ZNF512B binds RBBP4 via a variant NuRD interaction motif and aggregates chromatin in a NuRD complex-independent manner
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA991947 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25180630_1.fastq.gz | Fastqsanger.gz | |||
| SRR25180630_2.fastq.gz | Fastqsanger.gz | |||
| SRR25180631_1.fastq.gz | Fastqsanger.gz | |||
| SRR25180631_2.fastq.gz | Fastqsanger.gz | |||
| SRR25180632_1.fastq.gz | Fastqsanger.gz |
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Project description:The evolutionary conserved histone variant H2A.Z plays a crucial role in various DNA-based processes but the underlying mechanisms are not completely understood. Recently, we identified the zinc finger (ZNF) protein ZNF512B as an H2A.Z-, HMG20A- and PWWP2A-associated protein. Here, we report ZNF512B as a novel nucleosome remodeling and deacetylase (NuRD) complex binding protein. We discovered a conserved amino acid sequence within ZNF512B that resembles a NuRD-interaction domain (NIM) previously identified in FOG-1. By solving the crystal structure of this domain directly bound to the NuRD component RBBP4 and by applying several biochemical assays we demonstrate that this novel internal NIM sequence is both necessary and sufficient for high-affinity NuRD binding. Transcriptome analyses and reporter assays identify ZNF512B as regulator (repressor) of gene expression, in both NuRD-dependent and -independent modes. Surprisingly, high levels of ZNF512B expression lead to concomitant nuclear protein and chromatin aggregation foci that form independent of the interaction with the NuRD complex but depend on ZNF512B’s zinc fingers. Our study has implications for diseases in which ZNF512B’s expression is deregulated, such as cancer and neurodegenerative diseases and reveal the existence of more proteins as potential NuRD interactors.
2024-10-29 | GSE236639 | GEO
Project description:The evolutionary conserved histone variant H2A.Z plays a crucial role in various DNA-based processes but the underlying mechanisms are not completely understood. Recently, we identified the zinc finger (ZNF) protein ZNF512B as an H2A.Z-, HMG20A- and PWWP2A-associated protein. Here, we report ZNF512B as a novel nucleosome remodeling and deacetylase (NuRD) complex binding protein. We discovered a conserved amino acid sequence within ZNF512B that resembles a NuRD-interaction domain (NIM) previously identified in FOG-1. By solving the crystal structure of this domain directly bound to the NuRD component RBBP4 and by applying several biochemical assays we demonstrate that this novel internal NIM sequence is both necessary and sufficient for high-affinity NuRD binding. Transcriptome analyses and reporter assays identify ZNF512B as regulator (repressor) of gene expression, in both NuRD-dependent and -independent modes. Surprisingly, high levels of ZNF512B expression lead to concomitant nuclear protein and chromatin aggregation foci that form independent of the interaction with the NuRD complex but depend on ZNF512B’s zinc fingers. Our study has implications for diseases in which ZNF512B’s expression is deregulated, such as cancer and neurodegenerative diseases and reveal the existence of more proteins as potential NuRD interactors.
2024-10-30 | PXD043366 | Pride
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| S-EPMC11602157 | biostudies-literature
Project description:Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen targeting active regulatory elements, we identify the zinc finger protein ZNF512B as a key suppressor of SASP. ZNF512B loss induces DNA damage, activates cGAS-STING signaling, and triggers inflammatory transcriptional reprogramming. In contrast, ZNF512B promotes preferential DNA repair at regulatory genomic regions, limiting SASP induction. Mechanistically, ZNF512B is rapidly recruited to DNA damage sites via distinct zinc finger domains and facilitates NuRD complex targeting to damaged chromatin, enabling precise repair. In human neuromuscular organoids, ZNF512B deficiency induces inflammation, lineage imbalance, and cytokine secretion resembling ALS-associated pathology. In vivo, ZNF512B overexpression reduces DNA damage and inflammation following acute liver injury. Together, these findings support a mechanism of preferential DNA repair that contributes to maintaining genome integrity to suppress SASP and inflammation.
