Biology subjects

Duc, J.

Publications and source records attributed to Duc, J..

16 recordsLinked to original sources

bioRxiv2025

Antxr2-mediated fine-tuning of Collagen VI ensures skeletal muscle function

Tissue function relies on the extracellular matrix (ECM) that surrounds cells, providing structural and biochemical support. The complex ECM composition depends on an adequately tuned balance between the deposition and degradation of each of its components. Disequilibrium may cause disease, as observed for Collagen VI (COL6), for which mutations lead to muscular dystrophy. Here, we investigated the role of Anthrax Toxin Receptor 2 (ANTXR2/CMG2), a receptor that controls the turnover of COL6, in skeletal muscle. We show that ANTXR2 is mostly expressed by fibro-adipogenic precursors and that its deficiency in ANTXR2 null (Antxr2-/-) mice leads to a premature and irregular COL6 accumulation in intramuscular connective tissue. This results in tissue stiffening and gradual, non-functional muscle hypertrophy, marked by impaired locomotion and myopathic signs. Our findings further indicate that COL6 accretion drives these alterations, as revealed by Antxr2-/-::Col6a1-/- double knockout mice, highlighting the essential role of ANTXR2-mediated COL6 remodeling in maintaining ECM homeostasis and muscle functionality. SIGNIFICANCE STATEMENTRemodelling of the extracellular matrix (ECM) was long thought to rely almost exclusively on extracellular proteases. Increasing evidence, however, indicates that some ECM components may undergo intracellular degradation following receptor-mediated endocytosis, as we have found for Collagen VI (COL6). Here, we identify the COL6 receptor ANTXR2 as a critical regulator of ECM turnover in skeletal muscle.. When ANTXR2 is absent, COL6 builds up, followed by the accumulation of fibrillar collagens, without changes in gene expression. These alterations in muscle ECM lead to increased stiffness, myofiber defects and impaired locomotor activity. Our findings establish ANTXR2 as a key regulator in ECM remodelling, offering new insights into potential treatments for conditions associated with defective ECM remodeling, such as aging and congenital muscular dystrophies.

cell biology↗

bioRxiv2025

Tissue-specific restriction of TE-derived regulatory elements safeguards cell-type identity

Transposable elements (TEs) have extensively reshaped the cis-regulatory landscape of mammalian genomes, yet the mechanisms that govern their context-specific activity remain incompletely understood. KRAB zinc finger proteins (KZFPs), a large family of transcription factors specialized in TE recognition, are known repressors of TE-derived regulatory activity through TRIM28-mediated H3K9me3 deposition. Here, we expand this paradigm by uncovering noncanonical relationships between TEs and KZFPs. By generating a comprehensive epigenomic map of KZFP-bound TEs, we find that the regulatory activity of ancient mammalian L2/MIR elements is broadly delineated by KZFP binding patterns, despite low H3K9me3 enrichment. We further dissect this relationship by investigating the function of ZNF436, a non-canonical KZFP, highly expressed during in vivo human fetal heart development. Using loss-of-function approaches, we show that ZNF436 preserves cardiomyocyte function by promoting cardiac gene expression while restricting the activation of alternative lineage programs. Mechanistically, ZNF436 recruits specialized SWI/SNF chromatin remodeling complexes to limit the accessibility of L2/MIR-derived enhancers, many of which are active in non-cardiac tissues. These findings reveal a noncanonical, TRIM28-independent role for KZFPs in shaping cell-type-specific regulatory landscapes and emphasize the importance of repressing alternative regulatory programs alongside activating lineage-specific ones to safeguard cell identity.

genomics↗

bioRxiv2025

Cancer cells subvert the primate-specific KRAB zinc finger protein ZNF93 to control APOBEC3B

ZNF93 is a primate-restricted KRAB zinc finger protein responsible for repressing 20- to 12-million-year-old L1 transposable elements. Here, we reveal that ZNF93 also regulates the key cancer driver APOBEC3B--a mutagenic enzyme linked to tumorigenesis and cancer progression. ZNF93 depletion impairs DNA synthesis, activates replication and DNA damage checkpoints, and triggers proinflammatory phenotypes. Conversely, its overexpression enhances resistance to exogenous genotoxic stress, mirroring the effects observed with APOBEC3B depletion. ZNF93 expression correlates with cell proliferation rates and is overexpressed in many cancer types. These findings suggest that ZNF93 serves as a critical guardian of genome integrity, co-opted by cancer cells to counterbalance APOBEC3B-induced and L1-derived genomic instability and inflammation.

