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Via universitetsbibliotekets databas över doktorsavhandlingar kan du söka publicerade doktorsavhandlingar vid Göteborgs högskola/universitet från 1902 och framåt. Databasen innehåller också information om kommande disputationer.

UB:s databas över doktorsavhandlingar

Kommande disputationer

Interpretations of old wood. Figuring mid-twelfth century church architecture in west Sweden

[2017-11-23] Title: Interpretations of old wood. Figuring mid-twelfth century church architecture in west Sweden Authors: Linscott, Kristina Abstract: This thesis explores mid-twelfth century church architectures in west Sweden. The architectures are investigated in the light of a case, five parish churches’ naves, in particular their attics and surviving mid-twelfth century roofs. Working from the insight that these roofs were most likely visible from the rooms below, the thesis presents in-depth analysis of the sites, buildings, and their organisation of forms and volumes. The archaeological evidence is approached with architectural perspectives, and the study brings together a partly new view of the mid-twelfth century church architectures. The churches’ attics and roofs have seldom been in the focus in studies that interpret the historical church architectures. Thus, even if the uniquely old roofs are well preserved, we understand only fragments of how they may have been significant. The naves were created in a period before we have specific documentary evidence. Thus, as a study system, the idea that the archaeological physical remains establish ‘iterated, performed, articulations’ guide the work throughout. The physical evidence is approached with architectural perspectives. The historical architectures are viewed as a matrix for peoples’ beings and doings, which means that the architectures were both essential, present ‘everywhere’, and routine, ‘everyday’. The thesis presents relationships between the remains and architectural perspectives. Based on investigations in the buildings, and a 3D laser scan of one church, the analysis first focus on walls and roofs respectively and thereafter explores relationships between these. The interpretations show that the naves’ masonry walls formed a firm and ‘cave-like’ setting, and that the roofs contrasted with a light and ‘lively’ character. The roof in one nave, in Gökhems’ church, articulates or marks ‘zones’ in the room below, interpreted as the ‘west’, ‘middle’ and ‘east’. Thereafter the thesis focus attention on four architectural themes in a sequence of events, i.e. ‘discovery and approach’, ‘portal and doorway’, ‘entry and exploration’ and finally, ‘recalled in visual memory’. In these, the focus is on the same church in Gökhem however, some investigations connect to stave churches in Norway, as well as to a woven picture of a church, in a tapestry from north Sweden. In the last part, the thesis cast light on some important subsequent changes. The results provides a basis for future projects, pointing to the importance of the wooden built remains in Sweden and Norway, working from ‘site topology’, and analysis of medieval built environment from the viewpoint of preserved textiles. The five churches are part of a Swedish national heritage and they were, together with many other small churches in Sweden, extensively restored during the twentieth century. In this process, they lost some of their local diversity. As we now try to fit these monuments, which have a national identity, into an increasingly complex world with many identities, new understandings of the churches’ varying pasts are important. The thesis seeks to strengthen archaeological and architectural perspectives within conservation, and argues to include roofs as particularly significant, in future monument assessments.

Fitness, cognition and cardiovascular disease. Epidemiological studies.

