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

Tribolet-Hardy, Jonas de; Thorball, Christian W; Forey, Romain; Planet, Evarist; Duc, Julien; Khubieh, Bara; Offner, Sandra; Fellay, Jacques; Imbeault, Michaël; Turelli, Priscilla; Trono, Didier

doi:10.1101/2023.02.27.530095

Cited by 9 publications

(14 citation statements)

References 74 publications

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“…Interestingly, we recovered a dominant, new peak on chromosome 4 that was associated with L1M3a RNA levels but to which we could not attribute a protein-coding mediator. The index SNV for this locus, rs6819237, resides within an intron of ZNF141 , which has been shown to bind L1PA elements (de Tribolet-Hardy et al 2023). Second, the eQTL scan using the nearby intergenic L1 profiles recapitulated the results of our initial scan for the HLA loci ( Supplementary Figure S7B, Supplementary Table S3F) .…”

Section: Resultsmentioning

confidence: 99%

An eQTL-based Approach Reveals Candidate Regulators of LINE-1 RNA Levels in Lymphoblastoid Cells

Bravo,

Mizrahi,

Kim

et al. 2023

Preprint

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Long interspersed element 1 (L1) are a family of autonomous, actively mobile transposons that occupy ~17% of the human genome. The pleiotropic effects L1 induces in host cells - promoting genome instability, inflammation, or cellular senescence - are established, and L1's associations with aging and aging diseases are widely recognized. However, because of the cell type-specific nature of transposon control, the catalogue of L1 regulators remains incomplete. Here, we employ an eQTL approach leveraging transcriptomic and genomic data from the GEUVADIS and 1000Genomes projects to computationally identify new candidate regulators of L1 expression in lymphoblastoid cell lines. To cement the role of candidate genes in L1 regulation, we experimentally modulate the levels of top candidates in vitro, including IL16, STARD5, HSDB17B12, and RNF5, and assess changes in TE family expression by Gene Set Enrichment Analysis (GSEA). Remarkably, we observe subtle but widespread upregulation of TE family expression following IL16 and STARD5 overexpression. Moreover, a short-term 24 hour exposure to recombinant human IL16 was sufficient to transiently induce subtle but widespread upregulation of L1 subfamilies. Finally, we find that many L1 expression-associated genetic variants are co-associated with aging traits across genome-wide association study databases. Our results expand the catalogue of genes implicated in L1 transcriptional control and further suggest that L1 contributes to aging processes. Given the ever-increasing availability of paired genomic and transcriptomic data, we anticipate this new approach to be a starting point for more comprehensive computational scans for transposon transcriptional regulators.

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Section: Resultsmentioning

confidence: 99%

An eQTL-based Approach Reveals Candidate Regulators of LINE-1 RNA Levels in Lymphoblastoid Cells

Bravo,

Mizrahi,

Kim

et al. 2023

Preprint

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“…HEK293T cells overexpressing HA-tagged constructs were generated as described in de Tribolet-Hardy et al, 2023 1 . In short, cDNAs for ZNF274 constructs were codon-optimized, synthesized using the GeneArt service from ThermoFisher and cloned into the doxycycline inducible expression vector pTRE-3HA.…”

Section: Methodsmentioning

confidence: 99%

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

Begnis,

Duc,

Offner

et al. 2024

Preprint

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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.

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“…Krüppel-associated box (KRAB) domain-containing zinc-finger family proteins (KZFP) are one of the largest groups of transcription factors in tetrapods (de Tribolet-Hardy et al, 2023). It has been reported that the expressed HERVs in tumors (such as LTR70, LTR25, LTR5B, and LTR5_Hs) are predominantly in the vicinity of TSSs of KZFP genes and some of these HERVs could act as enhancers modulating the expression of KZFP genes in LUAD cells (Ito et al, 2020).…”

Section: Lung Cancermentioning

confidence: 99%

Endogenous retroviral solo-LTRs in human genome

Chen,

Huang,

Wang

et al. 2024

Front. Genet.

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Human endogenous retroviruses (HERVs) are derived from the infection and integration of exogenetic retroviruses. HERVs account for 8% of human genome, and the majority of HERVs are solitary LTRs (solo-LTRs) due to homologous recombination. Multiple findings have showed that solo-LTRs could provide an enormous reservoir of transcriptional regulatory sequences involved in diverse biological processes, especially carcinogenesis and cancer development. The link between solo-LTRs and human diseases still remains poorly understood. This review focuses on the regulatory modules of solo-LTRs, which contribute greatly to the diversification and evolution of human genes. More importantly, although inactivating mutations, insertions and deletions have been identified in solo-LTRs, the inherited regulatory elements of solo-LTRs initiate the expression of chimeric lncRNA transcripts, which have been reported to play crucial roles in human health and disease. These findings provide valuable insights into the evolutionary and functional mechanisms underlying the presence of HERVs in human genome. Taken together, in this review, we will present evidences showing the regulatory and encoding capacity of solo-LTRs as well as the significant impact on various aspects of human biology.

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

Cited by 9 publications

References 74 publications

An eQTL-based Approach Reveals Candidate Regulators of LINE-1 RNA Levels in Lymphoblastoid Cells

An eQTL-based Approach Reveals Candidate Regulators of LINE-1 RNA Levels in Lymphoblastoid Cells

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

Endogenous retroviral solo-LTRs in human genome

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