Classical Dogma Research Articles

Skeletal stem and progenitor cells in bone development and repair.

Bone development, growth, and repair are complex processes involving various cell types and interactions, with central roles played by skeletal stem and progenitor cells. Recent research brought new insights into the skeletal precursor populations that mediate intramembranous and endochondral bone development. Later in life, many of the cellular and molecular mechanisms determining development are reactivated upon fracture, with powerful trauma-induced signaling cues triggering a variety of postnatal skeletal stem/progenitor cells (SSPCs) residing near the bone defect. Interestingly, in this injury context, the current evidence suggests that the fates of both SSPCs and differentiated skeletal cells can be considerably flexible and dynamic, and that multiple cell sources can be activated to operate as functional progenitors generating chondrocytes and/or osteoblasts. The combined implementation of in vivo lineage tracing, cell surface marker-based cell selection, single-cell molecular analyses, and high-resolution in situ imaging has strongly improved our insights into the diversity and roles of developmental and reparative stem/progenitor subsets, while also unveiling the complexity of their dynamics, hierarchies, and relationships. Albeit incompletely understood at present, findings supporting lineage flexibility and possibly plasticity among sources of osteogenic cells challenge the classical dogma of a single primitive, self-renewing, multipotent stem cell driving bone tissue formation and regeneration from the apex of a hierarchical and strictly unidirectional differentiation tree. We here review the state of the field and the newest discoveries in the origin, identity, and fates of skeletal progenitor cells during bone development and growth, discuss the contributions of adult SSPC populations to fracture repair, and reflect on the dynamism and relationships among skeletal precursors and differentiated cell lineages. Further research directed at unraveling the heterogeneity and capacities of SSPCs, as well as the regulatory cues determining their fate and functioning, will offer vital new options for clinical translation toward compromised fracture healing and bone regenerative medicine.

β-Adrenergic Signal and Epigenomic Regulatory Process for Adaptive Thermogenesis.

Activation of β-adrenergic (β-AR) signaling induces fight-or-flight stress responses which include enhancement of cardiopulmonary function, metabolic regulation, and muscle contraction. Classical dogma for β-AR signaling has dictated that the receptor-mediated response results in an acute and transient signal. However, more recent studies support more wide-ranging roles for β-AR signaling with long-term effects including cell differentiation that requires precisely timed and coordinated integration of many signaling pathways that culminate in precise epigenomic chromatin modifications. In this chapter, we discuss cold stress/β-AR signaling-induced epigenomic changes in adipose tissues that influence adaptive thermogenesis. We highlight recent studies showing dual roles for the histone demethylase JMJD1A as a mediator of both acute and chronic thermogenic responses to cold stress, in two distinct thermogenic tissues, and through two distinct molecular mechanisms. β-AR signaling not only functions through transient signals during acute stress responses but also relays a more sustained signal to long-term adaptation to environmental changes.

The maternal epigenome as a window into the in utero environment that the foetus experiences

Maternal stress pre-pregnancy and exposure to stress in utero has life-long negative consequences for the developing foetus. There is growing evidence that this passes through changes in foetal epigenetic markers such as DNA methylation. We hypothesize that the mother’s prior life experience and changes in her external environment will change the in utero environment she provides to the developing foetus, and both will be reflected in changes to the mother’s epigenome. As classical dogma states that during embryo all DNA methylation marks are removed and replaced de novo, this raises the question as to how to assess the in utero environment, examining the role it plays in the transmission of environmental cues. We suggest that the maternal epigenome can act as a proxy for the developmental environment she provided to her offspring in utero; this developmental environment determines the child’s epigenome and lifelong health trajectory. Furthermore, we suggest that the maternal origin of the placental decidua make this the perfect sample for assessing the in utero environment in the context of the mothers’ prior life experience, mediating maternal exposure to infant phenotype.