genetics↗

bioRxiv2025

Transposable element co-option drives transcription factor neofunctionalization

Gene duplication and domain acquisition are key mechanisms driving protein diversification. However, the impact of these processes on the function and evolution of transcription factors (TFs) remains poorly characterized. Here, we show that the DUF3669 domain, found in a subset of KRAB zinc-finger proteins (KZFPs), originated from the co-option of a fragment of a LINE-1 transposable element ORF1p. Similar to its LINE-1-encoded ancestor, the DUF3669 domain promotes KZFPs trimerization and enables the formation of nuclear condensates with ribonucleoparticle properties, which critically influence the genomic recruitment and action of these TFs. Thus, our study uncovers a direct link between TE co-option and TF neofunctionalization, highlighting how mobile genetic elements shape the evolution of protein functionality.

genetics↗

bioRxiv2025

Zinc-finger proteins with a co-opted capsid domain anchor nucleosomes over transposon sequences

Transposable elements (TEs) are frequently co-opted as cis-regulatory sequences that govern multiple aspects of host biology. The regulatory activity of these domesticated sequences are controlled by host factors, notably KRAB domain-containing zinc-finger proteins (KZFPs) in tetrapods. Here, we report that SCAN domain-containing zinc-finger proteins (SZFPs), which originally arose through capture of a retroviral capsid domain by a KZFP gene, have expanded and diversified their DNA recognition specificity to bind distinct TE subfamilies. We further demonstrate that SZFPs anchor nucleosomes at their target sites, and that their depletion leads to global shifts of nucleosomes away from underlying TE-derived sequences, occasionally accompanied by a gain of enhancer-associated chromatin states. Thus, SZFPs represent a novel layer of chromatin regulation centered on rapidly evolving TE-derived regulatory sequences.

genetics↗

bioRxiv2024

Evolutionarily recent transcription factors partake in human cell cycle regulation

The cell cycle is a fundamental process in eukaryotic biology and is accordingly controlled by a highly conserved core signaling cascade. However, whether recently evolved proteins also influence this process is unclear. Here, we systematically map the influence of evolutionarily recent transcription factors (TFs) on human cell cycle progression. We find that the genomic targets of select young TFs, many of which belong to the rapidly evolving Kruppel-associated box (KRAB) zinc-finger proteins (KZFP) family, exhibit synchronized cell cycle expression. Systematic perturbation studies reveal that silencing recent TFs disrupts normal cell cycle progression, which we experimentally confirm for ZNF519, a simian-restricted KZFP. Further, we show that the therian-specific KZFP ZNF274 sets the cell cycle expression and replication timing of hundreds of clustered genes. These findings highlight an underappreciated level of lineage specificity in cell cycle regulation.

cell biology↗

bioRxiv2024

Clusters of lineage-specific genes are anchored by ZNF274 in repressive perinucleolar compartments

Long known as the site of ribosome biogenesis, the nucleolus is increasingly recognized for its role in shaping 3D genome organization. Still, the mechanisms governing the targeting of selected regions of the genome to nucleolus-associated domains (NADs) remain enigmatic. Here we reveal the essential role of ZNF274, a SCAN-bearing member of the Kruppel-associated box (KRAB)-containing zinc finger proteins (KZFP) family, in sequestering lineage-specific gene clusters within NADs. Ablation of ZNF274 triggers transcriptional activation across entire genomic neighborhoods - encompassing, among others, protocadherin and KZFP-encoding genes - with loss of repressive chromatin marks, altered 3D genome architecture and de novo CTCF binding. Mechanistically, ZNF274 anchors target DNA sequences at the nucleolus and facilitates their compartmentalization via a previously uncharted function of the SCAN domain. Our findings illuminate the mechanisms underlying NADs organization and suggest that perinucleolar entrapment into repressive hubs constrains the activation of tandemly arrayed genes to enable selective expression and modulate cell differentiation programs during development.

molecular biology↗

bioRxiv2023

POU5F1B is a human-restricted ROCK inhibitor-sensitive oncoprotein that restructures membrane nanodomains to increase cell adhesion

