Research publications

Found 58 publicacions matching the indicated search criteria.
Marguerite-Marie Le Pannérer, Jeannine Diesch, Raquel Casquero, Michael Maher, Olga Garcia, Torsten Haferlach, Johannes Zuber, Andrea Kündgen, Katharina Götze, Marcus Buschbeck

Different Gene Sets Are Associated With Azacitidine Response In Vitro Versus in Myelodysplastic Syndrome Patients

HemaSphere 1 Nov 2022, 6 (11) .
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by dysplasia, ineffective hematopoiesis, and predisposition to secondary acute myeloid leukemias (sAML). Azacitidine (AZA) is the standard care for high-risk MDS patients not eligible for allogenic bone marrow transplantation. However, only half of the patients respond to AZA and eventually all patients relapse. Response-predicting biomarkers and combinatorial drugs targets enhancing therapy response and its duration are needed. Here, we have taken a dual approach. First, we have evaluated genes encoding chromatin regulators for their capacity to modulate AZA response. We were able to validate several genes, whose genetic inhibition affected the cellular AZA response, including 4 genes encoding components of Imitation SWItch chromatin remodeling complex pointing toward a specific function and co-vulnerability. Second, we have used a classical cohort analysis approach measuring the expression of a gene panel in bone marrow samples from 36 MDS patients subsequently receiving AZA. The gene panel included the identified AZA modulators, genes known to be involved in AZA metabolism and previously identified candidate modulators. In addition to confirming a number of previously made observations, we were able to identify several new associations, such as NSUN3 that correlated with increased overall survival. Taken together, we have identified a number of genes associated with AZA response in vitro and in patients. These groups of genes are largely nonoverlapping suggesting that different gene sets need to be exploited for the development of combinatorial drug targets and response-predicting biomarkers.
David Corujo, Roberto Malinverni, Juan Carrillo-Reixach, Oliver Meers, Arce Garcia-Jaraquemada, Marguerite-Marie Le Panne´rer, Vanesa Valero, Ainhoa Pérez, Álvaro Del Río-Álvarez, Laura Royo, Beatriz Pérez-González, Helena Raurell, Rafael D. Acemel, José M. Santos-Pereira, Marta Garrido-Pontnou, José Luis Gómez-Skarmeta, Lorenzo Pasquali, Josep Manyé, Carolina Armengol, Marcus Buschbeck

MacroH2As regulate enhancer-promoter contacts affecting enhancer activity and sensitivity to inflammatory cytokines

Cell Reports 21 Jun 2022, 39 (12) .
MacroH2A histone variants have a function in gene regulation that is poorly understood at the molecular level. We report that macroH2A1.2 and macroH2A2 modulate the transcriptional ground state of cancer cells and how they respond to inflammatory cytokines. Removal of macroH2A1.2 and macroH2A2 in hepatoblastoma cells affects the contact frequency of promoters and distal enhancers coinciding with changes in enhancer activity or preceding them in response to the cytokine tumor necrosis factor alpha. Although macroH2As regulate genes in both directions, they globally facilitate the nuclear factor κB (NF-κB)-mediated response. In contrast, macroH2As suppress the response to the pro-inflammatory cytokine interferon gamma. MacroH2A2 has a stronger contribution to gene repression than macroH2A1.2. Taken together, our results suggest that macroH2As have a role in regulating the response of cancer cells to inflammatory signals on the level of chromatin structure. This is likely relevant for the interaction of cancer cells with immune cells of their microenvironment.
Guberovic I, Farkas M, Corujo D, Buschbeck M

Evolution, structure and function of divergent macroH2A1 splice isoforms.

Semin Cell Dev Biol 11 Apr 2022, . Epub 11 Apr 2022
The replacement of replication-coupled histones with non-canonical histone variants provides chromatin with additional properties and contributes to the plasticity of the epigenome. MacroH2A histone variants are counterparts of the replication-coupled histone H2A. They are characterized by a unique tripartite structure, consisting of a histone fold, an unstructured linker, and a globular macrodomain. MacroH2A1.1 and macroH2A1.2 are the result of alternative splicing of the MACROH2A1 gene and can have opposing biological functions. Here, we discuss the structural differences between the macrodomains of the two isoforms, resulting in differential ligand binding. We further discuss how this modulates gene regulation by the two isoforms, in cases resulting in opposing role of macroH2A1.1 and macroH2A1.2 in development and differentiation. Finally, we share recent insight in the evolution of macroH2As. Taken together, in this review, we aim to discuss in unprecedented detail distinct properties and functions of the fascinating macroH2A1 splice isoforms.
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Fernández-Serrano M, Winkler R, Santos JC, Le Pannérer MM, Buschbeck M, Roué G

Histone Modifications and Their Targeting in Lymphoid Malignancies.

