Purpose: autism spectrum disorders are associated with defects in social response and communication that often occur in the context of intellectual disability. Rett syndrome is one example in which ...epilepsy, motor impairment, and motor disturbance may co-occur. Mutations in histone demethylases are known to occur in several of these syndromes. Herein, we aimed to identify whether mutations in the candidate histone demethylase JMJD1C (jumonji domain containing 1C) are implicated in these disorders. Methods: we performed the mutational and functional analysis of JMJD1C in 215 cases of autism spectrum disorders, intellectual disability, and Rett syndrome without a known genetic defect. Results: we found seven JMJD1C variants that were not present in any control sample (~ 6,000) and caused an amino acid change involving a different functional group. From these, two de novo JMJD1C germline mutations were identified in a case of Rett syndrome and in a patient with intellectual disability. The functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. We confirmed that JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity. Conclusions: our findings indicate that mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability.
Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous ...sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epigenetic regulation and, in particular, DNA methyl-
ation have been linked to the underlying genetic
sequence. DNA methylation quantitative trait loci
(meQTL) have been identified through ...significant
associations between the genetic and epigenetic
codes in physiological and pathological contexts.
We propose that interrogating the interplay between
polymorphic alleles and DNA methylation is a power-
ful method for improving our interpretation of risk
alleles identified in genome-wide association studies
that otherwise lack mechanistic explanation. We
integrated patient cancer risk genotype data and
genome-scale DNA methylation profiles of 3,649 pri-
mary human tumors, representing 13 solid cancer
types. We provide a comprehensive meQTL catalog
containing DNA methylation associations for 21%
of interrogated cancer risk polymorphisms. Differen-
tially methylated loci harbor previously reported and
as-yet-unidentified cancer genes. We suggest that
such regulation at the DNA level can provide a considerable amount of new information about the
biology of cancer-risk alleles.
Epigenetic regulation and, in particular, DNA methyl-
ation have been linked to the underlying genetic
sequence. DNA methylation quantitative trait loci
(meQTL) have been identified through ...significant
associations between the genetic and epigenetic
codes in physiological and pathological contexts.
We propose that interrogating the interplay between
polymorphic alleles and DNA methylation is a power-
ful method for improving our interpretation of risk
alleles identified in genome-wide association studies
that otherwise lack mechanistic explanation. We
integrated patient cancer risk genotype data and
genome-scale DNA methylation profiles of 3,649 pri-
mary human tumors, representing 13 solid cancer
types. We provide a comprehensive meQTL catalog
containing DNA methylation associations for 21%
of interrogated cancer risk polymorphisms. Differen-
tially methylated loci harbor previously reported and
as-yet-unidentified cancer genes. We suggest that
such regulation at the DNA level can provide a considerable amount of new information about the
biology of cancer-risk alleles.
Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we ...wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies.
Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we ...wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies.
Most of the studies characterizing DNA methylation patterns have been restricted to particular genomic loci in a limited number of human samples and pathological conditions. Herein, we present a ...compromise between an extremely comprehensive study of a human sample population with an intermediate level of resolution of CpGs at the genomic level. We obtained a DNA methylation fingerprint of 1628 human samples in which we interrogated 1505 CpG sites. The DNA methylation patterns revealed show this epigenetic mark to be critical in tissue-type definition and stemness, particularly around transcription start sites that are not within a CpG island. For disease, the generated DNA methylation fingerprints show that, during tumorigenesis, human cancer cells underwent a progressive gain of promoter CpG-island hypermethylation and a loss of CpG methylation in non-CpG-island promoters. Although transformed cells are those in which DNA methylation disruption is more obvious, we observed that other common human diseases, such as neurological and autoimmune disorders, had their own distinct DNA methylation profiles. Most importantly, we provide proof of principle that the DNA methylation fingerprints obtained might be useful for translational purposes by showing that we are able to identify the tumor type origin of cancers of unknown primary origin (CUPs). Thus, the DNA methylation patterns identified across the largest spectrum of samples, tissues, and diseases reported to date constitute a baseline for developing higher-resolution DNA methylation maps and provide important clues concerning the contribution of CpG methylation to tissue identity and its changes in the most prevalent human diseases
