139 research outputs found
Untersuchungen zur Regulierung und Funktion der Mitogen-aktivierten Proteinkinase ERK5 = Regulation and Function of the Mitogen-activated Protein Kinase ERK5
No full textMitogen activated protein kinases (MAPKs) are found in all eukaryotic cells and represent crucial elements in the signal transduction from the plasma membrane to the nucleus. Although a broad variety of extracellular stimuli activate MAPKs, they evoke very distinct cellular responses. The amplitude and duration of MAPK activation determine signal identity and ultimately cell fate. A tight and finely tuned regulation is therefore critical for a specific cellular response. The role and the regulation of extracellular signal-regulated kinase 5 (ERK5), a MAPK with a large and unique C-terminal tail, were studied in different cellular systems. The study highlights two aspects of ERK5 regulation: control of the phosphorylation state and regulated protein stability. In analogy to other MAPKs ERK5 is activated by dual phosphorylation of threonine and tyrosine residues in its activation motif. A first part of the study concentrates on whether and how the protein tyrosine phosphatase PTP-SL is involved in the downregulation of the ERK5 signal. The direct interaction of both proteins is shown to result in mutual modulation of their enzymatic activities. PTP-SL is a substrate of ERK5 and, independent of its phosphorylation, binding to the kinase enhances its catalytic phosphatase activity. On the other hand, interaction with PTP-SL does not only downregulate enzymatic ERK5 activity but also effectively impedes its translocation to the nucleus. The second part of this study focuses on the interaction of ERK5 with c-Abl and its oncogenic variants Bcr/Abl and v-Abl. In this study these tyrosine kinases are demonstrated to regulate ERK5 by two mechanisms: first, by induction of kinase activity and secondly, by stabilisation of the ERK5 protein. Stabilisation involves the direct interaction of unique ERK5 domains with Abl kinases and is independent of MAPK cascade activation. The level of ERK5 and its intrinsic basal activity – rather than its activation – are essential for v-Abl-induced transformation as well as for survival of Bcr/Abl-positive leukaemia cells. Stabilisation of ERK5 thus contributes to cell survival and should therefore be considered as an additional aspect in therapy of chronic myeloid leukaemia. Taken together, the results obtained in this study demonstrate that diverse pathways regulate ERK5 signalling by affecting kinase activity, localisation and protein stability. While the phosphatase PTP-SL is involved in negative regulation of ERK5, Abl kinases potently activate ERK5 and increase its half-life. Protein stabilisation thus is presented as a novel mechanism in the regulation of MAPKs.Mitogen-aktivierte Proteinkinasen (MAPKn) werden in allen eukaryontischen Zellen exprimiert und spielen eine bedeutende Rolle in der Weiterleitung von Signalen von der Plasmamembran zum Zellkern. Obwohl eine Vielzahl von unterschiedlichsten Stimulanzien MAPKn aktiveren, rufen diese doch sehr spezifische und vor allem adequate Reaktionen der Zelle hervor. Die molekularen Grundlagen für dieses Pradoxon sind weitgehend unbekannt. Es ist allerdings klar, daß die Amplitude und die Dauer der MAPKn-Aktivierung zwei entscheidende Parameter sind, die den weiteren Signalweg definieren und somit das Schicksal der Zelle festlegen. Daher müssen MAPKn einer sehr stringenten und fein regulierbaren Kontrolle unterliegen. In der vorliegenden Arbeit wurde die Funktion und die Regulierung der durch extrazelluläre Signale regulierten Kinase 5 (ERK5), einer MAPK mit einem außergewöhnlich langen und strukturell einzigartigen C-Terminus, in unterschiedlichen Zellsystemen untersucht. Zwei Aspekte der Regulierung von ERK5 werden insbesonders hervorgehoben: die Kontrolle des Phosphorilierungsstatus und die beeinflußbare Proteinstabilität. In Analogie zu anderen MAPKs wird ERK5 durch die Phosphorilierung eines Threonin und eines Tyrosinrestes aktiviert. Der erste Teil dieser Studie konzentriert sich auf die Frage ob und wie die Phosphatase PTP-SL und der Regulierung der ERK5 beteiligt sein könnte. Es konnte gezeigt werden, daß