Biology subjects

Planet, E.

Publications and source records attributed to Planet, E..

At least 19 recordsLinked to original sources

bioRxiv2026

An overexpression platform reveals the functional diversity of human KRAB-Zinc Finger Proteins in maintaining cellular homeostasis

Kruppel associated box zinc finger proteins (KZFPs) form the largest family of transcriptional regulators in mammals, yet most remain uncharacterized. Here we established a scalable framework to probe KZFP function. An arrayed inducible overexpression screen of 366 human KZFPs in K562 cells identified factors that alter cellular proliferation, enabling functional prioritization. Integrative transcriptomic, chromatin and proteomic analyses revealed diverse mechanisms, including transposable element-linked repression (ZNF43), promoter proximal regulation (ZNF257), and SCAN domain dependent transcriptional activation (ZNF498/ZSCAN25 and ZNF18). These results highlight the functional diversity of KZFPs and provide a strategy for their annotation.

genetics↗

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↗

bioRxiv2025

Identification of the Lipid Oxygen Radical Defense pathway and its epigenetic control

Membrane phospholipids are vulnerable to oxidative radicals, and uncontrolled lipid peroxidation affects cell viability. Cells have evolved quality control and defense mechanisms, of which the genetic regulation is not fully understood. Here, we identify what we have coined the Lipid Oxygen Radical Defense (LORD) pathway. It is epigenetically repressed by a complex comprising the KRAB-zinc finger protein ZNF354A, the scaffold protein KAP1/TRIM28, the histone methyltransferase SETDB1, and the transcriptional activator ATF2. Upon lipid peroxide accumulation, p38- and JNK-dependent phosphorylation of ATF2, KAP1/TRIM28, and ZNF354A leads to disassembly of the repressive complex, releasing ZNF354A from specific DNA loci and activating a network of protective genes, including NRF2 targets. The pathway affects the cellular sensitivity to oxidative stress and ferroptosis, revealing a novel layer of epigenetic control in lipid quality control and damage repair. This positions the LORD pathway as a promising therapeutic target for diseases linked to chronic inflammation, neurodegeneration and cancer.

cell biology↗

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↗

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

Ancestral genome reconstruction enhances transposable element annotation by identifying degenerate integrants

Growing evidence indicates that transposable elements (TEs) play important roles in evolution by providing genomes with coding and non-coding elements. Identification of TE-derived functional elements, however, has relied on TE annotations in individual species, which limits its scope to relatively intact TE sequences and misses elements derived from evolutionarily old TEs. Here, we report a novel approach to uncover previously unannotated degenerate TEs (degTEs) by probing multiple ancestral genomes reconstructed from hundreds of species. We applied this method to the human genome and discovered 1,452,810 degTEs, representing a 10.8% increase over the most recent human TE coverage. Further, we discovered that degTEs contribute to various cis-regulatory elements as well as transcription factor binding sites, including those of a known TE-controlling family, the KRAB zinc-finger proteins. We also report unannotated chimeric transcripts between degTEs and human genes expressed in embryos. This study provides a novel methodology and a freely available resource that will facilitate the investigation of TE co-option events on a full scale.

genomics↗

bioRxiv2023

KRAB zinc finger proteins ZNF587/ZNF417 protect lymphoma cells from replicative stress-induced inflammation

Heterochromatin loss and genetic instability enhance cancer progression by favoring clonal diversity, yet uncontrolled replicative stress can lead to mitotic catastrophe and inflammatory responses promoting immune rejection. KRAB-containing zinc finger proteins (KZFPs) are epigenetic modulators, which for many control heterochromatin at transposable element (TE)-embedded regulatory sequences. We identified a cluster of 18 KZFPs associated with poor prognosis in diffuse large B cell lymphoma (DLBCL). We found their upregulation to correlate with increased copy number alterations and suppression of immune responses in tumor samples. Upon depleting two that target evolutionarily recent TEs, the primate-specific ZNF587 and ZNF417 paralogs, the proliferation of DLBCL cell lines was drastically impaired and replicative stress abruptly induced with marked alterations of the chromatin landscape and multiplication of DNA replication origins. Furthermore, ZNF587/417 knockdown upregulated interferon/inflammatory-related genes through activation of the cGAS-STING DNA sensing pathway, augmented the susceptibility of tumor cells to macrophage-mediated phagocytosis, and modified their immunogenicity through an increased surface expression of HLA-I and reshuffling of their immunopeptidome. ZNF587 and ZNF417 are thus pro-oncogenic factors allowing for higher degrees of genetic instability through attenuation of replicative stress and secondary inflammation, an influence that likely facilitates the clonal expansion, diversification, and immune evasion of cancer cells.