EPEN-13. PATTERN OF RELAPSE IN POSTERIOR FOSSA EPENDYMOMA GROUP A

Abstract PURPOSE/OBJECTIVE Posterior fossa ependymoma group A (PF-EPN-A) is a poor prognostic ependymoma subgroup, predominantly seen in infants and young children. Among all ependymomas, most of the recurrences are seen in patients with the PF-EPN-A subgroup. Despite advances in neurosurgery and postoperative adjuvant therapy, management of these tumors remains challenging, and recurrence occurs in over 50% of cases. In this study, we aimed to evaluate the pattern of relapse in PF-EPN-A. MATERIALS AND METHODS The clinical features, treatment strategies and relapse patterns of patients diagnosed and treated with PF-EPN-A at the Hospital for Sick Children, Toronto have been evaluated retrospectively. RESULTS Seventy-five patients were diagnosed with PF-EPN-A at the Hospital for Sick Children, Toronto from 01 June 1996 to 01 June 2022. All patients were treated with surgery +/- focal radiation +/- chemotherapy after diagnosis. Out of 75 patients, 38 (50.6%) had recurrent disease. Twenty-three patients (60.5%) had a local relapse while 15 patients (40.5) experienced a distant relapse. Out of 23 patients who had a local relapse, only 8 patients (34%) developed a local relapse after a gross total resection (GTR). Other 15 patients developed a local relapse after either subtotal (STR) or near total resection (nTR). Out of 15 patients who experienced a distant relapse, 10 patients (66%) developed a distant relapse after GTR. Time to relapse was mean 32 months (11-132 months) after GTR and 24 months (1-98 months) after STR /nTR. CONCLUSIONS The modern management approach (more aggressive resection and early conformal radiotherapy) changed the relapse pattern and the classical dogma that “nearly all relapses in ependymoma are local’’ in modern series. This study supported the importance of GTR in the management of PF-EPN-A and also demonstrated that PF-EPN-A tends to recur more on distant sites rather than locally when the initial surgical intervention is a GTR.

Transcriptional coactivation by EHMT2 restricts glucocorticoid-induced insulin resistance in a study with male mice

The classical dogma of glucocorticoid-induced insulin resistance is that it is caused by the transcriptional activation of hepatic gluconeogenic and insulin resistance genes by the glucocorticoid receptor (GR). Here, we find that glucocorticoids also stimulate the expression of insulin-sensitizing genes, such as Irs2. The transcriptional coregulator EHMT2 can serve as a transcriptional coactivator or a corepressor. Using male mice that have a defective EHMT2 coactivation function specifically, we show that glucocorticoid-induced Irs2 transcription is dependent on liver EHMT2’s coactivation function and that IRS2 play a key role in mediating the limitation of glucocorticoid-induced insulin resistance by EHMT2’s coactivation. Overall, we propose a model in which glucocorticoid-regulated insulin sensitivity is determined by the balance between glucocorticoid-modulated insulin resistance and insulin sensitizing genes, in which EHMT2 coactivation is specifically involved in the latter process.

EBV dUTPase: A Novel Modulator of Inflammation and the Tumor Microenvironment in EBV-Associated Malignancies.

There is increasing evidence that put into question the classical dogma that the Epstein-Barr virus (EBV) exists in cells as either a lytic virus in which new progeny is produced or in a latent state in which no progeny is produced. Notably, a third state has now been described, known as the abortive-lytic phase, which is characterized by the expression of some immediate early (IE) and early (E) genes, but no new virus progeny is produced. While the function of these IE and E gene products is not well understood, several recent studies support the concept they may contribute to tumor promotion by altering the tumor microenvironment (TME). The mechanisms by which these viral gene products may contribute to tumorigenesis remain unclear; however, it has been proposed that some of them promote cellular growth, immune evasion, and/or inhibit apoptosis. One of these EBV early gene products is the deoxyuridine triphosphate nucleotidohydrolase (dUTPase) encoded by BLLF3, which not only contributes to the establishment of latency through the production of activin A and IL-21, but it may also alter the TME, thus promoting oncogenesis.