die direkte Interaktion dieser beiden Proteine zur gegenseitigen Beeinflussung ihrer enzymatischen Aktivitäten führt. PTP-SL ist nicht nur ein Substrat für die ERK5 sondern besitzt auch im Komplex mit ERK5 eine höhere Aktivität. Andererseits ist PTP-SL in der Lage, die Aktivität von ERK5 runterzuregulieren und darüber hinaus auch die Translokation von ERK5 in den Nucleus zu inhibieren. Der zweite Scherpunkt dieser Arbeit liegt auf der Wechselwirkung von ERK5 mit der Tyrosinkinasen c-Abl und ihren onkogenen Varianten Bcr/Abl und v-Abl. Es konnte gezeigt werden, daß diese Tyrosinkinasen ERK5 in zweierlei Weise beeinflussen: Erstens führen sie zur klassischen Aktivierung von ERK5 und zweitens stabilisieren sie das ERK5-Protein. Die Bedeutung der Proteinstabilisierung wurde durch die Untersuchung der Funktion von ERK5 bei von Abl-Kinase vermittelten Prozessen veranschaulicht. Sowohl für die Vestärkung Transformierung von Nagerfibroblasten durch v-Abl als auch für das Überleben von Bcr/Abl-positiven Leukämiezellen waren die Proteinmenge und die Basalaktivität und nicht etwa die Aktivierung von ERK5 ausschlaggebend. Zusammengenommen zeigen die Ergebnisse dieser Arbeit, daß die ERK5-vermittelte Signale durch Beeinflussung der Kinaseaktivität, der zellulären Lokalisation und der Proteinstabilität von ERK5 reguliert werden können. Während die Phosphatase PTP-SL an der Negativregulierung der ERK5 beteiligt ist, verstärken Abl-Kinasen ihre Aktivität und verlängern darüberhinaus die Halbwertszeit des Proteines in der Zelle. Proteinstabilisierung stellt somit einen neuen Aspekt in der Kontrolle von MAPKn dar
Barcelona conference on epigenetics and cancer 2016 – beyond cancer genomes
No full textThe Barcelona Conference on Epigenetics and Cancer (BCEC) entitled “Beyond Cancer Genomes” took place October 13th and 14th 2016 in Barcelona. The 2016 BCEC was the fourth edition of a series of annual conferences coordinated by Marcus Buschbeck and subsequently organized by leading research centers in Barcelona together with B•DEBATE, a joint initiative of BIOCAT and “La Caixa” Foundation. Salvador Aznar-Benitah, Eduard Batlle, and Raúl Méndez from the Institute for Research in Biomedicine in Barcelona selected the 2016 BCEC panel of speakers. As the title indicates, this year's conference expanded the epigenetic focus to include additional cancer-relevant topics, such as tumor heterogeneity and RNA regulation. Methods to develop therapeutic approaches on the basis of novel insights have been discussed in great detail. The conference has attracted 217 participants from 11 countries
The Role of macroH2A1 histone variant in muscle metabolism and development
No full textIn the eukaryotic nucleus, DNA, wrapped around a core of histone proteins. Replication-coupled histones can be exchanged by histone variants. In mammals, H2A can be replaced by three distinct macroH2A proteins. Alternative splicing of the macroH2A1 transcript further gives rise to macroH2A1.1 and macroH2A1.2 isoforms. We discovered that the expression of macroH2A1 splice isoforms switch during myogenic differentiation. From predominant expression of macroH2A1.2 in proliferating myoblasts to high expression of macroH2A1.1 in differentiated myotubes. This switch has two major consequences. First, both isoforms differentially regulate a number of genes and the dynamics of cell fusion. Second, macroH2A1.1 impacts on cellular metabolism by binding and inhibiting the major nicotinamide adenine dinucleotide-consuming enzyme in the nucleus, the cellular stress sensor PARP1. Finally, we provide evidence that the PARP1 inhibitory capacity of macroH2A is an ancestral function of the protein ranging back to the origins of multicellular life.En el núcleo eucariótico, el ADN se encuentra envuelto alrededor de un núcleo de proteínas histonas. Las histonas acopladas a la replicación pueden intercambiarse por variantes de histonas. La histona H2A puede ser reemplazada por tres proteínas macroH2A distintas. El empalme alternativo de la transcripción de macroH2A1 da lugar a las isoformas macroH2A1.1 y macroH2A1.2. La expresión de las isoformas de empalme macroH2A1 cambia durante la diferenciación miogénica: desde la expresión predominante de macroH2A1.2 en mioblastos en proliferación hasta la expresión alta de macroH2A1.1 en miotubos diferenciados. Este cambio tiene dos consecuencias principales. Primero, ambas isoformas regulan diferencialmente una serie de genes y la dinámica de la fusión celular. En segundo lugar, la macroH2A1.1 tiene un impacto en el metabolismo celular al unirse e inhibir el PARP1, la enzima que consume nicotinamida adenina dinucleótido. Finalmente, proporcionamos evidencia de que la capacidad inhibitoria macroH2A es una función ancestral de la proteína que se remonta a los orígenes de la vida multicelular.Programa de doctorat en Biomedicin
