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Primate-restricted KRAB zinc finger proteins control gene expression in human brain

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144192 | GEO | 2020/01/24

REPOSITORIES: GEO

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

Project description: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 co-opted 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 (ESCs). 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.

| S-EPMC7455193 | biostudies-literature

Primate-restricted KRAB zinc finger proteins control gene expression in human brain

Project description:Primate-restricted KRAB zinc finger proteins control gene expression in human brain

| PRJNA602996 | ENA

Structural Evolution of Gene Promoters Driven by Primate-Specific KRAB Zinc Finger Proteins.

Project description:Krüppel-associated box (KRAB) zinc finger proteins (KZNFs) recognize and repress transposable elements (TEs); TEs are DNA elements that are capable of replicating themselves throughout our genomes with potentially harmful consequences. However, genes from this family of transcription factors have a much wider potential for genomic regulation. KZNFs have become integrated into gene-regulatory networks through the control of TEs that function as enhancers and gene promoters; some KZNFs also bind directly to gene promoters, suggesting an additional, more direct layer of KZNF co-option into gene-regulatory networks. Binding site analysis of ZNF519, ZNF441, and ZNF468 suggests the structural evolution of KZNFs to recognize TEs can result in coincidental binding to gene promoters independent of TE sequences. We show a higher rate of sequence turnover in gene promoter KZNF binding sites than neighboring regions, implying a selective pressure is being applied by the binding of a KZNF. Through CRISPR/Cas9 mediated genetic deletion of ZNF519, ZNF441, and ZNF468, we provide further evidence for genome-wide co-option of the KZNF-mediated gene-regulatory functions; KZNF knockout leads to changes in expression of KZNF-bound genes in neuronal lineages. Finally, we show that the opposite can be established upon KZNF overexpression, further strengthening the support for the role of KZNFs as bona-fide gene regulators. With no eminent role for ZNF519 in controlling its TE target, our study may provide a snapshot into the early stages of the completed co-option of a KZNF, showing the lasting, multilayered impact that retrovirus invasions and host response mechanisms can have upon the evolution of our genomes.

| S-EPMC10653712 | biostudies-literature

Roles of human endogenous retroviruses and KRAB-zinc finger proteins in tumor progression

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-09-29 | GSE141803 | GEO

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-01-18 | GSE229471 | GEO

Adaptive evolution of gene promoters driven by primate-specific KRAB zinc finger proteins

Project description:RNA analysis of CRISPR/Cas9 ZNF519 knockout (KO), ZNF441 knockout (KO), ZNF468 knockout (KO) and wild type hESC-derived cortical organoids and ChIP-seq analysis of CRISPR/Cas9 ZNF519 knockout (KO) and wild type hESC-derived cortical organoids, and HEK293 cells with ZNF519 overexpression (OE).

2022-04-25 | GSE201315 | GEO

Zinc fingers function cooperatively with KRAB domain for nuclear localization of KRAB-containing zinc finger proteins.

Project description:Multiple nuclear localization domains have been identified in nuclear proteins, and they finely control nuclear import and functions of those proteins. ZNF268 is a typical KRAB-containing zinc finger protein (KRAB-ZFP), and previous studies have shown that the KRAB domain reinforces nuclear localization of KRAB-ZFPs by interacting with KAP1. In this study, we find that some of 24 zinc fingers of ZNF268 also possess nuclear localization activity. Results of mutagenesis studies suggest that KRAB and zinc fingers are both necessary, and they function both independently and cooperatively for the nuclear localization of ZNF268. However, the subnuclear targeting activities of KRAB and zinc fingers are different. KRAB targets proteins in nucleoplasm, but not in the nucleolus, which is mediated by interaction with KAP1, while zinc fingers target proteins in the whole nucleus uniformly. The cooperative activities of KAP1-KRAB-zinc fingers result in the precise nucleoplasmic, but not nucleolar localization of KRAB-ZFPs. Our studies reveal a novel mechanism for the subcellular localization of KRAB-ZFPs and may help us to further explore their biological functions.

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Multiparameter functional diversity of human C2H2 zinc finger proteins

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-10-25 | E-GEOD-76496 | biostudies-arrayexpress

An evolutionary arms race between KRAB zinc finger genes 91/93 and SVA/L1 retrotransposons

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-09-29 | E-GEOD-60211 | biostudies-arrayexpress

MAGE proteins regulate KRAB zinc finger transcription factors and KAP1 E3 ligase activity.

Project description:Expression of Melanoma AntiGen Encoding (MAGE) genes, particularly MAGE-A3, has been correlated with aggressive clinical course, the acquisition of resistance to chemotherapy and poor clinical outcomes of melanoma and other malignancies. MAGE proteins bind to KAP1, a gene repressor and ubiquitin E3 ligase which also binds KRAB domain containing zinc finger transcription factors (KZNFs), and MAGE expression may affect KZNF mediated gene regulation. To investigate mechanisms for these effects, we tested the hypothesis that differences in KRAB domain composition affect KZNF poly-ubiquitination and determine whether MAGE expression increases, decreases, or has no effect on KZNFs mediated gene repression. Using an integrated reporter gene responsive to repression by KRAB domain fusion proteins, we found that MAGE-A3 relieved KZNF mediated repression and induced KZNF poly-ubiquitination and degradation in association with expression of the A+B box KRAB domain. In contrast, MAGE-A3 enhanced KAP1 mediated repression of KZNFs expressing A or A+b box KRAB domains but caused no increase in poly-ubiquitination or degradation. MAGE-A3 has no significant impact on KZNFs with KRAB domains containing the Scan box motif. These data support our hypothesis by showing that the effects of MAGE-A3 on gene repression depend on the type of KZNF KRAB domain involved.

| S-EPMC4221552 | biostudies-literature

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