[2017-11-23] Title: Fitness, cognition and cardiovascular disease. Epidemiological studies. Authors: Lindgren, Martin Abstract: Abstract Physical activity and fitness have well established health bringing benefits. Low soci-oeconomic status is a known risk factor for cardiovascular disease. This association is commonly attributed to individual factors such as educational attainment, supposedly bringing about health-related behaviours. However, individual factors do not fully account for the observed health disparities, demanding further investigation. The aims of this thesis were to investigate how physical activity and fitness varies according to neighbourhood socioeconomic status among middle-aged individuals in the Gothenburg region, using data collected for the SCAPIS-pilot study in 2012. Additional aims were to identify the role of factors related to fitness and cognitive function in the development of heart failure and cardiovascular disease in youth, with an extended follow up via population registries. For this purpose, we used data from the Swedish military service conscription registry, containing information of about 1.8 million Swedish men. We separately studied the association between cardiorespiratory fitness, muscle strength, resting heart rate, and cognitive capacity for future cardiovascular disease, recorded in the national inpatient- and cause of death registries. Data from the SCAPIS-pilot showed that inhabitants of low-SES areas have a lower general activity level, lower rate of fulfilment of the national physical activity guide-lines, and 12% lower levels of cardiorespiratory fitness, on average. These disparities translate into increased risk of cardiovascular disease, found in previous studies. Con-scripts with lower levels of cardiorespiratory fitness and muscle strength, lower cogni-tive test scores, and higher resting heart rate showed increased risk of developing heart failure at an early age. High resting heart rate was not associated with increased risk for any other of the cardiovascular outcomes that were studied. In summary, the results of this thesis provide new knowledge about how physical activity and cardiorespiratory fitness are potential mediators of social inequalities in cardiovascular disease. In addition, new information regarding factors in early life that influence cardiovascular health in middle age is provided. Keywords: Epidemiology, Physical activity, Fitness, Heart rate, Cognition, Heart failure

Rural/urban redux: Conceptual problems and material effects

[2017-11-20] Title: Rural/urban redux: Conceptual problems and material effects Authors: Dymitrow, Mirek Abstract: Concepts are the basic building blocks of all knowledge, while the strength of the theories that guide any societal project is dependent on the quality those concepts. Contrarily, the utilization of questionable concepts will result in questionable material effects. As two of the oldest geographical concepts still in widespread use, ‘rural’ and ‘urban’ stand in stark contrast to the immense changes encountered by society over the last century, let alone decades. Steady, fast-paced transformations in the environmental, economic and social dimensions have rendered the rural/urban binary a contentious one – a conceptual vestige of sorts, whose blurred and malleable characteristics, immense spatial coverage and aspectual all-inclusiveness have come to form an odd marriage between bygone world views and a globalized 21st-century reality of interconnectedness. The aim of this thesis is to critically evaluate our use of the concepts ‘rural/urban’ in order to help erase the contagion of indifference attached to them in a recalcitrant reality of admissibility. This compilation thesis consists of five theoretically and methodically diverse papers and a summative part inspired by a much wider range of ideas. By combining geographical perspectives with insights from critical theory, cognitive psychology and STS, this eclectic work addresses the phenomenon of rural/urban thinking using a new syntax and a new argumentative narrative with the ambition to change the way that thinking is apprehended and acted upon. With a focus on performativity, constitution and implications of concepts governed by various subject positions and psychosocial factors, this work lays the groundwork for an under-researched dimension of ‘rural/urban’ – that of the human condition – amidst an exceptionally rich conceptual literature on what ‘rural/urban’ “is” or “means”. Three basic conclusions stem from this work. Firstly, anyone talking about ‘rural/urban’ is performing it, and we have no mandate to project ‘rural/urban’ performances onto “people out there” and then evaluate how ‘rural/urban’ is like by examining those people’s actions. Secondly, ‘rural/urban’ are ridden with too many problems with regard to their basic conceptual constitution that their signification is unlikely to converge with what we are trying to explain. Thirdly, since ‘rural/urban’ as spatial concepts are often used with regard to human activities, there is a risk of conflating land with people, and thus forfeiting the core of our approach. Given these three important conceptual problems there is also the likelihood that ‘rural/urban’ may tacitly contribute to the retention of some pressing societal problems. This thesis makes the case for reconfiguring our relationship with familiar conceptions of societal organization. Its principal contribution is to help facilitate decisions on whether ‘rural/urban’ are truly analytically contributory to a specific line of action or whether they serve merely as a cultural ostinato acquired by external, scientifically and societally undesirable, mechanisms.