Int J Mol Sci 27 Dec 2021, 23 (1) . Epub 27 Dec 2021
In a wide range of lymphoid neoplasms, the process of malignant transformation is associated with somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction, and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes. In the last two decades, the field has made a major effort to develop therapies that target these epigenetic alterations. In this review, we discuss which epigenetic alterations occur in B-cell non-Hodgkin lymphoma. Furthermore, we aim to present in a close to comprehensive manner the current state-of-the-art in the preclinical and clinical development of epigenetic drugs. We focus on therapeutic strategies interfering with histone methylation and acetylation as these are most advanced in being deployed from the bench-to-bedside and have the greatest potential to improve the prognosis of lymphoma patients.
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Iva Guberovic, Sarah Hurtado-Bagès, Ciro Rivera-Casas, Gunnar Knobloch, Roberto Malinverni, Vanesa Valero, Michelle M. Leger, Jesús García, Jerome Basquin, Marta Gómez de Cedrón, Marta Frigolé-Vivas, Manjinder S. Cheema, Ainhoa Pérez, Juan Ausió, Ana Ramírez de Molina, Xavier Salvatella, Iñaki Ruiz-Trillo, Jose M. Eirin-Lopez, Andreas G. Ladurner, Marcus Buschbeck

Evolution of a histone variant involved in compartmental regulation of NAD metabolism

Nat Struct Mol Biol 28, 1009–1019 (2021). 9 Dec 2021, .
NAD metabolism is essential for all forms of life. Compartmental regulation of NAD+ consumption, especially between the nucleus and the mitochondria, is required for energy homeostasis. However, how compartmental regulation evolved remains unclear. In the present study, we investigated the evolution of the macrodomain-containing histone variant macroH2A1.1, an integral chromatin component that limits nuclear NAD+ consumption by inhibiting poly(ADP-ribose) polymerase 1 in vertebrate cells. We found that macroH2A originated in premetazoan protists. The crystal structure of the macroH2A macrodomain from the protist Capsaspora owczarzaki 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 lifecycle suggested that the metabolic function of macroH2A was associated with nonproliferative stages. Taken together, we provide insight into the evolution of a chromatin element involved in compartmental NAD regulation, relevant for understanding its metabolism and potential therapeutic applications.
Jeannine Diesch, Marguerite-Marie Le Pannérer, René Winkler, Raquel Casquero, Matthias Muhar, Mark van der Garde, Michael Maher, Carolina Martínez Herráez, Joan J. Bech-Serra, Michaela Fellner, Philipp Rathert, Nigel Brooks, Lurdes Zamora, Antonio Gentilella, Carolina de la Torre, Johannes Zuber, Katharina S. Götze & Marcus Buschbeck

Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis

Nat Commun 12, 6060 (2021). 18 Oct 2021, .
The nucleotide analogue azacitidine (AZA) is currently the best treatment option for patients with high-risk myelodysplastic syndromes (MDS). However, only half of treated patients respond and of these almost all eventually relapse. New treatment options are urgently needed to improve the clinical management of these patients. Here, we perform a loss-of-function shRNA screen and identify the histone acetyl transferase and transcriptional co-activator, CREB binding protein (CBP), as a major regulator of AZA sensitivity. Compounds inhibiting the activity of CBP and the closely related p300 synergistically reduce viability of MDS-derived AML cell lines when combined with AZA. Importantly, this effect is specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is only incorporated into DNA. The identification of immediate target genes leads us to the unexpected finding that the effect of CBP/p300 inhibition is mediated by globally down regulating protein synthesis.
Chen-Jen Hsu, Oliver Meers, Marcus Buschbeck, Florian H. Heidel