The consequences of cohesin mutations in myeloid malignancies
No full textThe author(s) declare financial support was received for the research, authorship, and/or publication of this article. SB and ED are funded by the Marie Skłodowska Curie Training network 'INTERCEPT-MDS' H2020-MSCA-ITN-2020-953407. Research in the Buschbeck lab is further supported by the following grants: the national grant PID 2021-126907NB-I00 from FEDER/Ministerio de Ciencia e Innovación-Agencia Estatal de Investigación, AGAUR 2021-SGR-260, Fundació La Marató de TV3 257/C/2019 and PRYGN222668BUSC from the Fundación AECC. Research at the IJC is supported by the 'La Caixa' Foundation, the Fundació Internacional Josep Carreras, Celgene Spain and the CERCA Programme/Generalitat de Catalunya.Recurrent somatic mutations in the genes encoding the chromatin-regulatory cohesin complex and its modulators occur in a wide range of human malignancies including a high frequency in myeloid neoplasms. The cohesin complex has a ring-like structure which can enclose two strands of DNA. A first function for the complex was described in sister chromatid cohesion during metaphase avoiding defects in chromosome segregation. Later studies identified additional functions of the cohesin complex functions in DNA replication, DNA damage response, 3D genome organisation, and transcriptional regulation through chromatin looping. In this review, we will focus on STAG2 which is the most frequently mutated cohesin subunit in myeloid malignancies. STAG2 loss of function mutations are not associated with chromosomal aneuploidies or genomic instability. We hypothesize that this points to changes in gene expression as disease-promoting mechanism and summarize the current state of knowledge on affected genes and pathways. Finally, we discuss potential strategies for targeting cohesion-deficient disease cells
The metabolic aspects of macroH2A histone variants
No full text[eng] The histone variant macroH2A is the only structural chromatin component containing a macrodomain. In vertebrates, two genes and one event of alternative splicing give rise to three macroH2A proteins that differ in their macrodomains. As histone variants, macroH2A proteins contribute to the protein content of chromatin (Buschbeck & Hake, 2017). On the other hand, the capacity to bind ADP-ribose via its macrodomain is limited to the splice variant macroH2A1.1 (Kustatscher et al., 2005). As a consequence, macroH2A1.1, but not macroH2A1.2 or macroH2A2, binds auto-ADP-ribosylated PARP1 (Timinszky et al., 2009). Since the alternative splicing of the exon 5 affects the binding pocket of macroH2A1.2, as a consequence it cannot bind ADP-ribose (Kustatscher et al., 2005) and it remains an orphan protein.
In the first study presented here, we investigated the evolution of the macrodomain-containing histone variant macroH2A1.1, an integral chromatin component that limits nuclear NAD+ consumption by inhibiting PARP1. We found that macroH2A originated in pre-metazoan protists. The crystal structure of the macroH2A macrodomain from the protist Capsaspora allowed us to identify highly conserved principles of ligand binding and pinpoint key residue substitutions, selected for during the evolution of the vertebrate stem lineage. Metabolic characterization of the Capsaspora life cycle indicated that the metabolic function of macroH2A was associated with non-proliferative stages. Taken together, we provide insight into the evolution of a chromatin element involved in compartmental NAD regulation, relevant for understanding of its metabolism and potential therapeutic applications.