Olim tradita fuerunt? On the obsoleteness of the sollemnia verba in Inst. 3.15pr.

According to the classical dogma, the act of stipulatio was performed through the exchange of sollemnia verba, which were, according to my working hypothesis, verbs introducing the duty to perform a future act, a concept lucidly displayed by Pomponian (Dig. 45.1.5.1), hence the ‘Pomponian tenet’. Documents preserved on papyrus, composed by ‘new-Romans’ after the Constitutio Antoniniana, exhibit a completely different concept: a stipulation-clause confirming a past, contractually significant activity. It is asked (but not conclusively answered) to what extend this alternative formulation has paved the way to the abandonment of the ‘Pomponian tenet’ by the emperor Leo in 472 ce (CJ 8.37.10). As we draw from Justinian’s interpretation of CJ 8.37.10 in Inst. 3.15.1, the sollemnia verba, the use of which became outdated after Leo, was not the language of the stipulation-clause as incorporated in the written documentation of the contract, but that of the act of stipulatio, which, as before, was meant in the keep verbal.

Cell transplantation: history of development, bioetic and legal aspects, prospects for treatment traumatic brain injury

In the modern world, a doctor of any specialty knows about a relatively new direction in the treatment of severe and previously untreatable diseases - stem cell (SC) transplantation. A scientific discussion around this is an actively developing direction. At present time laboratory studies of the cell therapy have gone beyond the limits of the experiment and began to actively find their application in practical medicine, which gives rise to scientific, ethical, legal and legislative problems. Thousands of laboratory experiments and clinical studies are carried out around the world, hundreds of stem cell culture laboratories and clinics are opened that use cell transplantation for the treatment of a wide range of diseases. The world governments start introduce SC transplantation into the medical system. The classical dogma that CNS cells are unable to regenerate has been challenged in recent decades by studies demonstrating new mechanisms of stem cell migration in the brain in trauma models. One of the most popular and promising areas for using cell therapy is treatment of nervous system diseases. Today, the actual problem for society is the cost of treating the consequences of moderate and severe traumatic brain injury, due to the wide prevalence (30-40% of all types of traumas), high disability rate in the working-age population and the global trend increase number of TBI cases by constant development of the technogenic environment. The review provides information on the history of development, legal, bioethical aspects, the prospects for the use of SC in the treatment of TBI.

BMP8 and activated brown adipose tissue in human newborns

The classical dogma states that brown adipose tissue (BAT) plays a major role in the regulation of temperature in neonates. However, although BAT has been studied in infants for more than a century, the knowledge about its physiological features at this stage of life is rather limited. This has been mainly due to the lack of appropriate investigation methods, ethically suitable for neonates. Here, we have applied non-invasive infrared thermography (IRT) to investigate neonatal BAT activity. Our data show that BAT temperature correlates with body temperature and that mild cold stimulus promotes BAT activation in newborns. Notably, a single short-term cold stimulus during the first day of life improves the body temperature adaption to a subsequent cold event. Finally, we identify that bone morphogenic protein 8B (BMP8B) is associated with the BAT thermogenic response in neonates. Overall, our data uncover key features of the setup of BAT thermogenesis in newborns.

Neuroinflammation in Autoimmune Disease and Primary Brain Tumors: The Quest for Striking the Right Balance.

According to classical dogma, the central nervous system (CNS) is defined as an immune privileged space. The basis of this theory was rooted in an incomplete understanding of the CNS microenvironment, however, recent advances such as the identification of resident dendritic cells (DC) in the brain and the presence of CNS lymphatics have deepened our understanding of the neuro-immune axis and revolutionized the field of neuroimmunology. It is now understood that many pathological conditions induce an immune response in the CNS, and that in many ways, the CNS is an immunologically distinct organ. Hyperactivity of neuro-immune axis can lead to primary neuroinflammatory diseases such as multiple sclerosis and antibody-mediated encephalitis, whereas immunosuppressive mechanisms promote the development and survival of primary brain tumors. On the therapeutic front, attempts are being made to target CNS pathologies using various forms of immunotherapy. One of the most actively investigated areas of CNS immunotherapy is for the treatment of glioblastoma (GBM), the most common primary brain tumor in adults. In this review, we provide an up to date overview of the neuro-immune axis in steady state and discuss the mechanisms underlying neuroinflammation in autoimmune neuroinflammatory disease as well as in the development and progression of brain tumors. In addition, we detail the current understanding of the interactions that characterize the primary brain tumor microenvironment and the implications of the neuro-immune axis on the development of successful therapeutic strategies for the treatment of CNS malignancies.

