Biology subjects

Vervoort, S.

Publications and source records attributed to Vervoort, S..

5 recordsLinked to original sources

bioRxiv2024

MORC2 phosphorylation fine tunes its DNA compaction activity

Variants in the poorly characterised oncoprotein, MORC2, a chromatin remodelling ATPase, lead to defects in epigenetic regulation and DNA damage response. The C-terminal domain (CTD) of MORC2, frequently phosphorylated in DNA damage, promotes cancer progression, but its role in chromatin remodelling remains unclear. Here, we report a molecular characterisation of full-length, phosphorylated MORC2, demonstrating its preference for binding open chromatin and functioning as a DNA sliding clamp. We identified a phosphate interacting motif within the CTD that dictates ATP hydrolysis rate and cooperative DNA binding. The DNA binding impacts several structural domains within the ATPase region. We provide the first visual proof that MORC2 induces chromatin remodelling through ATP hydrolysis-dependent DNA compaction, regulated by its phosphorylation state. These findings highlight phosphorylation of MORC2 CTD as a key modulator of chromatin remodelling, presenting it as a potential therapeutic target.

molecular biology↗

bioRxiv2021

Epigenetic changes in autoimmune monocytes contribute to disease and can be targeted by JAKinhibition

How the local inflammatory environment regulates epigenetic changes in the context of autoimmune diseases remains unclear. Here we assessed the transcriptional and active enhancer profile of monocytes derived from the inflamed joints of Juvenile Idiopathic Arthritis (JIA) patients, a model well-suited for studying autoimmune diseases. RNA-sequencing analysis demonstrated that synovial-derived monocytes display an activated phenotype, characterized by increased expression of surface activation markers and multiple chemokines and cytokines. This increased expression is regulated on the epigenetic level, as ChIP-sequencing indicated increased H3K27 acetylation of genes upregulated in synovial monocytes. IFN signaling-associated genes are increased and epigenetically altered in synovial monocytes, suggesting a role for IFN in establishing the inflammatory phenotype. Treatment of human synovial monocytes with the Janus-associated kinase (JAK) inhibitor Ruxolitinib, which inhibits IFN signaling, transformed the activated enhancer landscape and reduced disease-associated gene expression, thereby inhibiting the inflammatory phenotype. Taken together, these data provide novel insight into epigenetic regulation of autoimmune disease-patient derived monocytes and suggest that altering the epigenetic profile can be a therapeutic approach for the treatment of autoimmune diseases.

immunology↗

bioRxiv2021

Inhibition of pyrimidine biosynthesis targets protein translation in AML.

The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anti-cancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) by down-regulation of the multi-functional transcription factor YY1, has potent activity against AML in vivo and is well tolerated with minimal impact on normal blood development. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.

cancer biology↗

bioRxiv2020

Loss of erythroblasts in acute myeloid leukemia causes iron redistribution with clinical implications

Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis and limited treatment strategies. Determining the role of cell-extrinsic regulators of leukemic cells is vital to gain clinical insights into the biology of AML. Iron is a key extrinsic regulator of cancer but its systemic regulation remains poorly explored in AML. To address this question, we studied iron metabolism in AML patients at diagnosis and mechanisms involved using the syngeneic MLL-AF9-induced AML mouse model. We found that AML is a disorder with a unique iron profile not associated with inflammation or transfusion and characterized by high ferritin, low transferrin, high transferrin saturation (TSAT), and high hepcidin. The increased TSAT in particular, contrasts with observations in other cancer types and in anemia of inflammation. Using the MLL-AF9 mouse model of AML, we demonstrated that leukemic blasts take up iron and that the AML-induced loss of erythroblasts is responsible for iron redistribution and an increase in TSAT. We also show that elevated TSAT at diagnosis is independently associated with increased overall survival in AML and suggest that TSAT may be a relevant prognostic marker in AML.

cancer biology↗

bioRxiv2020

Conserved human effector Treg signature is reflected in transcriptomic and epigenetic landscape

Treg are critical regulators of immune homeostasis, and increasing evidence demonstrates that environment-driven Treg differentiation into effector (e)Treg is crucial for optimal functioning. However, human Treg programming under inflammatory conditions remains poorly understood. Here, we combine transcriptional and epigenetic profiling to identify the human eTreg core signature. Functional autoimmune inflammation-derived Treg display a unique transcriptional profile characterized by upregulation of both a core Treg (FOXP3, CTLA-4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identified a specific human eTreg signature that includes the vitamin D receptor (VDR) as predicted key-regulator in eTreg differentiation. H3K27ac/H3K4me1 occupancy revealed pronounced changes in the (super-)enhancer landscape, including enrichment of the binding motif for VDR and BATF. The observed Treg profile showed striking overlap with tumor-infiltrating Treg. Our data demonstrate that human inflammation-derived Treg acquire a specific eTreg profile guided by epigenetic changes. The core eTreg profile is conserved, and fine-tuned by environment-specific adaptations.

immunology↗