Genetic features and genomic targets of human KRAB-zinc finger proteins

Genome Research, Год журнала: 2023, Номер 33(8), С. 1409 - 1423

Опубликована: Авг. 1, 2023

Krüppel-associated box (KRAB) domain-containing zinc finger proteins (KZFPs) are one of the largest groups transcription factors encoded by tetrapods, with 378 members in human alone. KZFP genes often grouped clusters reflecting amplification gene and segment duplication since 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, facilitate co-option regulatory potential TEs for benefit host. Here, we present a comprehensive survey genetic features targets KZFPs, notably completing past analyses adding data on close to hundred members. General principles emerge from our study TE-KZFP system, which point multipronged evolutionary mechanisms underlaid highly complex combinatorial modes action strong influences speciation.

Язык: Английский

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Mini-heterochromatin domains constrain the cis-regulatory impact of SVA transposons in human brain development and disease

Nature Structural & Molecular Biology, Год журнала: 2024, Номер unknown

Опубликована: Июнь 4, 2024

Abstract SVA (SINE (short interspersed nuclear element)–VNTR (variable number of tandem repeats)– Alu ) retrotransposons remain active in humans and contribute to individual genetic variation. Polymorphic alleles harbor gene regulatory potential can cause disease. However, how insertions are controlled functionally impact human disease is unknown. Here we dissect the epigenetic regulation influence SVAs cellular models X-linked dystonia parkinsonism (XDP), a neurodegenerative disorder caused by an insertion at TAF1 locus. We demonstrate that KRAB zinc finger protein ZNF91 establishes H3K9me3 DNA methylation over SVAs, including polymorphic alleles, neural progenitor cells. The resulting mini-heterochromatin domains attenuate cis -regulatory SVAs. This critical for XDP pathology; removal local heterochromatin severely aggravates molecular phenotype, increased intron retention reduced expression. Our results provide unique mechanistic insights into transposon recognized their constrained innate defense system.

Язык: Английский

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Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells

PLoS Genetics, Год журнала: 2022, Номер 18(6), С. e1010225 - e1010225

Опубликована: Июнь 15, 2022

Domestication of transposable elements (TEs) into functional cis-regulatory is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as enhancers while others not underappreciated. SINE-VNTR-Alus (SVAs) youngest group transposons in human genome, where ~3,700 copies annotated, nearly half which human-specific. Many studies indicate that SVAs among most frequently gene regulation, but underlying such processes have yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and genomics to elucidate genomic features underlie SVA domestication stem-cell regulation. We found ~750 induced pluripotent stem cells. These significantly closer genes harbor more transcription factor binding sites than non-co-opted SVAs. show long DNA motif composed flanking YY1/2 OCT4 enriched these two factors bind consecutively on TE sequence. used CRISPRi epigenetically repress active cell-like NCCIT Epigenetic perturbation strongly attenuated YY1/OCT4 influenced neighboring expression. Ultimately, repression resulted ~3,000 differentially expressed genes, 131 were nearest an annotated SVA. In summary, demonstrated modulate expression, uncovered location sequence composition contribute regulatory networks.

Язык: Английский

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Wybutosine hypomodification of tRNAphe activates HERVK and impairs neuronal differentiation

iScience, Год журнала: 2024, Номер 27(5), С. 109748 - 109748

Опубликована: Апрель 16, 2024

We previously reported that loss of function TYW1 led to cerebral palsy with severe intellectual disability through reduced neural proliferation. However, whether affects differentiation is unknown. In this study, we first demonstrated blocked the formation OHyW in tRNA

Язык: Английский

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Resolving the three-dimensional interactome of human accelerated regions during human and chimpanzee neurodevelopment

Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Multi-omics analysis reveals critical cis-regulatory roles of transposable elements in livestock genomes

iScience, Год журнала: 2025, Номер 28(3), С. 112049 - 112049

Опубликована: Фев. 18, 2025

Язык: Английский

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Transposable elements may enhance antiviral resistance in HIV-1 elite controllers