Enhanced response of radioresistant carcinoma cell line to heterogeneous dose distribution of grid; the role of high-dose bystander effect

Purpose The classical dogma that restricted the radiation effect to the directly irradiated cells has been challenged by the bystander effect. This off-target phenomenon which was manifested in adjacent cells via signaling of fully exposed cells might be involved in high-dose Grid therapy as well. Here, an in-vitro study was performed to examine the possible extent of carcinoma cells response to the inhomogeneous dose distribution of Grid irradiation in the context of the bystander effect. Materials and methods Bystander effect was investigated in human carcinoma cell lines of HeLa and HN5 adjacent to those received high-dose Grid irradiation using ‘medium transfer’ and ‘cell-to-cell contact’ strategies. Based on the Grid peak-to-valley dose profile, medium transfer was exerted from 10 Gy uniformly exposed donors to 1.5 Gy uniformly irradiated recipients. Cell-contact bystander was evaluated after nonuniform dose distribution of 10 Gy Grid irradiation using cloning cylinders. GammaH2AX foci, micronucleus and clonogenic assays besides gene expression analysis were performed. Results Various parameters (ɑ/β, D37, D50) extracted from survival curve which fitted to the Linear Quadratic model, verified more radioresistance of HN5. Survival fraction at 2 Gy (SF2) indicated as 0.42 ± 0.06 in HeLa and 0.5 ± 0.03 in HN5. The level of survival decrease, DNA damages and micronucleus of cells located in the Grid shielded areas (1.5 Gy cell-to-cell contact bystander cells) were significantly more than the values obtained from cells which were irradiated by merely uniform dose of 1.5 Gy. The gH2AX foci and micronuclei frequencies were enhanced in cell-contact bystander approximately more than 1.8 times. Relative expression of DNA damage repair pathway genes (Xrcc6 and H2afx) in bystander cells increased significantly. The most cell survival reduction (11.6 times) was revealed in the Grid bystander cells of radioresistant cell line (HN5). No statistically significant difference between 10 Gy uniform beam and Grid non-uniform beam was observed. Conclusions Various endpoints confirmed an augmented response of cells in the valley dose region of the Grid block significantly (compared with the cells irradiated by identical dose of uniform beam), suggesting the role of high-dose bystander effect which was more pronounced in resistant carcinoma cell lines. These findings could provide a partial explanation for the Grid beneficial response seen in a number of pre-clinical and clinical studies.

Two parallel worlds of memory T cells.

In contrast with the classical dogma that the pathways generating either memory or ‘exhausted’ T cells are strictly segregated, data now identify a clonally distinct hybrid memory T cell subpopulation with an exhausted phenotype.

Acute Kidney Injury: A Bona Fide Complication of Diabetes.

The landscape of kidney disease in diabetes has shifted. The classical dogma of "diabetic nephropathy" progressing through stages of albuminuria, leading to decline in glomerular filtration rate and end-stage kidney disease (ESKD), has been replaced by a more nuanced understanding of the complex and heterogeneous nature of kidney disease in diabetes. Paralleling this evolution, standardized definitions have resulted in a growing appreciation that acute kidney injury (AKI) is increasing in its incidence rapidly and that people with diabetes are much more likely to develop AKI than people without diabetes. Here, I propose that AKI should be considered a complication of diabetes alongside other complications that similarly do not fit neatly into the historical microvascular/macrovascular paradigm. In this article, we take a look at the evidence indicating that diabetes is a major risk factor for AKI and we review the causes of this increased risk. We consider the long-term implications of AKI in diabetes and its potential contribution to the future development of chronic kidney disease, ESKD, and mortality. Finally, we look toward the future at strategies to better identify people at risk for AKI and to develop new approaches to improve AKI outcomes. Recognizing AKI as a bona fide complication of diabetes should open up new avenues for investigation that may ultimately improve the outlook for people living with diabetes and at risk for kidney disease.