Clinical and Molecular Studies on Impacted Canines and the Regulatory Functions and Differentiation Potential of the Dental Follicle

[2017-11-20] Title: Clinical and Molecular Studies on Impacted Canines and the Regulatory Functions and Differentiation Potential of the Dental Follicle Authors: Uribe-Trespalacios, Pamela Abstract: Background: Impaction of the permanent maxillary canines, which is a common problem in dentistry, may require surgery and long-term orthodontic treatment. Until now, impaction has mostly been linked to physical obstructions and the direction of movement of the tooth. However, the molecular co-ordination of bone formation and bone resorption necessary for the eruption process, which is suggested to be regulated by the dental follicle, needs to be investigated further. Aims: The overall objectives of this thesis were to determine which clinical factors are related to impacted canines, and to investigate the regulatory functions and differentiation potential of the dental follicle. Patients and methods: The positions of impacted and normally erupting canines (orthopantograms), the skeletal variables (profile radiographs), and dento-alveolar traits (casts) were evaluated as potential predictive factors for impaction using a multivariate data analysis (N=90 patients). The gene expression profiles of boneregulatory markers were determined by RT-qPCR and immunofluorescence staining of human dental follicles. Whole dental follicles (N=11) obtained from impacted canines, with or without signs of root resorption, and from control teeth (normal erupting teeth and mesiodens), together with the apical (N=15) and coronal (N=15) segments (processed independently), were analysed. In vitro osteogenic differentiation of human dental follicle cells (hDFC) was followed by the quantification of gene expression of osteoblast-phenotypic markers and Alizarin Red staining. Quantifications of the molecular permeability of gap junctional intercellular communication and of CX43 expression were performed with the dye parachute technique and flow cytometry, respectively. Next-generation sequencing and bioinformatics processing were used for the identification of differentially regulated genes and pathways involved in the differentiation of hDFC. Results: Clinical variables related to the spatial location of the un-erupted tooth exert the strongest influences on impaction. However, they cannot be attributed to the cause of impaction, and they cannot be used as predictors. The RT-qPCR analyses revealed that the transcript levels for osteoclast-related markers (M-CSF, MCP-1, RANKL) were minimally expressed compared to those for osteoblastic markers (RUNX2, COL-1, OSX, ALP, OCN). No differential patterns of expression were identified between the impacted canines, with or without clinical signs of root resorption, or compared to the follicles from mesiodens or the normally erupting teeth. When the apical and coronal sections were analysed independently, significant differential expression was detected for the RANKL gene in the coronal part of the dental follicles, as compared with their corresponding apical parts. The induced expression levels of RANKL and OPG in cultured hDFC obtained from different patients were also significantly different. CX43 was observed to be highly expressed in the follicular tissues, and its expression was increased when the cells were cultured in osteogenic medium, and even further enhanced when the cells were exposed to silica (Si). We found that multipotent stem cells residing in the dental follicle could be induced to differentiate towards an osteoblastic lineage under favourable in vitro conditions, resulting in regulation of the osteoblastic phenotypic markers (RUNX2, OSX, BMP2, ALP, and OCN) and active deposition of a mineralised matrix. In addition, Si enhanced osteogenic differentiation in combination with osteogenic induction medium, as revealed by increases in the expression of CX43 and gap junction communication activity in the hDFC. Conclusions: The results presented in the thesis reveal that clinical variables are influential, but not determinants, for tooth impaction. The dental follicle in the late pre-eruptive stage mainly expresses osteoblastregulatory markers, whereas the levels of osteoclast-related markers are very low. Significant expression of CX43 and gap junction communication activity were detected, indicating an important role for these factors in the functional processes in the dental follicle. The significant upregulation of RANKL expression in the coronal part of the dental follicles suggests the importance of recruiting and activating osteoclasts, so as to form the eruption path through the alveolar bone. Moreover, the differential expression of induced RANKL in cultured hDFC may explain the diversity of events noted in the clinical setting during tooth eruption. Mesenchymal cells located in the dental follicle provide the optimal precursors, which can be cultured under in vitro conditions and further triggered with Si to differentiate towards an osteoblastic lineage.

