Biology subjects

Deniz, O.

Publications and source records attributed to Deniz, O..

11 recordsLinked to original sources

bioRxiv2026

TEgment dissects transposable element reactivation upon CDK9 inhibition in acute myeloid leukemia

Cyclin-dependent kinase 9 (CDK9) inhibition represents a promising therapeutic strategy in cancers that disrupts RNA polymerase II pause release and collapses oncogenic transcripts. Here, we show that CDK9 inhibition also induces widespread transposable element (TE) activation across diverse cancer types. In acute myeloid leukemia (AML), CDK9 inhibition induces rapid epigenetic reprogramming and robust TE upregulation. To dissect this non-canonical transcriptional response, we developed TEgment, a TE-centric RNA-sequencing analysis pipeline that classifies TE expression into distinct structural modalities: standalone, readthrough, protein-coding gene-embedded (5'UTR, coding exons, and 3'UTRs), lncRNA-embedded, intron-retained, and TE-initiated/terminated transcription events. Applying TEgment to CDK9-inhibited AML revealed that TEs are predominantly expressed as readthrough, 3'UTR-embedded, and lncRNA-embedded transcripts rather than autonomous units, challenging prevailing assumptions about TE reactivation. TEgment provides a versatile framework for resolving TE transcriptional modalities at locus and structural levels, enabling precise interpretation of TE-derived transcripts in cancer and other contexts.

genomics↗

bioRxiv2026

Nuclear Factor Y controls epithelial growth by regulating mTOR in the Drosophila midgut

The intestinal epithelial lining is highly dynamic, with size and cellular composition adapting to nutrient status. This requires regulation of intestinal stem cell (ISC) proliferation and enterocyte (EC) size. How the absorptive area of the intestine matches physiological nutrient conditions remains unclear. Here, we show that the Nuclear Factor Y (NF-Y) transcription factor plays a role in this process. NF-Y loss-of-function (LOF) in ISCs led to high proliferation and cell growth, a phenotype influenced by dietary nutrients. NF-Y LOF also increased nutrient metabolism, shown by more mitochondria and larger lipid droplets in progenitors. Mechanistically, NF-Y restrains mTOR complex 1 (mTORC1) activity in ISC by controlling transcription of mTORC1 signaling components such as Iml1 and Sestrin. Overall, our results demonstrate that NF-Y limits excessive intestinal epithelial growth under nutrient-rich conditions. HighlightsO_LINF-Y is a cell-autonomous regulator of ISC activity C_LIO_LINF-Y restricts ISC proliferation and epithelial growth under nutrient-rich condition C_LIO_LINF-Y regulates mitochondrial biogenesis and lipid storage in progenitors C_LIO_LINF-Y limits mTORC1 activity in progenitors C_LI

physiology↗

bioRxiv2025

Epigenetic silencing of transposable elements by IRF2BP2 is a selective dependency of myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous malignancy with limited curative treatment options. Transposable elements (TEs) are now recognized as key regulators of genome function, with aberrant activation implicated in cancer. However, their tumor-type-specific roles remain poorly characterized. Using single-cell Perturb-seq, we systematically screened for chromatin-associated regulators in primary AML patient cells to uncover dependencies required for leukemia cell viability. Our screen identified IRF2BP2 as an AML-selective dependency, functioning as a repressor of TE expression. Loss of IRF2BP2 induced differentiation, apoptosis, and impaired leukemic cell fitness, phenotypes linked to transcriptional activation of TEs, particularly evolutionarily young human endogenous retrovirus K (HERV-K). Mechanistically, IRF2BP2 cooperates with TRIM28 and DNMT1 to epigenetically silence TE expression. CRISPR-mediated activation of HERV-K/LTR5_Hs recapitulated the phenotypic effects of IRF2BP2 loss, while targeted re-silencing of HERV-K/LTR5_Hs partially rescued the effects, establishing a causal link between TE regulation and AML maintenance. Our findings highlight tumor-suppressive functions of TEs in leukemia and reveal IRF2BP2 as a key regulator of TE silencing in AML. Targeting the epigenetic machinery governing TE repression may represent a promising therapeutic avenue for differentiation-inducing and immunomodulatory strategies in AML.

cancer biology↗

bioRxiv2025

Spalt-related is an integrated stress response-activated inhibitor of mTORC1-mediated growth