Frontal lobectomy: From an historical view to new concepts

Almost a century ago, neurosurgeons performed the first surgical disconnections of the frontal lobe (leucotomies) in psychiatric diseases, and then frontal lobectomies (FL), mainly in epilepsy. Since these initial resections, which induced a high rate of neurologic consequences, FL were conceptually associated to a combination of cognitive, emotional and behavioral symptoms known under the term of “frontal syndrome”. However, because of a recent paradigmatic shift from a localizationist to a connectomal theory of neural processing, and thanks to advances in brain mapping techniques, the traditional concept of irrevocable frontal syndrome generated by FL has been called into question [1] . Indeed, in the more recent field of neurooncological surgery, massive FL have been achieved up to individual eloquent networks identified by intraoperative direct electrical stimulation both at cortical and subcortical levels [2] . Using this philosophy of functional mapping-based resection, the existence of a huge potential of cortical plasticity has been evidenced, allowing a preservation of neurologic and neurocognitive status, including executive functions, mentalizing and metacognition, following unilateral or even bilateral FL [3] . Such a functional compensation is possible owing to the preservation of the white matter tracts that represent the limitation of neuroplasticity [4] . In fact, to prevent the occurrence of a “frontal syndrome”, which is most of the time the consequence of a dysconnectionism syndrome, the goal of FL is to surgically spare the intra-lobar connectivity (e.g. the frontal aslant tract), the inter-lobar long-range association fibers (e.g. the superior longitudinal fasciculus, arcuate fasciculus and inferior fronto-occipital fasciculus) as well as the projection fibers (e.g. the fronto-striatal tract) [5] . This improved knowledge of the functional connectome enables to significantly increase the overall survival while preserving the quality of life of brain tumor patients [6] . In addition, these new insights into cerebral processing can be applied to other fields of neurosurgery, such as brain-computer interface, to neurology and neurorehabilitation, by elaborating specific programs of cognitive remediation, and to basic neurosciences by proposing new behavioral models challenging the classical localist dogma.

To be or not to be cell autonomous? Autophagy says both.

Although cells are a part of the whole organism, classical dogma emphasizes that individual cells function autonomously. Many physiological and pathological conditions, including cancer, and metabolic and neurodegenerative diseases, have been considered mechanistically as cell-autonomous pathologies, meaning those that damage or defect within a selective population of affected cells suffice to produce disease. It is becoming clear, however, that cells and cellular processes cannot be considered in isolation. Best known for shuttling cytoplasmic content to the lysosome for degradation and repurposing of recycled building blocks such as amino acids, nucleotides, and fatty acids, autophagy serves a housekeeping function in every cell and plays key roles in cell development, immunity, tissue remodeling, and homeostasis with the surrounding environment and the distant organs. In this review, we underscore the importance of taking interactions with the microenvironment into consideration while addressing the cell autonomous and non-autonomous functions of autophagy between cells of the same and different types and in physiological and pathophysiological situations.

Information Society for Enlightened Voting

Among the millions of words uttered and written on the subject of democracy,Winston Churchill’s are among the most famous:“Democracy is the worst form of government except all those other forms thathave been tried from time to time.” [4] The occasion of the remark – it was madeon 11 November 1947, when the great wartime leader spoke for the oppositionin Britain’s House of Commons – is a reminder of how far the world has sincetravelled. Yet the passing of six decades notwithstanding, mankind is stillsubservient to the classical dogma embodied in Churchill’s phrase: that democracyis synonymous with universal suffrage.It was always open to question. But today, new and evolving technologiesenable us to discard it – not to abolish democracy (who would want to do that?),but to enrich democracy with more effective, more innovative and more moralforms of enlightened government across the world.