”¿Es que crees que estoy loco?” La narración de la conciencia en tres novelas de Ramón Hernández

[2017-11-20] Title: ”¿Es que crees que estoy loco?” La narración de la conciencia en tres novelas de Ramón Hernández Authors: García Nespereira, Sofía Abstract: This dissertation aims to explore how one character’s alleged madness can be called into question. Ramón Hernández’s novels often create an ambiguity about events that befall the main character: have they imagined the plot or did it really happen in the novel’s world? Using three novels by Hernández, this thesis makes the assertion that it is the reader himself who has the last word. On the one hand, the stories show a character that is perceived as mad by her surroundings, but on the other hand, there are textual signals that allow an opposing view. Based on both classical and cognitive narratology, this study examines how the text constructs this ambiguity, and how, through different strategies, the text invites the reader to attribute a consciousness to the characters. The textual analysis shows how the novels encourage a reading in which the reader is asked to adopt the characters’ positions and to feel as they do. This will affect the reader's perception of the assumed madness of the character, which henceforth becomes problematic. Some features that can elicit contradictory responses in relation to the character’s consciousness are homonymy of narrators, which can create confusion as to who (both which narrator; and narrator or character) is speaking; unreliability, where the credibility of first-person narrators can create doubts about events within the narrative the prolific use of the historical present, where the ‘nows’ and ‘thens’ become temporally equalized; or the polysemy of perception verbs, where ‘see’ can also mean ‘remember’, ‘imagine’, ‘hallucinate’. The results of the study suggest that the doubt triggered by the texts can be explained by a narrative clash between two forces. Namely, the novels’ focus on the narration of a character’s experience in the way he/she perceives it, which create closeness between reader and character, and the use of strategies that threaten that closeness.

Language ability in patients with low-grade glioma - detecting signs of subtle dysfunction

[2017-11-17] Title: Language ability in patients with low-grade glioma - detecting signs of subtle dysfunction Authors: Antonsson, Malin Abstract: Background: Low-grade glioma (LGG) is a slow-growing brain tumour often situated in or near areas involved in language and/or cognitive functions. Consequently, there is a risk that patients develop language impairments due to tumour growth or surgical resection. Purposes: The main aim of this thesis was to investigate language ability in patients with LGG in relation to surgical treatment. Language ability was investigated using various sensitive methods such as a test of high-level language. To acquire norms for the test used to investigate high-level language, normative values were obtained in a methodological study (Study I). Methods: In Study I, 100 adults were assessed using a Swedish test of high-level language (BeSS) and a test of verbal working memory. Relationships between these tests and demographic variables were investigated. In Study II, the language ability of 23 newly diagnosed LGG patients was assessed and compared with that of a reference group. The patients were also asked about self-perceived changes in language. In Study III, the language ability of 32 LGG patients was assessed before surgery, early after surgery and at three-months follow-up. The patients’ language ability was compared across these assessment points and with a reference group. Finally, in Study IV, 20 LGG patients wrote a short narrative before and after surgery. The aim was to explore whether the lexical-retrieval difficulties previously seen in oral language could be seen in writing as well. Keystroke logging was used to explore writing fluency and word-level pauses. Here, too, comparisons were made between the assessment points and with a reference group. Results and conclusions: Study I showed that demographic variables had a limited impact on performance on the BeSS whereas verbal working memory influenced performance. Hence verbal working memory was found to influence performance on a test of high-level language. In Study II, the LGG group performed worse than the reference group on tests of lexical retrieval. However, the majority of the newly diagnosed patients with presumed LGG had normal or nearly normal language ability prior to surgery. Only a few patients reported a change in their language ability. In Study III, most patients with a tumour in the left hemisphere manifested language impairment shortly after surgery, but the majority of them had returned to their pre-operative level of performance three months after surgery. Language impairment in patients with a tumour in the right hemisphere was rare at all assessment points. In Study IV, LGG patients had a higher proportion of pauses within words before surgery than the reference group did. After surgery, the patients’ production rate decreased and the proportion of pauses before words increased. Measures of lexical retrieval showed moderate to strong relationships with writing fluency both before and after surgery. The higher frequency of word-level pauses could indicate a lexical deficit. Overall, lexical-retrieval deficits were the most common type of impairment found both before and after surgery in patients with presumed LGG.