Anabolic and catabolic processes are coordinated by a conserved regulatory network, which includes the nutrient sensing protein kinase mTOR complex 1 (mTORC1) and the insulin- and stress-responsive transcription factor FoxO. In physiological setting these regulators align growth, storage, reproduction, and aging with nutrient availability. Here, we identify transcription factor Spalt-related (Salr), previously implicated in organogenesis, as a negative regulator of growth and lipid storage. In the Drosophila fat body Salr activates catabolic gene expression and restricts mTORC1-mediated cell growth. The genomic binding of Salr overlaps extensively with that of FoxO and similar convergence is observed between their mammalian homologs SALL1 and FOXO1. Both Salr and FoxO are activated upon fasting but respond to distinct cues: while FoxO displays transient activation and is responsive to AKT inhibition, Salr is activated in a slow and sustained manner through the integrated stress response. Once activated, Salr counters nuclear localization of FoxO. Together, Salr and FoxO are converging transcriptional activators of catabolism during nutrient stress.

cell biology↗

bioRxiv2025

Metabolic control of enteroendocrine cell fate through a redox state sensor CtBP

Enteroendocrine (EE) cells monitor the intestinal nutrient composition and consequently control organismal physiology through hormonal signaling. In addition to the immediate effects on hormone secretion, nutrients influence EE cell abundance by affecting the determination and maintenance of cell fate. EE cells are known to import and respond to dietary sugars, but how the sugar-induced changes in the intracellular metabolic state are sensed to control the immediate and long-term responses of EE cells, remains poorly understood. We report that the NADH binding transcriptional cofactor C-terminal binding protein (CtBP) acts at the interface between nutrient sensing and fate regulation of Drosophila larval EE cells, thus controlling organismal energy metabolism and survival on a high sugar diet. CtBP dimerization in EE cells is regulated through the redox balance of nicotinamide cofactors controlled by glycolysis and pentose phosphate pathway, allowing EE cells sense their internal metabolic state in response to sugar catabolism. CtBP interacts with the EE cell fate determining transcription factor Prospero through a conserved binding motif and binds to genomic targets controlling EE cell fate and size, such as components of Notch and insulin/mTOR pathways. Collectively, our findings uncover a modality where changes in intracellular redox state serve as an instructive signal to control EE cell function to globally control organismal homeostasis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/662346v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@3baaeorg.highwire.dtl.DTLVardef@d505edorg.highwire.dtl.DTLVardef@178361dorg.highwire.dtl.DTLVardef@128e210_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes

The t(6;9)(p22.3;q34.1) translocation/DEK::NUP214 fusion protein defines a distinct subgroup of younger AML patients classified as a separate disease entity by the World Health Organization. DEK is a nuclear factor with multifunctional roles, including gene regulation, while its fusion partner, NUP214, plays a pivotal role in nuclear export by interacting with transport receptors such as XPO1. However, the precise mechanism by which DEK::NUP214 drives leukemia remains unclear. A comprehensive multi-omics comparison of 57 AML primary samples (including whole genome sequencing, targeted sequencing, transcriptomics, and drug screening with > 500 compounds) revealed that t(6;9) cases display a selective response to XPO1 inhibitors (Selinexor & Eltanexor) and a distinct transcriptomic signature characterized by the overexpression of FOXC1 and HOX genes that are key leukemia mediators. CUT&RUN experiments demonstrated the direct binding of DEK::NUP214 to the promoters of FOXC1 and HOXA/B clusters. Strikingly, the expression of these genes and the binding of DEK::NUP214 to their regulatory regions were selectively reduced upon XPO1 inhibition in t(6;9) cells. Altogether, these results identified a novel function of DEK::NUP214 as an XPO1-dependent transcriptional activator of key leukemia drivers and provide a rationale to explore the use of XPO1 inhibitors in this patient population.

cancer biology↗

bioRxiv2024

MLX phosphorylation stabilizes the ChREBP-MLX heterotetramer on tandem E-boxes to control carbohydrate and lipid metabolism

The heterodimeric ChREBP-MLX transcription factor complex is a key mediator that couples intracellular sugar levels to carbohydrate and lipid metabolism. To promote the expression of target genes, two ChREBP-MLX heterodimers form a heterotetramer to bind a tandem element with two adjacent E-boxes, called Carbohydrate Responsive Element (ChoRE). How the ChREBP-MLX hetero-tetramerization is achieved and regulated, remains poorly understood. Here we show that MLX phosphorylation on an evolutionarily conserved motif is necessary for the heterotetramer formation on the ChoRE and the transcriptional activity of the ChREBP-MLX complex. We identified CK2 and GSK3 as MLX kinases that coordinately phosphorylate MLX. High intracellular glucose-6-phosphate accumulation inhibits MLX phosphorylation and heterotetramer formation on the ChoRE, impairing ChREBP-MLX activity. Physiologically, MLX phosphorylation is necessary in Drosophila to maintain sugar tolerance and lipid homeostasis. Our findings suggest that MLX phosphorylation is a key mechanism for the ChREBP-MLX heterotetramer formation to regulate carbohydrate and lipid metabolism.

cell biology↗

bioRxiv2019

Endogenous retroviruses are a source of oncogenic enhancers in acute myeloid leukemia