Evolution confers new species with distinctive biological features that can translate in either purely mechanistic speciation or novel phenotypes. Retrotransposition in the last Hominidae common ancestor of the pluripotency regulator POU5F1/OCT4 led to human POU5F1B, which promotes gastrointestinal cancer growth and metastasis through unknown mechanisms. Here, we show that POU5F1B fosters cell invasiveness by inducing plasma membrane remodeling. This ability exquisitely depends on a series of post-translational modifications. Ubiquitination of two lysine residues found exclusively in human POU5F1B results in its cytoplasmic retention, contrasting with the nuclear POU5F1. ZDHHC17-mediated S-acylation then triggers POU5F1B association with membrane nanodomains enriched in cell adhesion and signaling molecules. This is accompanied by the cell surface clustering and accelerated turnover of focal adhesion proteins, with enhanced cell invasiveness. Finally, screening for inducers of POU5F1B degradation, we found its stability to depend critically on Rho-associated protein kinases, revealing potential avenues for the treatment of POU5F1B-expressing tumors.

cancer biology↗

bioRxiv2023

Genetic features and genomic targets of human KRAB-Zinc Finger Proteins

Kruppel-associated box (KRAB) domain-containing zinc finger proteins (KZFPs) are one of the largest groups of transcription factors encoded by tetrapods, with 378 members in human alone. KZFP genes are often grouped in clusters reflecting amplification by gene and segment duplication since the gene family first emerged more than 400 million years ago. Previous work has revealed that many KZFPs recognize transposable element (TE)-embedded sequences as genomic targets, and that KZFPs facilitate the co-option of the regulatory potential of TEs for the benefit of the host. Here, we present a comprehensive survey of the genetic features and genomic targets of human KZFPs, notably completing past analyses by adding data on more than a hundred family members. General principles emerge from our study of the TE-KZFP regulatory system, which point to multipronged evolutionary mechanisms underlaid by highly complex and combinatorial modes of action with strong influences on human speciation.

genomics↗

bioRxiv2022

Statistical learning quantifies transposable element-mediated cis-regulation

BackgroundTransposable elements (TEs) have colonized the genomes of most metazoans, and many TE-embedded sequences function as cis-regulatory elements (CREs) for genes involved in a wide range of biological processes from early embryogenesis to innate immune responses. Because of their repetitive nature, TEs have the potential to form CRE platforms enabling the coordinated and genome-wide regulation of protein-coding genes by only a handful of trans-acting transcription factors (TFs). ResultsHere, we directly test this hypothesis through mathematical modeling and demonstrate that differences in expression at protein-coding genes alone are sufficient to estimate the magnitude and significance of TE-contributed cis-regulatory activities, even in contexts where TE-derived transcription fails to do so. We leverage hundreds of overexpression experiments and estimate that, overall, gene expression is influenced by TE-embedded CREs situated within approximately 200kb of promoters. Focusing on the cis-regulatory potential of TEs within the gene regulatory network of human embryonic stem cells, we find that pluripotency-specific and evolutionarily young TE subfamilies can be reactivated by TFs involved in post-implantation embryogenesis. Finally, we show that TE subfamilies can be split into truly regulatorily active versus inactive fractions based on additional information such as matched epigenomic data, observing that TF binding may better predict TE cis-regulatory activity than differences in histone marks. ConclusionOur results suggest that TE-embedded CREs contribute to gene regulation during and beyond gastrulation. On a methodological level, we provide a statistical tool that infers TE-dependent cis-regulation from RNA-seq data alone, thus facilitating the study of TEs in the next-generation sequencing era.

genomics↗

bioRxiv2022

Efficient and sensitive profiling of RNA-protein interactions using TLC-CLIP

RNA-binding proteins are instrumental for post-transcriptional gene regulation, yet transcriptomewide methods to profile RNA-protein interactions remain technically challenging. We present an improved library preparation strategy for crosslinking and immunoprecipitation (CLIP) that involves tailing and ligation of cDNA molecules (TLC) for increased sensitivity and efficiency. TLC-CLIP eliminates time-consumingpurifications, reduces sample loss and minimises experimental steps, allowing precise profiling of RNA-protein interactions from limited starting material at nucleotide resolution.

molecular biology↗

bioRxiv2021

Primate-specific cis- and trans-regulators shape transcriptional networks during human development

The human genome contains more than 4.5 million inserts derived from transposable elements (TE), the result of recurrent waves of invasion and internal propagation throughout evolution. For new TE copies to be inherited, they must become integrated in the genome of the germline or preimplantation embryo, which requires that their source TE be expressed at these stages. Accordingly, many TEs harbor DNA binding sites for the pluripotency factors OCT4, NANOG, SOX2, KLFs and are transiently expressed during embryonic genome activation. Here, we describe how many primate-restricted TEs have additional binding sites for lineage-specific transcription factors driving their expression during human gastrulation and later steps of fetal development. These TE integrants serve as lineage-specific enhancers fostering the transcription, amongst other targets, of KRAB-zinc finger proteins of similar evolutionary age, which in turn corral the activity of TE-embedded regulatory sequences in an equally lineage-restricted fashion. Thus, TEs and their KZFP controllers play broad roles in shaping transcriptional networks during early human development.

