults.

Despite the superior efficacy of high-dose influenza vaccines, over one-third of older adults fail to respond. Yet, the mechanisms underlying this impaired vaccine responsiveness remain poorly understood. Here, we performed longitudinal profiling of older adults (n=60) receiving high-dose influenza vaccination to identify immune programs associated with vaccine responsiveness. Strong responders exhibited a primed baseline immune state characterized by elevated plasma cytokines and chemokines, followed by enhanced IFN-γ responses and coordinated transcriptional and epigenetic activation of cDC2 cells at day 1. By day 7, CD4+ T-cell trajectories diverged: strong responders preferentially expanded influenza-specific activated cTfh1 (CXCR5 + CXCR3 + ICOS + CD38 +) and influenza-specific Th10 (CXCR5 - CXCR3 + PD1 + IL10 +) cells, whereas weak responders expanded regulatory cTfr (CXCR5 + FOXP3 +) cells. Th10 expansion correlated with plasmablast and antibody responses and was independently validated in a larger influenza vaccination cohort, including younger adults. Functionally, Th10 cells promoted memory B-cell differentiation into plasmablasts and production of influenza-specific IgGs. TCR analyses revealed minimal clonal overlap between Th10 and cTfh1 cells. Together, these findings identify divergent helper and regulatory CD4+ T cell programs associated with vaccine responsiveness and establish Th10 cells as a previously unrecognized component of vaccine-induced humoral immunity.

Journal Article↗

PubMed2006

Regulation of Th2 differentiation and Il4 locus accessibility.

Helper T cells coordinate immune responses through the production of cytokines. Th2 cells express the closely linked Il4, Il13, and Il5 cytokine genes, whereas these same genes are silenced in the Th1 lineage. The Th1/Th2 lineage choice has become a textbook example for the regulation of cell differentiation, and recent discoveries have further refined and expanded our understanding of how Th2 differentiation is initiated and reinforced by signals from antigen-presenting cells and cytokine-driven feedback loops. Epigenetic changes that stabilize the active or silent state of the Il4 locus in differentiating helper T cells have been a major focus of recent research. Overall, the field is progressing toward an integrated model of the signaling and transcription factor networks, cis-regulatory elements, epigenetic modifications, and RNA interference mechanisms that converge to determine the lineage fate and gene expression patterns of differentiating helper T cells.

Animals↗

PubMed2006

Programming CD8+ T cells for effective immunotherapy.

The differentiation state of CD8+ T cells has emerged as a crucial determinant of their ability to respond to tumor and infection. Signals from T-cell receptors, co-stimulatory molecules and cytokine receptors direct the differentiation process. These signals 'program' sustained and heritable gene expression patterns that govern progressive differentiation and lineage commitment. The epigenetic mechanisms by which T cells are programmed are just beginning to be elucidated. Understanding the mechanisms that control CD8+ T-cell differentiation is important in the development of novel immunotherapy strategies.

Animals↗

PubMed2005

Maintenance of gene expression patterns.

In development, cells pass on established gene expression patterns to daughter cells over multiple rounds of cell division. The cellular memory of the gene expression state is termed maintenance, and the proteins required for this process are termed maintenance proteins. The best characterized are proteins of the Polycomb and trithorax Groups that are required for silencing and maintenance of activation of target loci, respectively. These proteins act through DNA elements termed maintenance elements. Here, we re-examine the genetics and molecular biology of maintenance proteins. We discuss molecular models for the maintenance of activation and silencing, and the establishment of epigenetic marks, and suggest that maintenance proteins may play a role in propagating the mark through DNA synthesis.

Animals↗

PubMed2005

DNA methylation and the expanding epigenetics of T cell lineage commitment.

During their development from progenitors, lymphocytes make a series of cell fate decisions. These decisions reflect and require changes in overall programs of gene expression. To maintain cellular identity, programs of gene expression must be iterated through mitosis in a heritable manner by epigenetic processes, which include DNA methylation, methyl-CpG-binding proteins, histone modifications, transcription factors and higher order chromatin structure. Current evidence is consistent with the notion that DNA methylation acts in concert with other epigenetic processes to limit the probability of aberrant gene expression and to stabilize, rather than to initiate, cell fate decisions. In particular, DNA methylation appears to be a non-redundant repressor of CD8 expression in TCR-gammadelta T cells and Th2 cytokine expression in Th1 and CD8 T cells, and is required to enforce clonally restricted Ly49 and KIR gene expression in NK cells. However, most of our knowledge is derived from in vitro studies, and the importance of DNA methylation in memory cell lineage fidelity in vivo remains to be shown convincingly.

Animals↗

PubMed1999

[Mechanisms for formation and maintenance of synapses mediated by biogenic amines: pathogenesis and therapy of mental retardation and developmental disabilities by genetic and epigenetic factors].