2026-06-18 | GSE206078 | GEO
Project description:Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen targeting active regulatory elements, we identify the zinc finger protein ZNF512B as a key suppressor of SASP. ZNF512B loss induces DNA damage, activates cGAS-STING signaling, and triggers inflammatory transcriptional reprogramming. In contrast, ZNF512B promotes preferential DNA repair at regulatory genomic regions, limiting SASP induction. Mechanistically, ZNF512B is rapidly recruited to DNA damage sites via distinct zinc finger domains and facilitates NuRD complex targeting to damaged chromatin, enabling precise repair. In human neuromuscular organoids, ZNF512B deficiency induces inflammation, lineage imbalance, and cytokine secretion resembling ALS-associated pathology. In vivo, ZNF512B overexpression reduces DNA damage and inflammation following acute liver injury. Together, these findings support a mechanism of preferential DNA repair that contributes to maintaining genome integrity to suppress SASP and inflammation.
2026-06-22 | GSE206076 | GEO
Project description:Zinc finger proteins are a large family of DNA-binding factors that play key roles in diverse cellular processes including gene regulation, RNA metabolism and cell cycle control. The zinc finger protein ZNF512B has recently been implicated in chromatin organization and transcriptional repression through its direct interaction with the nucleosome remodeling and deacetylase (NuRD) complex, its DNA-binding ability, and its association with the histone variant H2A.Z. Here, we uncover a previously unrecognized role for ZNF512B that is independent of both its zinc finger domains and NuRD association. We identify ZNF512B as a spindle-associated factor that regulates progression through mitosis, specifically controlling metaphase exit. ZNF512B’s N-terminal internal region, which contains 25 repeats of a six-residue motif predicted to form a β-helix structure, is required and sufficient for its spindle interaction. Elevated ZNF512B levels result in a profound metaphase arrest that is ultimately lethal, a phenotype arising from the combined activity of its spindle-binding and chromatin-tethering functions. Conversely, ZNF512B depletion accelerates stem cell proliferation, impairs differentiation, and upregulates genes linked to cell cycle progression. Our findings position ZNF512B as a multifunctional protein that acts as a transcriptional repressor, a chromatin aggregator and a novel mitotic exit regulator through spindle fiber binding.
2025-08-22 | GSE303898 | GEO
Project description:Active regions in the genome are more prone to DNA damage (Schwer et al., 2016), but the mutations occur less often in these regions (Martincorena et al., 2012; Monroe et al., 2022; Xia et al., 2020; Zhang and Yang, 2015), indicating involvement of unknown protective machinery. Chronic DNA damage signaling induces senescence associated secretory phenotype (SASP), which mediates pathophysiological functions of senescent cells during aging (Herranz and Gil, 2018), however, the molecular players governing SASP remain poorly understood. Here we performed a genome wide CRISPR screening by implementing a SASP specific reporter system and a guide RNA library targeting regulatory regions and identify several novel SASP repressors. ZNF512B is one such factor that prioritizes DNA repair around regulatory regions associated with highly expressed genes. ZNF512B selectively recruits NuRD nucleosome remodeling complexes to damage loci and ensure faithful timely manner repair. ZNF512B depletion induces SASP, and its overexpression inhibits SASP in various in vitro and in vivo models by modulating DNA repair. ZNF512B overexpression slows down cutaneous wound healing and reduces damage associated with acute liver injury by repression of SASP. ZNF512B is a known prognostic factor for amyotrophic lateral sclerosis (ALS) (Jiang et al., 2021; Tetsuka et al., 2013; Yang et al., 2015; Yu et al., 2018) and its ablation in human neuromuscular organoids leads to depletion of astroglia compartment, a possible mechanism leading to subsequent defects in neuromuscular pathology in ALS. Taken together these findings have important implications for our understanding of repair bias around functionally constrained regions to safeguard long term genome integrity during aging and age associated pathology.