Fisher, Neyman, and Bayes at FDA

ABSTRACTThe wise use of statistical ideas in practice essentially requires some Bayesian thinking, in contrast to the classical rigid frequentist dogma. This dogma too often has seemed to influence the applications of statistics, even at agencies like the FDA. Greg Campbell was one of the most important advocates there for more nuanced modes of thought, especially Bayesian statistics. Because two brilliant statisticians, Ronald Fisher and Jerzy Neyman, are often credited with instilling the traditional frequentist approach in current practice, I argue that both men were actually seeking very Bayesian answers, and neither would have endorsed the rigid application of their ideas.

CBIO-45DNA METHYLATION DICTATES TRANSCRIPTION FACTOR BINDING AND GENE ACTIVATION IN BRAIN TUMOR

Dysregulation of DNA methylation is a hallmark of cancers including malignant brain tumors; yet the functional impact of DNA methylation on tumor malignancy remains largely elusive. Classical dogma states that promoter CpG island methylation (mCpG) influences tumor biology by silencing tumor suppressor genes through interfering with transcription factor (TF)-DNA binding. In this study, we challenge this view by showing that many TFs, including kruppel-like factor 4 (KLF4), preferentially bind to mCpG-containing motifs, and have the ability to activate gene expression. KLF4 is a cancer driver gene up-regulated in high-grade gliomas. We found that KLF4 can bind to mCpG-containing motifs in a sequence-specific manner and activate gene expression. We generated a KLF4 mutant (R458A) that no longer bound to methylated DNA motif but retained KLF4 binding to unmethylated motif. We engineered GBM cell lines to express either doxycycline (Dox)-inducible KLF4 wild type (KLF4-wt) or Dox-inducible KLF4R458A mutant (KLF4-mut) transgenes. Neither KLF4-wt nor KLF4-mut had appreciable effect on cell proliferation and cell viability. However, KLF4-wt but not KLF4-mut induced noticeable morphology changes characterized by elongated, spindle-like phenotypes. We further showed that KLF4-wt but not KLF4-mut promoted GBM cell migration and adhesion. This cell response was partially reversed by the DNA methytransferase inhibitor 5-aza-2′-deoxycytidine (5-Aza), confirming by alternate methods a DNA methylation-dependent mechanism. We employed cell-motility q-PCR arrays and found that ∼10 genes involved in the cell motility pathway, including the small GTPase RhoC, were up-regulated by KLF4-wt but not KLF4-mut. ChIP-PCR demonstrated that KLF4 bound to its promoter region of RhoC via a mCpG-dependent mechanism. These data reveal the novel mechanism by which DNA methylation at CpG sites regulates cancer cell phenotype through transcription factor-dependent gene transactivation. Our studies will be paradigm shifting and will substantially impact our understanding on how CpG methylation influences tumor cell behavior such as migration and invasion.

Abstract 2863: DNA methylation dictates transcription factor binding and gene activation in brain tumor

