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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.

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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

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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.

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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

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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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

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

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

Project description:Krüppel-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 close to 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.

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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