Community onset sepsis in Sweden - a population based study

[2017-11-17] Title: Community onset sepsis in Sweden - a population based study Authors: Ljungström, Lars Abstract: Sepsis and previously “severe sepsis” are concepts used for denoting organ dysfunction caused by acute infection. Organ dysfunction correlates to increased case fatality rates. Sepsis is a common cause of hospitalization. Currently, sepsis is estimated to annually cause 30 million cases and 6 million deaths worldwide. The aims of this study were to explore the epidemiology, characteristics, and outcome of commu-nity onset severe sepsis in the adult population in Skaraborg, western Sweden. During a 9-month period, Sept. 2011 – June 2012, 2,462 consecutive episodes in 2,196 patients admitted to Ska-raborg Hospital and treated with intravenous antibiotics, were evaluated per protocol. The incidence of severe sepsis was 276/100,000. Age >85 years, cardiovascular disease, and diabetes mellitus were risk factors for acquiring severe sepsis. In 429 patients with severe sepsis, the 28-day case fatality rate was 25%, versus 4% in 1,767 with non-severe sepsis or no sepsis. Risk factors for 28-day case fatality were age >85 years, renal-, respiratory-, and cerebral dysfunc-tion. The respiratory tract was the most common focus of infection, seen in 41%. Applying the new sepsis definition launched in 2016 to this study population, the incidence of sepsis was 876/100,000 and the 28-day case fatality rate was 12%. During six weeks of the study, samples from 383 consecutive episodes of suspected sepsis in the emergency department were analyzed by multiplex polymerase chain reaction (PCR) for rapid detection of pathogenic bacteria in blood. We found that the multiplex PCR added some diagnostic value by detecting clinically relevant bacteria not identified by blood culture. During winter 2012, 432 nasopharyngeal samples were examined for respiratory viruses using multiplex PCR. We noted that viral infections or co-infections with bacteria were underestimated in patients with suspected sepsis, especially Influenza A virus, human metapneumovirus and respira-tory syncytial virus. Commonly used biomarkers for sepsis identification, lactate, C-reactive protein, procalcitonin and the neutrophil to lymphocyte count ratio (NLCR), were evaluated in 1,572 episodes of suspected sepsis. The combination of three or four biomarkers could improve the diagnosis of severe sepsis, having a sensitivity of 85%. In patients with proven bacterial infection of any severity, the neutro-phil to lymphocyte count ratio or procalcitonin exhibited equivalent performance. Six defined symptoms of sepsis; fever, dyspnea, acute change of mental status, severe pain, vomit-ing/diarrhea and muscle weakness were evaluated for early detection sepsis patients. Occurrence of >3 of these symptoms significantly predicted the presence or development of severe sepsis or septic shock, especially acute change of mental status and dyspnea.

Achilles tendon rupture: the evaluation and outcome of percutaneous and minimally invasive repair