In the second study, we described the structurally relevant elements for ligand binding by the orphan macroH2A isoform, macroH2A1.2. Furthermore, using targeted and untargeted approaches on the verge of in silico, in vitro and in cellulo approaches, we detected phospholipids as the first putative physiological ligands of macroH2A1.2. We further observed a behavioral phenotype in macroH2A1.2 knock-out mice and report for the first time the upregulation of macroH2A1.2 expression in the differentiated cells, more specifically in differentiated neurons. We postulate that macroH2A1.2 might have a binding-pocket related role in the regulation of behavior, similarly to what was observed for PPARα in hypothalamus, whereby it regulates animal behavior depending on the binding of its phospholipid ligands (Chakravarthy et al., 2007; Roy et al., 2016)
Role of histone variant macroH2A and other chromatin regulators in genome regulation and response to drugs
No full textThe relevance of epigenetics is increasingly recognized in haematopoietic diseases such as myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Variants of histones, such as macroH2As, and chromatin remodellers, such as the CHRAC complex, are key players in these epigenetic regulations. On the other hand, non-coding DNA regions, including long interspersed nuclear elements (LINEs), also show increasing relevance, notably in cancer. Here, we studied the relationship between LINEs and macroH2As in a hepatocarcinoma cell line. Computational analysis and experimental work led to conflicting results regarding a potential repressive role of macroH2As on LINEs. In addition, we studied the role of macroH2As as well as other chromatin regulators in the response to the epigenetic treatments Azacitidine and Decitabine in MDS/AML cell lines and a cohort of patient's samples. We were able to show that reduced expression of macroH2A1 and CHRAC complex component, BAZ1A, sensitized MDS/AML cell lines to epigenetic treatments. Furthermore, in patient sample, CHRAC complex components were less expressed in ten-eleven translocase 2 (TET2) mutants and in non-responders to Azacitidine.Cada vez se reconoce más la importancia de la epigenética en enfermedades hematopoyéticas como los síndromes mielodisplásicos (SMD) y la leucemia mieloide aguda (LMA). Las variantes de histonas, como las macroH2A, y los remodeladores de la cromatina, como el complejo CHRAC, son actores claves en estas regulaciones epigenéticas. Por otra parte, las regiones de ADN no codificante, incluidos los elementos nucleares intercalados largos (LINEs), también muestran una relevancia creciente, especialmente en el cáncer. Aquí estudiamos la relación entre los LINEs y las macroH2As en una línea celular de hepatocarcinoma. El análisis computacional y el trabajo experimental condujeron a resultados contradictorios respecto a un potencial papel represivo de las macroH2As sobre los LINEs. Además, estudiamos el papel de las macroH2As, así como de otros reguladores de la cromatina, en la respuesta a los tratamientos epigenéticos Azacitidina y Decitabina en líneas celulares de SMD/LMA y en una cohorte de muestras de pacientes. Pudimos demostrar que la reducción de la expresión de macroH2A1 y del componente del complejo CHRAC, BAZ1A, sensibilizó a las líneas celulares de SMD/LMA a los tratamientos epigenéticos. Además, en la muestra de pacientes, los componentes del complejo CHRAC se expresaban menos en los mutantes de la \textit{ten-eleven} translocasa 2 (TET2) y en los que no respondían a la Azacitidina.Programa de doctorat en Biomedicin
The role of the histone variant macroH2A in the regulation of chromatin architecture
No full textTesi realitzada a l'Institut de Recerca contra la Leucèmia Josep CarrerasIn the eukaryotic cell nucleus, DNA is tightly wrapped around histone complexes, forming a dynamic structure known as chromatin. The nucleosome particle is the basic repeating unit of the chromatin fiber and its protein core is composed of the so-called core histones: H2A, H2B, H3 and H4. Depending on the cellular and genomic context, replication-coupled histones can be exchanged by histone variants. The bulk of the cellular histone pool is composed of "canonical" or replication-coupled histones, but a smaller fraction is constituted by histone variants, that diverge to different extents in their primary sequence from their replication-coupled counterparts. The replacement of replication-coupled core histones by histone variants provides chromatin with specific characteristics and can influence all functions occurring on the chromatin template including transcription and DNA repair.
MacroH2A histones are the most divergent histone variants in terms of sequence and structure when compared to its replication-coupled counterpart: in addition to an N-terminal histone fold, they contain a highly basic and unstructured linker region and a large macro domain in the C-terminus. The linker protrudes outside of the compact histone core of the nucleosome placing the macro domain in a very accessible position. There are three different macroH2A proteins in vertebrates: macroH2A1.1, macroH2A1.2 and macroH2A2. Differences in the sequence of the macrodomain provoke changes in the size and hydrophobicity of the macrodomain pocket. The macrodomain of macroH2A1.1 is able to bind and, in some contexts, inhibit the activity of the enzyme poly-ADP-ribose polymerase 1 (PARP1).
Multiple studies have implicated macroH2A proteins in development, cellular differentiation, somatic cell reprogramming and cancer. In general, macroH2A histones are considered to be stabilizing epigenetic factors that correlate with differentiated states, but the precise molecular mechanism by which they act on chromatin and their role in transcriptional regulation is still a complex and incomplete picture.