Genome biology, Год журнала: 2025, Номер 26(1)

Опубликована: Фев. 23, 2025

Less than 0.5% of people living with HIV-1 are elite controllers (ECs)—individuals who maintain undetectable plasma viremia without antiretroviral therapy, despite having replication-competent viral reservoirs. While EC CD4+ T cells have been investigated for gene expression signatures associated resistance, the and regulatory activity transposable elements (TEs) remain unexplored. TEs can directly impact host immune responses to pathogens, including HIV-1, suggesting their activities could contribute control. To begin testing this hypothesis, we conduct a TE-centric analysis public multi-omics data from ECs other populations. We find cell transcriptome retrotranscriptome distinct healthy controls, on viremic progressors. However, there is substantial transcriptomic heterogeneity among ECs. categorize into four clusters chromatin accessibility profiles antiviral factors. Several TE families known immuno-regulatory differentially expressed Their positively correlates in negatively KRAB zinc-finger (KZNF) repressors. This coordinated, locus-level variation forms network putative cis-regulatory genes involved restriction. propose that phenotype driven part by reduced KZNF-mediated repression specific TE-derived genes, heightening resistance against HIV-1. Our study reveals transcriptome, variable KZNF controllers, must be considered when deciphering control mechanisms.

Язык: Английский

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Resolving the three-dimensional interactome of Human Accelerated Regions during human and chimpanzee neurodevelopment

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 26, 2024

Abstract Human Accelerated Regions (HARs) are highly conserved across species but exhibit a significant excess of human-specific sequence changes, suggesting they may have gained novel functions in human evolution. HARs include transcriptional enhancers with activity and been implicated the evolution brain. However, our understanding how contributed to uniquely features brain is hindered by lack insight into genes pathways that regulate. It unclear whether acted altering expression gene targets between their chimpanzee orthologs or gaining new human, mechanism termed enhancer hijacking. We generated high-resolution map chromatin interactions for 1,590 neural stem cells (NSCs) comprehensively identify both species. targeted set 2,963 enriched neurodevelopmental processes including neurogenesis synaptic transmission. Changes HAR were correlated changes target expression. Conserved among differentially expressed NSCs non-human primate developing adult Species-specific did not converge on known biological significantly genes, alter via targets, also showed cell type-specific patterns brain, outer radial glia, which hypothesized contribute cortical expansion. Our findings support influenced provide means functionally link features.

Язык: Английский

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Transposons contribute to the acquisition of cell type-specific cis-elements in the brain

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Июнь 10, 2023

Mammalian brains have evolved in stages over a long history to acquire higher functions. Recently, several transposable element (TE) families been shown evolve into cis-regulatory elements of brain-specific genes. However, it is not fully understood how TEs are important for gene regulatory networks. Here, we performed single-cell level analysis using public data scATAC-seq discover TE-derived cis-elements that specific cell types. Our results suggest DNA derived from TEs, MER130 and MamRep434, can function as transcription factor-binding sites based on their internal motifs Neurod2 Lhx2, respectively, especially glutamatergic neuronal progenitors. Furthermore, MER130- MamRep434-derived were amplified the ancestors Amniota Eutheria, respectively. These acquisition with occurred different during evolution may contribute functions or morphologies brain.

Язык: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Фев. 27, 2023

ABSTRACT Krüppel-associated box (KRAB) domain-containing zinc finger proteins (KZFPs) are one of the largest groups transcription factors encoded by tetrapods, with 378 members in human alone. KZFP genes often grouped clusters reflecting amplification gene and segment duplication since 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, facilitate co-option regulatory potential TEs for benefit host. Here, we present a comprehensive survey genetic features targets KZFPs, notably completing past analyses adding data on hundred members. General principles emerge from our study TE-KZFP system, which point to multipronged evolutionary mechanisms underlaid highly complex combinatorial modes action strong influences speciation.

Язык: Английский

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