Abstract Dysregulation of DNA methylation is a hallmark in various types of cancers including malignant brain tumors. Although genome-wide methylation profiles (i.e., methylome) in brain tumors are increasingly becoming available, the functional impact of DNA methylation on tumor malignancy remains largely elusive. Classical dogma states that promoter CpG island methylation (mCpG) influences tumor biology by silencing tumor suppressor genes through interfering with transcription factor (TF)-DNA binding. In this study, we challenge this view by showing that many TFs, including krüppel-like factor 4 (KLF4), preferentially bind to mCpG-containing motifs and thereby transactivate gene expression. The cancer driver KLF4 is up-regulated in high-grade gliomas. We found that in addition to binding to conventional unmethylated DNA motifs, KLF4 bound to mCpG-containing motifs in a sequence-specific manner and thereby transactivated gene expression. We further demonstrated that the dual-binding activities of KLF4 were through distinct domains. Based on the crystal structure of KLF4, we generated a KLF4 mutant (R458A) that no longer bound to methylated DNA motif but retained KLF4 binding to unmethylated motif. This KLF4R458A mutant allowed us to uncouple the molecular and biological effects of KLF4-binding to methylated and unmethylated motifs in biological relevant systems such as glioblastoma (GBM) cells. We engineered GBM cell lines to express either doxycycline (Dox)-inducible KLF4 wild type (KLF4-wt) or Dox-inducible KLF4R458A mutant (KLF4-mut) transgenes. Neither KLF4-wt nor KLF4-mut had appreciable effect on cell proliferation and cell viability. However, compared with KLF4-mut expressing cells, KLF4-wt induced noticeable morphology changes characterized by elongated, spindle-like phenotypes. We further showed that KLF4-wt but not KLF4-mut promoted GBM cell migration and adhesion by scratch and transwell assays. This cell response was partially reversed by the DNA methytransferase inhibitor 5-aza-2′-deoxycytidine (5-Aza), confirming by alternate methods a DNA methylation-dependent mechanism. We employed cell-motility q-PCR arrays and found that ∼10 genes involved in the cell motility pathway were up-regulated by KLF4-wt but not KLF4-mut. Furthermore, for one of these genes, the small GTPase RhoC, ChIP-PCR demonstrated that KLF4 bound to its promoter region via a mCpG-dependent mechanism. Our separate large scale ChIP-sequencing revealed that KLF4 bound to ∼2733 DNA fragments through a methylation-dependent manner in brain tumor cells. These data reveal the novel mechanism by which DNA methylation at CpG sites regulates cancer cell phenotype through transcription factor-dependent gene transactivation. These findings are paradigm shifting and substantially impact our understanding on how CpG methylation influences tumor cell behavior such as migration and invasion. Citation Format: Shuli Xia, Qifeng Song, Jun Wan, Yijing Su, Yaxue Zheng, Hongjun Song, Jiang Qian, John Laterra, Heng Zhu. DNA methylation dictates transcription factor binding and gene activation in brain tumor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2863. doi:10.1158/1538-7445.AM2015-2863

Characterization of tissue-specific differential DNA methylation suggests distinct modes of positive and negative gene expression regulation.

BackgroundDNA methylation plays an important role in regulating gene expression during many biological processes. However, the mechanism of DNA-methylation-dependent gene regulation is not fully understood. Here, we explore two possible DNA methylation regulatory mechanisms with opposite modes of gene expression regulation.ResultsBy comparing the genome-wide methylation and expression patterns in different tissues, we find that majority of tissue-specific differentially methylated regions (T-DMRs) are negatively correlated with expression of their associated genes (negative T-DMRs), consistent with the classical dogma that DNA methylation suppresses gene expression; however, a significant portion of T-DMRs are positively correlated with gene expression (positive T-DMRs). We observe that the positive T-DMRs have similar genomic location as negative T-DMRs, except that the positive T-DMRs are more enriched in the promoter regions. Both positive and negative T-DMRs are enriched in DNase I hypersensitivity sites (DHSs), suggesting that both are likely to be functional. The CpG sites of both positive and negative T-DMRs are also more evolutionarily conserved than the genomic background. Interestingly, the putative target genes of the positive T-DMR are enriched for negative regulators such as transcriptional repressors, suggesting a novel mode of indirect DNA methylation inhibition of expression through transcriptional repressors. Likewise, two distinct sets of DNA sequence motifs exist for positive and negative T-DMRs, suggesting that two distinct sets of transcription factors (TFs) are involved in positive and negative regulation mediated by DNA methylation.ConclusionsWe find both negative and positive association between T-DMRs and gene expression, which implies the existence of two different mechanisms of DNA methylation-dependent gene regulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1271-4) contains supplementary material, which is available to authorized users.