Transposable Elements and Their KRAB-ZFP Controllers Regulate Gene Expression in Adult Tissues

Ecco, Gabriela; Cassano, Marco; Kauzlaric, Annamaria; Duc, Julien; Coluccio, Andrea; Offner, Sandra; Imbeault, Michaël; Rowe, Helen M.; Turelli, Priscilla; Trono, Didier

doi:10.1016/j.devcel.2016.02.024

Cited by 200 publications

(217 citation statements)

References 60 publications

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“…HERVs and LINEs). Conversely, many TE subfamilies are recognized by several KRAB-ZFPs, which most often target clearly distinct regions of their integrants, as has been observed for ERVKs (endogenous retrovirus K) in mouse and for HERVs and LINE-1s (L1s) in humans Ecco et al, 2016). Interestingly, in humans, it was observed that the age of the elements influences their pattern of KRAB-ZFP recruitment.…”

Section: Genomic Targets Of Human Krab Zinc Finger Proteinsmentioning

confidence: 93%

“…It was then suspected that the primary role of KRAB-ZFPs was to silence TEs, and that their evolutionary selection represented the host component of an arms race against these genetic invaders (Jacobs et al, 2014;Castro-Diaz et al, 2014;Thomas and Schneider, 2011). More recent data, however, suggest that KRAB-ZFPs fulfill a role that is far more elaborate and, in some cases at least, can contribute to the domestication of their TE targets for the benefit of the host (Ecco et al, 2016;Imbeault et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Although functional data on the role of individual human KRAB-ZFPs during this period are still missing, it is noteworthy that HERVH (human endogenous retrovirus H) integrants, which appear to play an important role in human ESC pluripotency, are recognized by several KRAB-ZFPs, the levels of which change as these cells switch from a naïve to a primed pluripotent state (Theunissen et al, 2016). Other KRAB-ZFPs controlling TEs in ESCs are ZNF91 and ZNF93, which respectively repress SVAs and LINE-1 (Jacobs et al, 2014), and the murine paralogs ZFP932 and Gm15446, which regulate ERVKs (Ecco et al, 2016). It is now established that, by controlling TEs, the KRAB-ZFP/KAP1 complex ensures the transcriptional homeostasis and normal differentiation of ESCs.…”

Section: Heterochromatin Induction In Early Development and Te Controlmentioning

confidence: 99%

“…2). Accordingly, many KRAB-ZFPs act as transcriptional repressors via the KAP1-nucleated induction of heterochromatin and, in early embryonic cells, via DNA methylation (Wolf and Goff, 2009;Quenneville et al, 2012;Rowe et al, 2013;Jacobs et al, 2014;Najafabadi et al, 2015;Ecco et al, 2016;Schmitges et al, 2016;Imbeault et al, 2017). However, not all KRAB-ZFPs bind KAP1, and the interactome of more ancient human family members, notably those endowed with SCAN or All KRAB-ZFPs contain a KRAB domain and an array of zinc fingers with DNA-binding potential, the sequence specificity of which is dictated mainly by three amino acids within each zinc finger (at positions 6, 3 and -1).…”

Section: Genomic Targets Of Human Krab Zinc Finger Proteinsmentioning

confidence: 99%

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KRAB zinc finger proteins

2017

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Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs) are the largest family of transcriptional regulators in higher vertebrates. Characterized by an N-terminal KRAB domain and a C-terminal array of DNA-binding zinc fingers, they participate, together with their co-factor KAP1 (also known as TRIM28), in repression of sequences derived from transposable elements (TEs). Until recently, KRAB-ZFP/KAP1-mediated repression of TEs was thought to lead to irreversible silencing, and the evolutionary selection of KRAB-ZFPs was considered to be just the host component of an arms race against TEs. However, recent advances indicate that KRAB-ZFPs and their TE targets also partner up to establish speciesspecific regulatory networks. Here, we provide an overview of the KRAB-ZFP gene family, highlighting how its evolutionary history is linked to that of TEs, and how KRAB-ZFPs influence multiple aspects of development and physiology.