[2017-11-17] Title: Achilles tendon rupture: the evaluation and outcome of percutaneous and minimally invasive repair Authors: Carmont, Michael R Abstract: Acute Achilles tendon rupture is common and has increasing incidence. This is thought to be due to increasing activity and sports participation in middle age. Sustaining an Achilles tendon rupture means a long rehabilitation period and many patients do not achieve full recovery of strength and function. One of the reasons for this reduced function is considered to be due to tendon elongation. The reasons for the lack of recovery has been discussed in earlier studies comparing operative and non-operative treatments. Operative treatment can be divided into open, minimally-invasive and percutaneous technique. Proponents for operative treatment consider open technique to prevent tendon elongation and reduce the re-rupture rate compared with non-operative treatment. Percutaneous repair is considered to lead to an increasing incidence of iatrogenic nerve damage and reduced repair strength compared with open repair but is considered to be advantageous because of lower risk of infections and wound problems. The purpose of this dissertation was to evaluate and optimise the results of percutaneous and minimally-invasive technique for an Achilles tendon rupture. Moreover, evaluation instruments were developed and an already existing validated questionnaire was culturally adapted in English to be used in the United Kingdom. Achilles Tendon Resting Angle (ATRA) is an indirect measure of tendon elongation. The method has been developed and validated in one of the studies in the dissertation. ATRA has subsequently been used to evaluate the clinical outcomes. The ATRA angle increases after an Achilles tendon rupture, then decreases after operative intervention to finally increase again during the first rehabilitation phase. The ATRA angle was shown to correlate with patient-reported symptoms and function as measured by heel rise height one year after injury. Thus, ATRA can provide an indication of function achieved after treatment of an Achilles tendon rupture. Achilles Tendon Total Rupture Score (ATRS) is a validated patient-reported questionnaire for evaluating limitations and physical activity after an Achilles tendon rupture. ATRS was originally developed for a Swedish population but has now been translated and culturally adapted to an English population in one of the studies. ATRS has also been used for evaluating patient-reported outcomes. Percutaneous and minimally-invasive operative techniques have been evaluated in 169 patients treated for an Achilles tendon rupture. Percutaneous technique was found to be more cost-effective in comparison to open procedure, with similar results regarding function and patient-reported symptoms. Minimally invasive repairs produced similar outcome to percutaneous repair but with a lower complication rate. Based on these results, minimally invasive repair is recommended for the operative treatment of an acute Achilles tendon rupture. In order to compare the strength of different suture materials after repair of the Achilles tendon, a cadaveric study was performed, in which the tendon was cyclically loaded. The result from this study shows that repair with non-absorbable suture has better strength in comparison to an absorbable one. However, there is still a lack of knowledge of why a patient suffering from an Achilles tendon rupture does not fully recover. Further studies involving how treatment and rehabilitation can be optimised is of value.

Acute Achilles tendon rupture - The impact of calf muscle performance on function and recovery

[2017-11-17] Title: Acute Achilles tendon rupture - The impact of calf muscle performance on function and recovery Authors: Brorsson, Annelie Abstract: There is an ongoing debate about the optimal treatment for patients with an acute Achilles tendon rupture. The overall purpose of this thesis was to acquire a greater knowledge of the way patients recover at different time points after the injury when treated with the currently recommended treatment protocols. This knowledge will then form the basis of the further development of treatment strategies with the ultimate goal of minimizing the risk of permanent disability after an Achilles tendon rupture. In Study I, a long-term follow-up of 66 patients included in a randomized, controlled trial revealed that, 7 years after the injury, there were continuing deficits in calf muscle endurance and strength. There was no continued improvement in calf muscle performance after the 2-year follow-up, apart from heel-rise height. Study II, a clinical prospective comparative study of a cohort of 93 patients, performed 3 months after the injury, concluded that standardized seated heel-rises were a safe and useful tool for evaluating calf muscle endurance and predicting future function and patient-reported symptoms. No differences in early calf muscle recovery were found between patients treated with surgery and patients treated with non-surgery, but the question of whether women recovered in the same way as men remained unanswered. In Study III, a clinical retrospective comparative study comprising 182 patients, it was found that female patients had a greater degree of deficit in heel-rise height compared with males, irrespective of treatment. Females had more symptoms after surgery, at both 6 and 12 months, but this difference was not found in non-surgically treated female patients. In Study IV, the effect of continued heel-rise height deficits on biomechanics during walking, running and jumping was further evaluated. This study revealed that heel-rise height, obtained during the single-leg standing heel-rise test, performed 1 year after the injury, was related to the long-term ability to regain normal ankle biomechanics. In this cross-sectional study, comprising 34 patients, the conclusion was drawn that minimizing tendon elongation and regaining heel-rise height may be important for the long-term recovery of ankle biomechanics, particularly during more demanding activities such as jumping. This thesis shows that the early recovery of heel-rise height and calf muscle endurance has a significant impact on lower leg function and patient-reported outcome in the long term after an acute Achilles tendon rupture. No differences in early or late calf muscle recovery were found between patients treated with surgery and patients treated with non-surgery. Furthermore, it is concluded that females have more symptoms after surgery, but this difference is not found in non-surgically treated female patients. This knowledge could now form a new basis for developing more effective, individualized treatment protocols with the aim of optimizing the treatment after an acute Achilles tendon rupture.

