Biology subjects

Andrieu, G.

Publications and source records attributed to Andrieu, G..

5 recordsLinked to original sources

bioRxiv2026

Epromoter 3D interaction-associated regulation in T-acute Lymphoblastic Leukemia

Background: Promoters have been traditionally seen as contiguous gene-adjacent cis-regulatory elements. Yet, substantial studies corroborate that Epromoters (promoters with enhancer activity) engage in distal forms of gene regulation. Although in the three-dimensional (3D) space enhancer-promoter networks have been well studied, the contribution of the circuits of promoter-promoter (P-P) interactions is poorly understood. Furthermore, whether the regulatory aspects of P-P interactions in cancer may be controlled by physical 3D-mediated Epromoter interactions remains elusive. Results: We show that Epromoter-mediated 3D interactions regulate target genes and participate in cluster co-regulation, playing a critical role in T-cell acute Lymphoblastic Leukemia (T-ALL). To achieve this, we first leveraged survival CRISPR screenings in T-ALL model cells (Jurkat) to identify potential Epromoters. By integrating these findings with an H3K27ac HiChIP dataset from T-ALL cells, we characterized a set of Epromoters that establish 3D genome interactions with other promoters. We observed that promoters organize into dense, promoter-rich genomic clusters, and that among them, the clusters enriched with Epromoters actively regulate complex gene expression networks. To investigate gene coregulation, we integrated transcriptomic data from T-ALL patients and found that promoter-promoter (P-P) pairs exhibit positive correlation at multiple levels, and that several Jurkat Epromoter candidate clusters are significantly co-regulated in the patient cohort. To experimentally validate these candidates, we utilized CRISPRi to inhibit Epromoters, which revealed direct transcriptional regulation of multiple target genes within each hub. Finally, we performed cell competition assays to confirm that these Epromoters are vital for T-ALL cell survival. Conclusions: Our analysis provides support for the role of Epromoters in the regulation of 3D P-P interactions and co-regulation of promoter hubs, and how these interactions play a critical part in T-ALL cell survival.

cancer biology↗

bioRxiv2026

USP7 maintains hematopoietic stem cell dormancy and function by stabilizing HMGA2

Hematopoietic stem cell (HSC) longevity critically depends on maintaining a deep dormant state, yet the molecular mechanisms that preserve this rare and functionally essential population remain poorly understood. Here, we identify the deubiquitinase USP7 as a key regulator of long-term HSC dormancy. Using a Usp7+/- mouse model, we uncover selective depletion of hematopoietic stem and progenitor cells (HSPCs), which is associated with impaired long-term repopulation capacity. Strikingly, H2B-GFP label-retention assays reveal a profound loss of dormant HSCs in Usp7+/- mice, demonstrating a failure to maintain the most quiescent stem cell fraction in vivo. Consistently, single-cell RNA sequencing shows erosion of the transcriptional dormancy program, linking USP7 activity to the preservation of stem cell identity at both functional and molecular levels. Mechanistically, ultra-low-input proteomic profiling and biochemical approaches identify HMGA2 as a novel USP7 substrate, suggesting that ubiquitin-dependent regulation of chromatin architecture contributes to the control of HSC dormancy. Together, our findings establish USP7 as a critical regulator of HSC dormancy, revealing a previously unrecognized post-translational mechanism controlling stem cell longevity, with implications for aging, regeneration, and hematopoietic disorders.

cell biology↗

bioRxiv2026

Translocation-driven chr19-der(14) interaction is associated with disease-specific transcriptional programs in mantle cell lymphoma

Mantle cell lymphoma (MCL) is defined by the t(11;14)(q13;q32) translocation, which drives constitutive CCND1 expression, yet the broader regulatory consequences of this rearrangement remain incompletely understood. Here, we combined transcriptomic, epigenomic, Hi-C, and 3D-FISH analyses in primary MCL samples and cell lines to investigate the genome-wide impact of t(11;14) on chromatin organization and gene regulation beyond the rearranged chromosomes. We show that MCL cells exhibit widespread enhancer activation, accompanied by expansion of super-enhancer regions. The translocated CCND1 locus repositions toward the nuclear interior and acquires enhancer-like features. Genome-wide analysis highlighted chromosome 19 as a hotspot of transcriptional upregulation. Notably, Hi-C and 3D-FISH revealed recurrent interchromosomal contacts between chromosome 19 and the CCND1 locus, preferentially involving the derivative chromosome. These contacts colocalize with active RNA polymerase II and are associated with increased expression of nearby chr19 genes, suggesting an association between spatial proximity and transcriptional activation in trans. Minnelide treatment reduced chromatin accessibility at the CCND1 locus, decreased the frequency of chr19-der14 interactions, and partially reversed the MCL transcriptional program, while exerting strong anti-tumor effects in vitro and in vivo. Together, these findings identify a recurrent interchromosomal interaction associated with coordinated gene activation in MCL and suggest that spatial genome reorganization contributes to disease-specific transcriptional programs.

cancer biology↗

bioRxiv2023

ATP citrate lyase is an essential player of the metabolic rewiring induced by PTEN loss during T-ALL development.

Alterations inactivating the tumor suppressor gene PTEN drive the development of solid and hematological cancers, such as T-cell acute lymphoblastic leukemia (T-ALL), whereby PTEN loss defines poor-prognosis patients. We investigated the metabolic rewiring induced by PTEN loss in T-ALL, aiming at identifying novel metabolic vulnerabilities. We showed that the enzyme ATP citrate lyase (ACLY) is strictly required for the transformation of thymic immature progenitors and for the growth of human T-ALL, which remain dependent on ACLY activity even upon transformation. Whereas PTEN mutant mice all died within 17 weeks, the concomitant ACLY deletion prevented disease initiation in 70% of the animals, where it prevented the apoptosis of pre-malignant DP thymocytes by up-regulating BCL-2. Transcriptomic and metabolic analysis of primary T-ALL cells next translated our findings to the human pathology, showing that PTEN-altered T-ALL cells selectively activate ACLY and are specifically sensitive to its genetic targeting. ACLY activation thus represents a metabolic vulnerability with therapeutic potential for high-risk T-ALL patients.

cancer biology↗

bioRxiv2021

A multi-tiered map of EMT defines major transition points and identifies vulnerabilities

Epithelial to mesenchymal transition (EMT) is a complex cellular program proceeding through a hybrid E/M state linked to cancer-associated stemness, migration and chemoresistance. Deeper molecular understanding of this dynamic physiological landscape is needed to define events which regulate the transition and entry into and exit from the E/M state. Here, we quantified >60,000 molecules across ten time points and twelve omic layers in human mammary epithelial cells undergoing TGF{beta}-induced EMT. Deep proteomic profiles of whole cells, nuclei, extracellular vesicles, secretome, membrane and phosphoproteome defined state-specific signatures and major transition points. Parallel metabolomics showed metabolic reprogramming preceded changes in other layers, while single-cell RNA sequencing identified transcription factors controlling entry into E/M. Covariance analysis exposed unexpected discordance between the molecular layers. Integrative causal modeling revealed co-dependencies governing entry into E/M that were verified experimentally using combinatorial inhibition. Overall, this dataset provides an unprecedented resource on TGF{beta} signaling, EMT and cancer.

systems biology↗