evolutionary biology↗

bioRxiv2020

Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

Transposable elements (TEs) constitute 50% of the human genome and many have been co-opted throughout human evolution due to gain of advantageous regulatory functions controlling gene expression networks. Several lines of evidence suggest these networks can be fine-tuned by the largest family of TE controllers, the KRAB-containing zinc finger proteins (KZFPs). One tissue permissive for TE transcriptional activation (termed transposcription) is the adult human brain, however comprehensive studies on the extent of this process and its potential contribution to human brain development are lacking. In order to elucidate the spatiotemporal transposcriptome of the developing human brain, we have analysed two independent RNA-seq datasets encompassing 16 distinct brain regions from eight weeks post-conception into adulthood. We reveal an anti-correlated, KZFP:TE transcriptional profile defining the late prenatal to early postnatal transition, and the spatiotemporal and cell type specific activation of TE-derived alternative promoters driving the expression of neurogenesis-associated genes. We also demonstrate experimentally that a co-opted antisense L2 element drives temporal protein re-localisation away from the endoplasmic reticulum, suggestive of novel TE dependent protein function in primate evolution. This work highlights the widespread dynamic nature of the spatiotemporal KZFP:TE transcriptome and its potential importance throughout neurotypical human brain development.

genomics↗

bioRxiv2019

Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

In the first days of embryogenesis, transposable element-embedded regulatory sequences (TEeRS) are silenced by Kruppel-associated box (KRAB)-zinc finger proteins (KZFPs). Many TEeRS are subsequently coopted in transcription networks, but how KZFPs influence this process is largely unknown. We identify ZNF417 and ZNF587 as primate-specific KZFPs repressing HERVK (human endogenous retrovirus K) and SVA (SINE-VNTR-Alu) integrants in human embryonic stem cells (ESC). Expressed in specific regions of the human developing and adult brain, ZNF417/587 keep controlling TEeRS in ESC-derived neurons and brain organoids, secondarily influencing the differentiation and neurotransmission profile of neurons and preventing the induction of neurotoxic retroviral proteins and an interferon-like response. Thus, evolutionarily recent KZFPs and their TE targets partner up to influence human neuronal differentiation and physiology. One Sentence SummaryYoung transposable elements and their protein controllers team up to regulate the differentiation and function of human neurons.

evolutionary biology↗

bioRxiv2019

The KZFP/KAP1 system controls transposable elements-embedded regulatory sequences in adult T cells

Transposable elements-embedded regulatory sequences (TEeRS) are subjected to early embryonic repression through sequence-specific recruitment of KRAB zinc finger proteins (KZFPs), their cofactor KAP1/TRIM28 and associated chromatin modifiers. This modulates the TEeRS-mediated regulation of gene expression in embryonic stem cells (ESCs) and leads to DNA methylation-induced silencing. However, KZFPs are broadly expressed in adult tissues, suggesting that they control TEeRS throughout life. Confirming this hypothesis, we reveal here that the KZFP/KAP1 system exerts a highly dynamic control of TEeRS in adult human CD4+ T lymphocytes. First, we observed that in these cells many TEs are still bound by KAP1, the recruitment of which is dynamically regulated upon T cell receptor stimulation. Second, we found that KAP1 depletion induces broad transcriptional alterations in T cells, with de-repression of TE-based regulatory elements leading to the illegitimate activation of nearby genes. Finally, we show that the tissue-restricted expression of KZFPs correlates with KAP1-mediated lineage-specific chromatin signatures and transcriptional repression. These data support a model where TE-targeting KZFPs and KAP1 are important regulators of gene expression in adult human cells.

genomics↗

bioRxiv2018

DPPA2 and DPPA4 are necessary to establish a totipotent state in mouse embryonic stem cells

After fertilization of the transcriptionally silent oocyte, expression from both parental chromosomes is launched through so-called zygotic genome activation (ZGA), occurring in the mouse at the 2-cell stage. Amongst the first elements to be transcribed are the Dux gene, the product of which secondarily induces a wide array of ZGA genes, and a subset of evolutionary recent LINE-1 retrotransposons, which regulate chromatin accessibility in the early embryo. The maternally-inherited factors that activate Dux and LINE-1 transcription have so far remained unknown. Here we identify the paralog proteins DPPA2 and DPPA4 as responsible for this process.

developmental biology↗