Characterizing the role of long non coding RNAs epigenetic regulators in disease model

[2017-11-17] Title: Characterizing the role of long non coding RNAs epigenetic regulators in disease model Authors: Mishra, Kankadeb Abstract: Long non-coding RNAs (lncRNAs) are a class of biological molecules which are transcribed from DNA but are not translated into any protein. LncRNAs have been identified as critical players in gene regulation. Misregulation of lncRNAs has been considered as one of the underlying causes for cancer pathogenesis and in other human diseases. In the current thesis, I have addressed the epigenetic roles of lncRNAs in regulating gene expression in cell line based and disease model systems. We investigated the functional role of lncRNAs in the maintenance of active chromatin by sequencing lncRNAs associated with active chromatin enriched with H3K4me2 and WDR5. We identified 209 lncRNAs to be commonly enriched in H3K4me2 and WDR5 pulldown chromatin fractions and we named them as active chromatin associated RNAs (active CARs). Interestingly, 41% of active CARs mapped to divergent transcription units having transcription factor genes as their partner. CARs were found to regulate the expression of partner protein coding genes at the transcriptional level by recruiting WDR5 to maintain the active histone marks H3K4me2/H3K4me3 at these promoters. Depletion of active CARs results in reduced WDR5and H3K4me2/H3K4me3 occupancy at these promoters. However, in absence of WDR5, we found the levels of H3K4me2 to remain unchanged at divergent promoters. Taken together our findings indicates that, conversion of H3K4me2 to H3K4me3 is mediated via active CARs-WDR5 interaction at the active divergent promoter, whereas, the maintenance of H3K4me2 marks appears to be WDR5 independent. Additionally, we used transcriptome profiling approach, to identify lncRNAs that are differentially expressed between low- and high- risk neuroblastoma tumours. We report NBAT-1 lncRNA as an independent prognostic biomarker in predicting clinical outcome of neuroblastoma patients. The expression profile analysis showed NBAT-1 to be lowly expressed in high-risk tumours relative to low-risk tumours. Using cell line and mouse models we characterized NBAT-1 as a tumour suppressor lncRNA which regulates gene expression by interaction with PRC2 repressive chromatin complex. NBAT-1 lncRNA promotes differentiation and acts as a tumour suppressor by epigenetic regulation of genes to inhibit cell proliferation and invasion. Thirdly, we sought to study genomic imprinting in a disease model. Genomic imprinting is an epigenetic regulation of gene expression in a parent of origin-specific manner. Studies in mouse have identified Kncq1 imprinted domain to be epigenetically regulated by a 91kb long lncRNA Kcnq1ot1 which is expressed from the paternal chromosome to silence imprinted genes in cis. Using BW-syndrome human disease model, we identified a maternal 11p15.5 micro duplication which included the 5′ 20 kb of the non-coding KCNQ1OT1 gene. Its maternal transmission was associated with ICR2 hypomethylation and familial BWS phenotype. Normally ICR2 is methylated to repress KCNQ1OT1, thereby allowing maternal copies of the imprinted genes including growth inhibitor CDKN1C to be expressed. We demonstrated that this duplicated maternal KCNQ1OT1 RNA also interacts with chromatin through its most 5′ 20 kb sequence to silence CDKN1C. This provides a mechanism for biallelic silencing of CDKN1C which contributes to the BWS disease phenotype. In summary, by ChRIP-seq, RNA expression profiling in tumours and human patient-derived cell line based model systems, we have uncovered new roles of lncRNA in epigenetic gene regulation.

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