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Section: Genomic Targets Of Human Krab Zinc Finger Proteinsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Heterochromatin Induction In Early Development and Te Controlmentioning

confidence: 99%

Section: Genomic Targets Of Human Krab Zinc Finger Proteinsmentioning

confidence: 99%

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KRAB zinc finger proteins

2017

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“…In addition or alternatively, possible variegated or lack of ERV repression might relate to the rather low to moderate expression of the two KRABcontaining zinc finger proteins Zfp932 and Gm15446 in wild-type GV oocytes. These KRAB-ZFPs have recently been shown to control repression of various ERVK elements, known to also be silenced by Kap1 (also known as Trim28 or Tif1beta) and Setdb1 (Ecco et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos

et al. 2016

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Oocytes develop the competence for meiosis and early embryogenesis during their growth. Setdb1 is a histone H3 lysine 9 (H3K9) methyltransferase required for post-implantation development and has been implicated in the transcriptional silencing of genes and endogenous retroviral elements (ERVs). To address its role in oogenesis and pre-implantation development, we conditionally deleted Setdb1 in growing oocytes. Loss of Setdb1 expression greatly impaired meiosis. It delayed meiotic resumption, altered the dynamics of chromatin condensation, and impaired kinetochore-spindle interactions, bipolar spindle organization and chromosome segregation in more mature oocytes. The observed phenotypes related to changes in abundance of specific transcripts in mutant oocytes. Setdb1 maternally deficient embryos arrested during pre-implantation development and showed comparable defects during cell cycle progression and in chromosome segregation. Finally, transcriptional profiling data indicate that Setdb1 downregulates rather than silences expression of ERVK and ERVLMaLR retrotransposons and associated chimearic transcripts during oogenesis. Our results identify Setdb1 as a newly discovered meiotic and embryonic competence factor safeguarding genome integrity at the onset of life.

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The expression signature of cancer‐associated KRAB‐ZNF factors identified in TCGA pan‐cancer transcriptomic data

et al. 2019

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The KRAB ‐ ZNF (Krüppel‐associated box domain zinc finger) gene family is composed of a large number of highly homologous genes, gene isoforms, and pseudogenes. The proteins encoded by these genes, whose expression is often tissue‐specific, act as epigenetic suppressors contributing to the addition of repressive chromatin marks and DNA methylation. Due to its high complexity, the KRAB ‐ ZNF family has not been studied in sufficient detail, and the involvement of its members in carcinogenesis remains mostly unexplored. In this study, we aimed to provide a comprehensive description of cancer‐associated KRAB ‐ ZNF s using publicly available The Cancer Genome Atlas pan‐cancer datasets. We analyzed 6727 tumor and normal tissue samples from 16 cancer types. Here, we showed that a small but distinctive cluster of 16 KRAB ‐ ZNF s is commonly upregulated across multiple cancer cohorts in comparison to normal samples. We confirmed these observations in the independent panels of lung and breast cancer cell lines and tissues. This upregulation was also observed for most of the KRAB ‐ ZNF splicing variants, whose expression is simultaneously upregulated in tumors compared to normal tissues. Finally, by analyzing the clinicopathological data for breast and lung cancers, we demonstrated that the expression of cancer‐associated KRAB ‐ ZNF s correlates with patient survival, tumor histology, and molecular subtyping. Altogether, our study allowed the identification and characterization of KRAB ‐ ZNF factors that may have an essential function in cancer biology and thus potential to become novel oncologic biomarkers and treatment targets.

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Transposable Elements and Their KRAB-ZFP Controllers Regulate Gene Expression in Adult Tissues

Cited by 200 publications

References 60 publications

KRAB zinc finger proteins

KRAB zinc finger proteins

The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos

The expression signature of cancer‐associated KRAB‐ZNF factors identified in TCGA pan‐cancer transcriptomic data

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