Acute myeloid leukemia (AML) is a highly aggressive hematopoietic malignancy, defined by a series of genetic and epigenetic alterations, which result in deregulation of transcriptional networks. One understudied but important source of transcriptional regulators are transposable elements (TEs), which are widespread throughout the human genome. Aberrant usage of these sequences could therefore contribute to oncogenic transcriptional circuits. However, the regulatory influence of TEs and their links to disease pathogenesis remain unexplored in AML. Using epigenomic data from AML primary samples and leukemia cell lines, we identified six endogenous retrovirus (ERV) families with AML-associated enhancer chromatin signatures that are enriched in binding of key regulators of hematopoiesis and AML pathogenesis. Using both CRISPR-mediated locus-specific genetic editing and simultaneous epigenetic silencing of multiple ERVs, we demonstrate that ERV deregulation directly alters the expression of adjacent genes in AML. Strikingly, deletion or epigenetic silencing of an ERV-derived enhancer suppressed cell growth by inducing apoptosis in leukemia cell lines. Our work reveals that ERVs are a previously unappreciated source of AML enhancers that have the potential to play key roles in leukemogenesis. We suggest that ERV activation provides an additional layer of gene regulation in AML that may be exploited by cancer cells to help drive tumour heterogeneity and evolution.

genetics↗

bioRxiv2019

TET2 regulates the neuroinflammatory response in microglia

Epigenetic mechanisms regulate distinct aspects of the inflammatory response in various immune cell types. Despite the central role for microglia, the resident macrophages of the brain, in neuroinflammation and neurodegeneration little is known about their epigenetic regulation of the inflammatory response. Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-{kappa}B-dependent pathway. We found that TET2 regulates early gene transcriptional changes that lead to early metabolic alterations, as well as a later inflammatory response independently of its 5mC oxidation activity at the affected genes. We further show that TET2 regulates the proinflammatory response in microglia induced by intraperitoneal injection of LPS in vivo. We observed that microglia associated to amyloid {beta} plaques, recently defined as disease-associated microglia, expressed TET2 in brain tissue from individuals with Alzheimers disease (AD) and in 5xFAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response, and suggest TET2 as a potential target to combat neurodegenerative brain disorders.

neuroscience↗

bioRxiv2018

Functional evaluation of transposable elements as transcriptional enhancers in mouse embryonic and trophoblast stem cells

The recurrent invasion and expansion of transposable elements (TEs) throughout evolution brought with it a vast array of coding and non-coding sequences that can serve as substrates for natural selection. Namely, TEs are thought to have contributed to the establishment of gene regulatory networks via their cis-acting elements. Both the embryonic and extraembryonic lineages of the early mouse embryo are thought to have benefited from the co-option of TEs as distal enhancer elements. However, there is little to no evidence that these particular TEs play significant roles in the regulation of gene expression. Here we tested for roles of TEs as enhancers in mouse embryonic and trophoblast stem cells by combining bioinformatic analyses with genetic and epigenetic editing experiments. Epigenomic and transcriptomic data from wildtype cells suggested that a large number of TEs played a role in the establishment of highly tissue-specific gene expression programmes. Through genetic editing of individual TEs we confirmed a subset of these regulatory relationships. However, a wider survey via CRISPR interference of RLTR13D6 elements in embryonic stem cells revealed that only a minority play significant roles in gene regulation. Our results suggest that a small proportion of TEs contribute to the mouse pluripotency regulatory network, and highlight the importance of functional experiments when evaluating the role of TEs in gene regulation.

genetics↗

bioRxiv2017

SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells

BackgroundEndogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation also playing an important role. It has been suggested that SETDB1 protects ERVs from TET- dependent DNA demethylation, but the relevance of this mechanism for ERV expression remains unclear. Moreover, previous studies have been performed in primed ESCs, which are not epigenetically or transcriptionally representative of preimplantation embryos.\n\nResultsWe used naive ESCs to investigate the role of SETDB1 in ERV regulation and, in particular, its relationship with TET-mediated DNA demethylation. Naive ESCs show an increased dependency on SETDB1 for ERV silencing when compared to primed ESCs, including at the highly mutagenic intracisternal A particles (IAPs). We found that, in the absence of SETDB1, TET2 activates IAP elements in a catalytic-dependent manner. Surprisingly, however, TET2 does not drive changes in DNA methylation levels at IAPs, suggesting that it regulates these transposons indirectly. Instead, SETDB1 depletion leads to a TET2-dependent loss of H4R3me2s, which is indispensable for IAP silencing during epigenetic reprogramming.\n\nConclusionsOur results demonstrate a novel and unexpected role for SETDB1 in protecting IAPs from TET2-dependent histone arginine demethylation.

genetics↗