The aim of my PhD has been to characterize the role of the group of macroH2A histone variants in chromatin organization and transcription. In the first part of this study, we studied the role of macroH2A in the nuclear organization of chromatin in HepG2 cells, revealing that macroH2A removal results in a global loss of heterochromatin organization. We found that a fraction of macroH2A is enriched in H3K9me3-marked heterochromatin and is necessary for maintaining the higher-order organization of repetitive elements and their attachment to lamin B1.
In the second part of this study, we aimed to characterize the molecular mechanisms and domain requirements of the function of macroH2A in chromatin dynamics and organization. All macroH2As can suppress DNA damage-induced chromatin expansion. MacroH2A1.1 has the strongest effect which reflects its capacity to inhibit PARP1, while the highly basic linker region of all macroH2As can limit chromatin expansion to a lesser degree in a PARP1-independent manner. Moreover, the macroH2A2 linker is essential and sufficient to maintain H3K9me3-marked heterochromatin architecture.
Finally, we wanted to describe the changes in the transcription and phenotype of cells in a cancer model that depend on the presence of macroH2A. HepG2 cells lacking macroH2A expression have an increased colony formation and migratory capacity. Transcriptomic profiling of tumors derived from HepG2 cells shows significant gene expression changes that depend on macroH2A, which includes deregulation of genes related to cellular adhesion, development, hypoxia and inflammation. This includes the upregulation of the cancer-promoting gene DKK1, which is rendered sensitive to activation in response to inflammatory TNFα signaling in the absence of macroH2A.
In conclusion, our results identified a major function for macroH2A in heterochromatin organization and identified two distinct mechanisms by which macroH2A histones can affect chromatin dynamics. In addition, loss of macroH2A results in transcriptional changes relevant in a cancer context. We suggest that stabilization of chromatin structures by macroH2A could provide a mechanism to explain its contribution to stable cell states.En el nucli eucariòtic l’ADN es troba embolicat al voltant d’un complex proteic d’histones, formant la unitat estructural bàsica de la cromatina: el nucleosoma. En contextos cel·lulars i genòmics específics, les histones que formen part del nucleosoma es poden intercanviar per variants d’histona, que difereixen en seqüència i estructura de les formes “canòniques” i proporcionen característiques específiques a la cromatina que poden afectar processos com la transcripció o la resposta a dany de l’ADN.
Les histones macroH2A són variants de la histona macroH2A que es caracteritzen per una estructura tripartida: a més d’un domini histona en N-terminal, contenen una regió connectora que sobresurt del nucli proteic del nucleosoma i posiciona de manera accessible un domini macro globular. Diversos estudis han implicat les histones macroH2A en el desenvolupament, la diferenciació cel·lular, la reprogramació i el càncer. En general, es considera que actuen com a elements estabilitzadors de l’epigenoma, però els mecanismes moleculars darrera d’aquest paper no estan ben definits.
L’objectiu de la meva tesi ha estat caracteritzar el paper de les histones macroH2A en la organització de la cromatina i la regulació. Mitjançant estudis de pèrdua de funció en cèl·lules HepG2, hem determinat que macroH2A és essencial per la organització de l’heterocromatina i en particular manté l’estructura d’elements genòmics repetitius i la seva interacció amb la lamina nuclear. També hem identificat un paper de la regió connectora, carregada positivament, en la limitació de l’expansió de la cromatina en resposta a dany de l’ADN i en el manteniment d’estructures heterocromàtiques. Finalment, l’estudi transcripcional de tumors derivats de cèl·lules HepG2 revela canvis transcripcionals dependents de macroH2A rellevants en el context del càncer. En concret, l’absència de macroH2A provoca una sobreexpressió del gen DKK1, associat a diferents tipus de càncer, i permet la seva activació davant estimulació inflamatòria amb TNFα.