Most of the studies characterizing DNA methylation patterns have been restricted to particular genomic loci in a limited number of human samples and pathological conditions. Herein, we present a ...compromise between an extremely comprehensive study of a human sample population with an intermediate level of resolution of CpGs at the genomic level. We obtained a DNA methylation fingerprint of 1628 human samples in which we interrogated 1505 CpG sites. The DNA methylation patterns revealed show this epigenetic mark to be critical in tissue-type definition and stemness, particularly around transcription start sites that are not within a CpG island. For disease, the generated DNA methylation fingerprints show that, during tumorigenesis, human cancer cells underwent a progressive gain of promoter CpG-island hypermethylation and a loss of CpG methylation in non-CpG-island promoters. Although transformed cells are those in which DNA methylation disruption is more obvious, we observed that other common human diseases, such as neurological and autoimmune disorders, had their own distinct DNA methylation profiles. Most importantly, we provide proof of principle that the DNA methylation fingerprints obtained might be useful for translational purposes by showing that we are able to identify the tumor type origin of cancers of unknown primary origin (CUPs). Thus, the DNA methylation patterns identified across the largest spectrum of samples, tissues, and diseases reported to date constitute a baseline for developing higher-resolution DNA methylation maps and provide important clues concerning the contribution of CpG methylation to tissue identity and its changes in the most prevalent human diseases
La enfermedad de Alzheimer (EA) es una patología neurodegenerativa devastadora. Es la principal causa de demencia en las sociedades occidentales y actualmente no tiene cura. Sus síntomas no son ...evidentes hasta estados muy avanzados y su origen sigue siendo desconocido. Aunque se acepta que es una enfermedad multigénica, han sido pocos los genes asociados a la enfermedad y, conjuntamente, sólo pueden explicar un pequeño porcentaje de los casos. Se estima que cerca de 34 millones de personas están afectadas por la patología en todo el mundo y que esta cifra se duplicará en los próximos 20 años. Por lo que son necesarios más esfuerzos para identificar las causas que conducen a la aparición de esta patología.
En los últimos años la epigenética se ha mostrado como un mecanismo crucial en el funcionamiento del sistema nervioso y participa en la cognición, el aprendizaje y en la formación de la memoria. Muchas enfermedades neurológicas están causadas por mutaciones en la maquinaria epigenética y cada vez más indicios sugieren su importancia en muchas otras. La EA no es una excepción y los primeros estudios están empezando a identificar ya nuevos genes epigenéticamente alterados en la EA.
Conscientes de la importancia de la epigenética en el funcionamiento del sistema nervioso, el trabajo presentado en esta tesis ha pretendido profundizar en las causas de la EA desde un punto de vista epigenético. Para ello, hemos desarrollado nuevas herramientas de análisis epigenómico. Hemos determinado los patrones de metilación del cerebro de ratón y hemos identificado un subgrupo de genes alterados en modelos murinos y muestras post-mortem de EA. Además, hemos identificado genes epigenéticamente alterados desde las primeras fases de la enfermedad y hemos demostrado las consecuencias funcionales de dichas alteraciones.
En conjunto, los resultados presentados en esta tesis no sólo ponen de relieve la importancia de los cambios epigenéticos en la aparición y progresión de la EA sino que, además, ofrecen nuevas vías de diagnóstico y tratamiento reforzando la necesidad de incidir en esta vía de investigación que está empezando a ofrecer nuevas perspectivas para una enfermedad que actualmente no tiene cura.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder. It is the main cause of dementia in Western societies and currently has no cure. Symptoms only appear in late stages and it origin remains unknown. Although it is accepted that AD is a multigenic disease, few genes have been associated with these disease and, together, they only explain a small percentage of cases. It is estimated that around 34 million of people in the world is affected by AD and that this number will double in next 20 years. As consequence, more efforts are necessary to identify the causes of the disease.
In recent years, epigenetics has demonstrated to be crucial in nervous system and it is involved in cognition, learning and memory formation. Many neurological diseases are caused by mutations in the epigenetic machinery and many others are associated with epigenetic alterations. AD is not an exception and pioneer studies are starting to identify new genes epigenetically altered in these disease.
Due to the importance of epigenetics in nervous system, the work presented in this thesis aims to get insight of the causes of AD from an epigenetic perspective. To this end, we have developed new tools of epigenomic analysis, determined methylation patterns of mouse brain and described a subset of genes epigenetically altered in mouse models and post-mortem samples of AD. In addition, we have identified genes epigenetically altered from the earliest stages of the disease and demonstrated the functional consequences of these alterations.
In sum, the results presented in this thesis not only highlight the importance of epigenetic changes in the onset and progression of AD but also offer new avenues of diagnosis and treatments reinforcing the necessity of get deeper in this line of research that is already starting to provide a new perspectives for a disease that currently has no cure.
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