Fibers of the global projection system ramify tremendously and distribute in the diverse region of the brain. Biogenic amines in the global projection system have been shown to facilitate formation and maintenance of synapses in the developing and adult brain. In terms of serotonin 5-HT2A receptor was shown to mediate the function of serotonin. We raised specific antibodies against 5-HT2A receptor protein. Virtually all the neurons in the cerebral cortex expressed 5-HT2A receptor. By using the function of biogenic amines to facilitate synapse formation and maintenance a novel approach can be developed in the neuroscience. That is to perturb biogenic amines, to change synaptic density, and to examine changes in the ability of learning and memory. Removing serotonin and acetylcholine for a week, at the maximum 58% of synapses are decreased in the hippocampus. The animals losing synapses spent a longer latency compared to intact animals in Morris water maze. The level of biogenic amines in the developing brain has been known to decrease tremendously by genetic diseases such as phenylketonuria, Down syndrome and autism as well as environmental factors such as nutrition and stress. In those situations synapses in the brain are suggested to be decreased. Synaptic mechanism for mental retardation and developmental disability by the cascade appears to contribute for understanding pathophysiology and a new therapy.

Animals↗

PubMed1994

Dyslexia: a neuroscientific puzzle.

The initial assumptions as to the existence of neurodevelopmental disorders have been confirmed by almost a century of studies focused on the nature and causes of reading disability. Dyslexia is an umbrella term for the various manifestations of reading disabilities, each of which is related to its own complex of neuropsychological dysfunctions, sometimes accompanied by neurological symptoms that can be indicative of the specific location involved. Electro-physiology and neuro-imaging in relation to metabolic activity have also confirmed that, to some extent, there is dysfunction in various cerebral areas, more frequently in the left than in the right hemisphere, less often between the hemispheres (corpus callosum) and outside the classical language areas. The rather rare subtype referred to as visual dyslexia and the inter-modal disconnection type resembling alexia are eclipsed by dyslexias related to spoken language: the dysphonemic (auditory-phonological) subtype and the subtypes that are concerned with the production of speech (fluency, word-finding, syntax, sequences), semantics (language comprehension) and linguistic memory. Although it is considered that there are basic brain dysfunctions in dyslexics such as deficits in sequential information processing, there is no "grand unified theory" of dyslexia. There are some new insights as regards the aetiology. In addition to indications of such possible causes as perinatal brain damage, genetic or chromosomal anomalies that manifest themselves in the substrate in an unclear manner, there is also the possibility that the cortical language areas can be disturbed in their development (migration disorders and abnormal asymmetry) due to genetic or epigenetic hormonal and/or immunological factors, so that the normal left hemispheric dominance does not develop. The diagnosis and treatment of dyslexia should begin at an early age and should be acknowledged as being of great social importance.

Brain↗

PubMed2026

Splenic extramedullary hematopoiesis in myelofibrosis is shaped by transcriptomic and epigenetic dysregulation.

Myelofibrosis (MF) is a chronic, progressive myeloproliferative neoplasm characterized by bone marrow fibrosis, ineffective blood cell production, and neoplastic extramedullary hematopoiesis (EMH) occurring primarily within the spleen. To explore the molecular mechanisms underlying splenic EMH, we performed single-cell transcriptional and chromatin profiling of cells from MF spleens that had been surgically removed. We demonstrate significant expansion of hematopoietic stem and progenitor cells, coupled with aberrant differentiation toward the erythroid and megakaryocytic lineages, associated with a significant enrichment of inflammatory pathways with enhanced NF-κB signaling and IFN responses, as well as dysregulation of the inferred function of differentiation-defining transcription factors. Finally, we report a significant remodeling of the immune microenvironment in MF spleens, characterized by emergence of dysfunctional T cell subsets and inflammatory memory B cells, suggesting the concomitant establishment of a pro-inflammatory and immune-tolerant tumor microenvironment within the spleen that influences hematopoietic cell differentiation and impairs tumor immune surveillance.

Primary Myelofibrosis↗

PubMed2001

The VERNALIZATION 2 gene mediates the epigenetic regulation of vernalization in Arabidopsis.

The acceleration of flowering by a long period of low temperature, vernalization, is an adaptation that ensures plants overwinter before flowering. Vernalization induces a developmental state that is mitotically stable, suggesting that it may have an epigenetic basis. The VERNALIZATION2 (VRN2) gene mediates vernalization and encodes a nuclear-localized zinc finger protein with similarity to Polycomb group (PcG) proteins of plants and animals. In wild-type Arabidopsis, vernalization results in the stable reduction of the levels of the floral repressor FLC. In vrn2 mutants, FLC expression is downregulated normally in response to vernalization, but instead of remaining low, FLC mRNA levels increase when plants are returned to normal temperatures. VRN2 function therefore stably maintains FLC repression after a cold treatment, serving as a mechanism for the cellular memory of vernalization.

Agrobacterium tumefaciens↗