The Role of MacroH2A Histone Variants in Cancer

Cancers 2021, 13(12), 3003 15 Jun 2021, . Epub 15 Jun 2021
The epigenome regulates gene expression and provides a molecular memory of cellular events. A growing body of evidence has highlighted the importance of epigenetic regulation in physiological tissue homeostasis and malignant transformation. Among epigenetic mechanisms, the replacement of replication-coupled histones with histone variants is the least understood. Due to differences in protein sequence and genomic distribution, histone variants contribute to the plasticity of the epigenome. Here, we focus on the family of macroH2A histone variants that are particular in having a tripartite structure consisting of a histone fold, an intrinsically disordered linker and a globular macrodomain. We discuss how these domains mediate different molecular functions related to chromatin architecture, transcription and DNA repair. Dysregulated expression of macroH2A histone variants has been observed in different subtypes of cancer and has variable prognostic impact, depending on cellular context and molecular background. We aim to provide a concise review regarding the context- and isoform-dependent contributions of macroH2A histone variants to cancer development and progression.
Maximilian Lassi, Archana Tomar, Gemma Comas-Armangué, Rebekka Vogtmann
Dorieke J. Dijkstra, David Corujo, Raffaele Gerlini, Jonatan Darr, Fabienne Scheid, Jan Rozman, Antonio Aguilar-Pimentel, Omry Koren, Marcus Buschbeck, Helmut Fuchs, Susan Marschall, Valerie Gailus-Durner, Martin Hrabe de Angelis, Torsten Plösch, Alexandra Gellhaus and 
Raffaele Teperino

Disruption of paternal circadian rhythm affects metabolic health in male offspring via nongerm cell factors

Science Advances 26 May 2021: Vol. 7, no. 22, eabg6424 26 May 2021, .
Circadian rhythm synchronizes each body function with the environment and regulates physiology. Disruption of normal circadian rhythm alters organismal physiology and increases disease risk. Recent epidemiological data and studies in model organisms have shown that maternal circadian disruption is important for offspring health and adult phenotypes. Less is known about the role of paternal circadian rhythm for offspring health. Here, we disrupted circadian rhythm in male mice by night-restricted feeding and showed that paternal circadian disruption at conception is important for offspring feeding behavior, metabolic health, and oscillatory transcription. Mechanistically, our data suggest that the effect of paternal circadian disruption is not transferred to the offspring via the germ cells but initiated by corticosterone-based parental communication at conception and programmed during in utero development through a state of fetal growth restriction. These findings indicate paternal circadian health at conception as a newly identified determinant of offspring phenotypes.
Kumbhar R, Sanchez A, Perren J, Gong F, Corujo D, Medina F, Devanathan SK, Xhemalce B, Matouschek A, Buschbeck M, Buck-Koehntop BA, Miller KM

Poly(ADP-ribose) binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions.

J Cell Biol 18 May 2021, 220 (7) .
The histone demethylase KDM5A erases histone H3 lysine 4 methylation, which is involved in transcription and DNA damage responses (DDRs). While DDR functions of KDM5A have been identified, how KDM5A recognizes DNA lesion sites within chromatin is unknown. Here, we identify two factors that act upstream of KDM5A to promote its association with DNA damage sites. We have identified a noncanonical poly(ADP-ribose) (PAR)-binding region unique to KDM5A. Loss of the PAR-binding region or treatment with PAR polymerase (PARP) inhibitors (PARPi's) blocks KDM5A-PAR interactions and DNA repair functions of KDM5A. The histone variant macroH2A1.2 is also specifically required for KDM5A recruitment and function at DNA damage sites, including homology-directed repair of DNA double-strand breaks and repression of transcription at DNA breaks. Overall, this work reveals the importance of PAR binding and macroH2A1.2 in KDM5A recognition of DNA lesion sites that drive transcriptional and repair activities at DNA breaks within chromatin that are essential for maintaining genome integrity.
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Michael Maher, Jeannine Diesch, Marguerite-Marie Le Pannérer, Marcus Buschbeck

Epigenetics in a Spectrum of Myeloid Diseases and Its Exploitation for Therapy

Cancers 2021, 13(7), 1746 6 Apr 2021, .
Mutations in genes encoding chromatin regulators are early events contributing to developing asymptomatic clonal hematopoiesis of indeterminate potential and its frequent progression to myeloid diseases with increasing severity. We focus on the subset of myeloid diseases encompassing myelodysplastic syndromes and their transformation to secondary acute myeloid leukemia. We introduce the major concepts of chromatin regulation that provide the basis of epigenetic regulation. In greater detail, we discuss those chromatin regulators that are frequently mutated in myelodysplastic syndromes. We discuss their role in the epigenetic regulation of normal hematopoiesis and the consequence of their mutation. Finally, we provide an update on the drugs interfering with chromatin regulation approved or in development for myelodysplastic syndromes and acute myeloid leukemia.