2026-06-22 | GSE206077 | GEO
Project description:Active regions in the genome are more prone to DNA damage (Schwer et al., 2016), but the mutations occur less often in these regions (Martincorena et al., 2012; Monroe et al., 2022; Xia et al., 2020; Zhang and Yang, 2015), indicating involvement of unknown protective machinery. Chronic DNA damage signaling induces senescence associated secretory phenotype (SASP), which mediates pathophysiological functions of senescent cells during aging (Herranz and Gil, 2018), however, the molecular players governing SASP remain poorly understood. Here we performed a genome wide CRISPR screening by implementing a SASP specific reporter system and a guide RNA library targeting regulatory regions and identify several novel SASP repressors. ZNF512B is one such factor that prioritizes DNA repair around regulatory regions associated with highly expressed genes. ZNF512B selectively recruits NuRD nucleosome remodeling complexes to damage loci and ensure faithful timely manner repair. ZNF512B depletion induces SASP, and its overexpression inhibits SASP in various in vitro and in vivo models by modulating DNA repair. ZNF512B overexpression slows down cutaneous wound healing and reduces damage associated with acute liver injury by repression of SASP. ZNF512B is a known prognostic factor for amyotrophic lateral sclerosis (ALS) (Jiang et al., 2021; Tetsuka et al., 2013; Yang et al., 2015; Yu et al., 2018) and its ablation in human neuromuscular organoids leads to depletion of astroglia compartment, a possible mechanism leading to subsequent defects in neuromuscular pathology in ALS. Taken together these findings have important implications for our understanding of repair bias around functionally constrained regions to safeguard long term genome integrity during aging and age associated pathology.
2026-06-22 | GSE206071 | GEO
Project description:Active regions in the genome are more prone to DNA damage (Schwer et al., 2016), but the mutations occur less often in these regions (Martincorena et al., 2012; Monroe et al., 2022; Xia et al., 2020; Zhang and Yang, 2015), indicating involvement of unknown protective machinery. Chronic DNA damage signaling induces senescence associated secretory phenotype (SASP), which mediates pathophysiological functions of senescent cells during aging (Herranz and Gil, 2018), however, the molecular players governing SASP remain poorly understood. Here we performed a genome wide CRISPR screening by implementing a SASP specific reporter system and a guide RNA library targeting regulatory regions and identify several novel SASP repressors. ZNF512B is one such factor that prioritizes DNA repair around regulatory regions associated with highly expressed genes. ZNF512B selectively recruits NuRD nucleosome remodeling complexes to damage loci and ensure faithful timely manner repair. ZNF512B depletion induces SASP, and its overexpression inhibits SASP in various in vitro and in vivo models by modulating DNA repair. ZNF512B overexpression slows down cutaneous wound healing and reduces damage associated with acute liver injury by repression of SASP. ZNF512B is a known prognostic factor for amyotrophic lateral sclerosis (ALS) (Jiang et al., 2021; Tetsuka et al., 2013; Yang et al., 2015; Yu et al., 2018) and its ablation in human neuromuscular organoids leads to depletion of astroglia compartment, a possible mechanism leading to subsequent defects in neuromuscular pathology in ALS. Taken together these findings have important implications for our understanding of repair bias around functionally constrained regions to safeguard long term genome integrity during aging and age associated pathology.
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Project description:In the developing subpallium, the fate decision between neurons and glia is driven by expression of Dlx1/2 or Olig1/2 respectively, two sets of transcription factors (TFs) with a mutually repressive relationship. The mechanism by which Dlx1/2 repress progenitor and oligodendrocyte fate, while promoting transcription of genes needed for differentiation, is not fully understood. We identified a motif within DLX1 that binds RBBP4, a NuRD complex subunit. ChIP-seq studies of genomic occupancy of DLX1 and six different members of the NuRD complex show that DLX1 and NuRD colocalize to putative regulatory elements (pREs) enriched near other transcription factor genes. Loss of Dlx1/2 leads to dysregulation of genome accessibility at pREs near genes repressed by Dlx1/2, including Olig2. Consequently, heterozygosity of Dlx1/2 and Rbbp4 leads to an increase in the production of OLIG2+ cells. These findings highlight the importance of the interplay between TFs and chromatin remodelers in regulating cell fate decisions.
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