En conclusió, aquest estudi revela un paper essencial de la histona macroH2A en la organització nuclear i proporciona evidències per un mecanisme molecular novell que implica la regió connectora de la proteïna. Addicionalment, l’absència de macroH2A provoca canvis transcripcionals rellevants en el context del càncer, en concret la sobreexpressió de DKK1. Proposem que l’estabilització d’estructures de cromatina per part de macroH2A pot proporcionar un mecanisme pel seu paper observat en mantenir estats transcripcionals i de diferenciació cel·lular estables
Epigenetic-Transcriptional Regulation of Fatty Acid Metabolism and Its Alterations in Leukaemia
No full textAltres ajuts: MM is supported by the Marie Skłodowska Curie Training network ChroMe (H2020-MSCA-ITN-2015-675610) and JD by a postdoctoral Sara Borrell fellowship from MINECO-ISCIII. Research in the Buschbeck lab is further supported by grants from MINECO-ISCIII, MINECO, the Deutsche Jose Carreras Leukaemie Stiftung and AGAUR . Research at the IJC is supported by the La Caixa Foundation, the Fundació Internacional Josep Carreras, Celgene Spain and the CERCA Programme/Generalitat de Catalunya.In recent years fatty acid metabolism has gained greater attention in haematologic cancers such as acute myeloid leukaemia. The oxidation of fatty acids provides fuel in the form of ATP and NADH, while fatty acid synthesis provides building blocks for cellular structures. Here, we will discuss how leukaemic cells differ from healthy cells in their increased reliance on fatty acid metabolism. In order to understand how these changes are achieved, we describe the main pathways regulating fatty acid metabolism at the transcriptional level and highlight the limited knowledge about related epigenetic mechanisms. We explore these mechanisms in the context of leukaemia and consider the relevance of the bone marrow microenvironment in disease management. Finally, we discuss efforts to interfere with fatty acid metabolism as a therapeutic strategy along with the use of metabolic parameters as biomarkers
The Role of histone variant macroH2A1 in muscle physiology and pathophysiology
No full textMacroH2A1.1 is one of the least understood histone variants and structural components of
chromatin. Generated by alternative splicing, macroH2A1.1 differs from the other macroH2A1
isoform in its capacity to bind NAD+-derived metabolites in vitro. This observation intrigued us
to speculate that macroH2A1.1 could link metabolic and epigenetic regulation. To test the
importance of this observation, we turned to skeletal muscle as this tissue is expressing the
highest levels of the metabolite-binding isoforms.
We demonstrate a switch in macroH2A1 splicing from the metabolite non-binding isoform to
macroH2A1.1 during normal myogenic differentiation. We demonstrate that macroH2A1.1 and
partly the integrity of its metabolite-binding pocket are important for proper myoblast fusion
and myotube maturation. We describe the altered bioenergetic and metabolic phenotype in
macroH2A1.1-depleted cells and correlate it to transcriptional alterations of genes. These
include genes encoding myosin heavy chain proteins, that are markers of muscle fibers differing
in their metabolic function. Correspondingly, we demonstrate a shift in the fiber type
composition of skeletal muscles from adult macroH2A1-deficient mice.
Therefore, we suggest that macroH2A1.1 is one of the epigenetic factors that define the
metabolic responsiveness of muscle relevant for whole body health and metabolic homeostasis.
We further venture the speculation that the alterations in skeletal muscles of macroH2A1-
deficient mice could contribute to their pre-diabetic phenotype.MacroH2A1.1 es una de las variantes de histonas y componentes estructurales de la cromatina
menos comprendidos. MacroH2A1.1 es generado por splicing alternativo y difiere de la otra
isoforma de macroH2A1 en su capacidad para unirse a metabolitos derivados de NAD+ in
vitro. Esta observación nos intrigó a especular que macroH2A1.1 podría vincular
metabolismo y regulación epigenética. Para probar la importancia de esta observación,
recurrimos a los músculos esqueléticos ya que observamos que este tejido expresa niveles
más altos de la isoforma macroH2A1.1.
Demostramos el cambio de la isoforma que no se une a metabolitos a macroH2A1.1 durante
diferenciación miogénica normal. Demostramos que macroH2A1.1 y en parte la integridad de
su bolsillo de unión a metabolitos son importantes para la adecuada fusión de mioblastos y
maduración de miotúbulos. Demostramos un fenotipo de la capacidad bioenergética y
metabólica alterada en las células deficientes en macroH2A1.1 y lo correlacionamos con
desregulación de expresión de los genes. Estos genes incluyen genes codificantes de la cadena
pesada de la miosina, proteinas marcadores de fibras musculares que difieren en su función
metabólica. Correspondientemente, observamos un cambio en la composición del tipo de
fibra de los músculos esqueléticos en ratones adultos deficientes en macroH2A1.
Por lo tanto, sugerimos que macroH2A1.1 es uno de los factores epigenéticos que definen la
respuesta metabólica de los músculos relevantes para la salud de todo el cuerpo y la
homeostasis metabólica. Nos atrevemos a especular que las alteraciones de músculos
esqueléticos en ratones deficientes en macroH2A1 podrían contribuir a su fenotipo
prediabético.Programa de doctorat en Biomedicin
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