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

Transposable elements contribute to the spatiotemporal microRNA landscape in human brain development

Transposable elements (TEs) contribute to the evolution of gene regulatory networks and are dynamically expressed throughout human brain development and disease. One gene regulatory mechanism influenced by TEs is the miRNA system of post-transcriptional control. miRNA sequences frequently overlap TE loci and this miRNA expression landscape is crucial for control of gene expression in adult brain and different cellular contexts. Despite this, a thorough investigation of the spatiotemporal expression of TE-embedded miRNAs in human brain development is lacking. Here, we identify a spatiotemporally dynamic TE-embedded miRNA expression landscape between childhood and adolescent stages of human brain development. These miRNAs sometimes arise from two apposed TEs of the same subfamily, such as for L2 or MIR elements, but in the majority of cases stem from solo TEs. They give rise to in silico predicted high-confidence pre-miRNA hairpin structures, likely represent functional miRNAs and have predicted genic targets associated with neurogenesis. TE-embedded miRNA expression is distinct in the cerebellum when compared to other brain regions, as has previously been described for gene and TE expression. Furthermore, we detect expression of previously non-annotated TE-embedded miRNAs throughout human brain development, suggestive of a previously undetected miRNA control network. Together, as with non-TE-embedded miRNAs, TE-embedded sequences give rise to spatiotemporally dynamic miRNA expression networks, the implications of which for human brain development constitute extensive avenues of future experimental research. To facilitate interactive exploration of these spatiotemporal miRNA expression dynamics, we provide the "Brain miRTExplorer" web application freely accessible for the community.

genomics↗

bioRxiv2021

Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer

Transposable elements (TEs) are interspersed repeats that contribute to more than half of the human genome, and TE-embedded regulatory sequences are increasingly recognized as major components of the human regulome. Perturbations of this system can contribute to tumorigenesis, but the impact of TEs on gene expression in cancer cells remains to be fully assessed. Here, we analyzed 275 normal colon and 276 colorectal cancer (CRC) samples from the SYSCOL colorectal cancer cohort and discovered 10,111 and 5,152 TE expression quantitative trait loci (eQTLs) in normal and tumor tissues, respectively. Amongst the latter, 376 were exclusive to CRC, likely driven by changes in methylation patterns. We identified that transcription factors are more enriched in tumor-specific TE-eQTLs than shared TE-eQTLs, indicating that TEs are more specifically regulated in tumor than normal. Using Bayesian Networks to assess the causal relationship between eQTL variants, TEs and genes, we identified that 1,758 TEs are mediators of genetic effect, altering the expression of 1,626 nearby genes significantly more in tumor compared to normal, of which 51 are cancer driver genes. We show that tumor-specific TE-eQTLs trigger the driver capability of TEs subsequently impacting expression of nearby genes. Collectively, our results highlight a global profile of a new class of cancer drivers, thereby enhancing our understanding of tumorigenesis and providing potential new candidate mechanisms for therapeutic target development.

genomics↗

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↗

bioRxiv2020

Ongoing evolution of KRAB zinc finger protein-coding genes in modern humans

BackgroundKruppel-associated box (KRAB) zinc finger proteins (KZFPs) constitute the largest and fastest evolving family of gene regulators encoded by the human genome. Recent data indicate that many KZFPs serve as repressors of transposable element-embedded regulatory sequences (TEeRS) and that the evolutionary turnover of KZFP genes is mainly attributable to the changing transposable element (TE) load of their hosts. However, how natural selection and genetic variation are shaping this process is still poorly defined. MethodsGenetic information was collected from nine primate species and 138,500 human genomes. Gene-wide as well as functional amino acid position specific constraint was calculated across all human KZFPs. ResultsWe found that the most conserved KZFPs, some of which go back close to 400 million years, have been subjected to marked negative selection in the evolutionarily recent past and are very homogeneous within the human population. In contrast, younger, largely primate-restricted family members present evidence of less negative selection than the rest of genome and lower levels of coding constraint, particularly within the sequences encoding the functional sites of their zinc finger (ZF) arrays. We defined 33 sets of KZFP paralogs, which pairwise displayed a broad range of coding constraints differentials, with more recently emerged paralogs usually displaying a higher frequency of putatively deleterious mutations and missense variants within the functional sites of their ZF arrays than their source gene. Finally, we identified three KZFP genes more constrained in the genomes of individuals of African ancestry than in Europeans, with their modes of expression or DNA targets pointing to possible links between these inter-populational genetic differences and regional differences in the prevalence of some diseases. ConclusionsThis work shows how the ongoing selection of KZFPs contributes to modern human genetic variation, in particular through the constraint of putatively deleterious- and missense variants in functional protein sites, and how ongoing interplays between environment and KZFP genes might be impacting the biology of modern humans.

genomics↗

bioRxiv2019

Integrated Proteogenomic Deep Sequencing and Analytics Accurately Identify Non-Canonical Peptides in Tumor Immunopeptidomes

Efforts to precisely identify tumor human leukocyte antigen (HLA) bound peptides capable of mediating T cell-based tumor rejection still face important challenges. Recent studies suggest that non-canonical tumor-specific HLA peptides that derive from annotated non-coding regions could elicit anti-tumor immune responses. However, sensitive and accurate mass-spectrometry (MS)-based proteogenomics approaches are required to robustly identify these non-canonical peptides. We present an MS-based analytical approach that characterizes the non-canonical tumor HLA peptide repertoire, by incorporating whole exome sequencing, bulk and single cell transcriptomics, ribosome profiling, and a combination of two MS/MS search tools. This approach results in the accurate identification of hundreds of shared and tumor-specific non-canonical HLA peptides and of an immunogenic peptide from a downstream reading frame in the melanoma stem cell marker gene ABCB5. It holds great promise for the discovery of novel cancer antigens for cancer immunotherapy.

cancer biology↗