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ChAHP (Adnp, Chd4, HP1) mediates sequence-specific recruitment of HP1 independent of H3K9 methylation

ABSTRACT: Activity-dependent neuroprotective protein (ADNP) is one of the most frequent autism spectrum disorder-associated gene products known to date. Here we show that Adnp interacts with the chromatin remodeler Chd4 and the heterochromatin protein HP1 to form a stable complex, which we refer to as ChAHP. Genetic ablation of ChAHP components or DNA binding sites in embryonic stem cells prematurely activates lineage-specific genes, revealing an important role for Adnp in restraining the differentiation capacity of pluripotent cells. Adnp targets the ChAHP complex to specific sequence motifs at euchromatic loci, representing an H3K9 methylation-independent mechanism of HP1 recruitment and gene silencing.

ORGANISM(S): Mus musculus

PROVIDER: GSE97945 | GEO | 2018/05/23

REPOSITORIES: GEO

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The HP1 protein interactome of mouse embryonic stem cells

Project description:The family of Heterochromatin Protein 1 (HP1) consists of highly conserved proteins, which have important functions in the nucleus of eukaryotic cells. In mammals there are three HP1 paralogs: HP1(alpha), Hp1(beta), and Hp1(gamma)They are encoded by the Cbx5, Cbx1, and Cbx3 genes, respectively. Hp1 and Hp1 stably interact with Chd4 and Adnp to form the ChAHP complex. In this project, Chd4, Adnp, and the three Cbx genes were endogenously tagged with a FLAG-Avi tag in mouse embryonic stem cells. The tagged proteins were subjected to tandem-affinity purification and analysis by mass spectrometry.

2018-05-22 | PXD006226 | Pride

Mus musculus

Project description:ChAHP (Adnp, Chd4, HP1) mediates sequence-specific recruitment of HP1 independent of H3K9 methylation

| PRJNA383413 | ENA

The ChAHP complex counteracts chromatin looping at Ctcf sites that have emerged from recent SINE expansions

Project description:Ctcf and cohesin are key players in the three dimensional organization of chromatin. Whereas genome-wide Ctcf binding has diverged substantially between species due to transposon-mediated motif expansions, demarcation of topologically associating domains (TADs) by Ctcf is remarkably well conserved. Yet, the Ctcf consensus motif poorly predicts TADs and the majority of Ctcf sites are not at TAD boundaries. Here we demonstrate that the ChAHP complex (Chd4, Adnp, HP1) competes with Ctcf for a common set of genomic binding sites. In absence of ChAHP, novel insulated regions are formed at ChAHP bound sites, whereas proximal canonical boundaries are weakened. These data reveal that Ctcf-mediated loop formation is modulated by a distinct zinc-finger protein complex. Strikingly, ChAHP bound loci are mainly situated within evolutionary young SINE B2 transposable elements. This further implicates ChAHP in maintenance of evolutionary conserved spatial chromatin organization by buffering novel Ctcf binding sites that emerged through SINE expansions.

2019-09-05 | GSE125129 | GEO

b1 integrin signaling governs necroptosis via the chromatin remodeling factor CHD4

Project description:Fibrosis, characterized by sustained activation of myofibroblasts and excessive extracellular matrix (ECM) deposition, is known to be associated with chronic inflammation. RIPK3, a key kinase mediating TNF-driven necroptosis signaling, is upregulated in fibrosis and contributes to the TNF-mediated inflammation. In biliary duct ligation-induced liver fibrosis, we found that myofibroblasts are the major cell type expressing RIPK3. Genetic ablation of b1 integrins, the major profibrotic ECM receptors in fibroblasts, not only abolished ECM fibrillogenesis but also blunted RIPK3 expression via an epigenetic mechanism mediated by the chromatin remodeling factor CHD4. While the function of CHD4 has been conventionally linked to NuRD and ChAHP complexes, we found that CHD4 potently repressed a set of genes, including Ripk3, with high locus specificity but independent of either the NuRD or ChAHP complex. Thus, our data uncover that b1 integrin intrinsically links fibrotic signaling to RIPK3-driven inflammation via a novel mode of action of CHD4.

2023-10-23 | GSE229795 | GEO

beta 1 integrin signaling governs necroptosis via the chromatin remodeling factor CHD4

Project description:Fibrosis, characterized by sustained activation of myofibroblasts and excessive extracellular matrix (ECM) deposition, is known to be associated with chronic inflammation. RIPK3, a key kinase mediating TNF-driven necroptosis signaling, is upregulated in fibrosis and contributes to the TNF-mediated inflammation. In bile duct ligation-induced liver fibrosis, we found that myofibroblasts are the major cell type expressing RIPK3. Genetic ablation of beta1 integrins, the major profibrotic ECM receptors in fibroblasts, not only abolished ECM fibrillogenesis but also blunted RIPK3 expression via an epigenetic mechanism mediated by the chromatin remodeling factor CHD4. While the function of CHD4 has been conventionally linked to NuRD and ChAHP complexes, we found that CHD4 potently repressed a set of genes, including Ripk3, with high locus specificity but independent of either the NuRD or ChAHP complex. Thus, our data uncover that beta1 integrin intrinsically links fibrotic signaling to RIPK3-driven inflammation via a novel mode of action of CHD4.

2023-10-30 | PXD041505 | Pride

Neuroprotective protein ADNP-dependent histone remodeling complex promotes Th2 immune cell differentiation (ATAC-Seq)

Project description:Type-2 immune responses are critical in tissue homeostasis, anti-helminth immunity and allergy. Th2 cells produce interleukin (IL)-4, IL-5 and IL-13 from the type-2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand this system we performed CRISPR-Cas9 screens targeting 1131 TFs during Th2 cell differentiation. We discovered that ADNP is indispensable for immune reactions to allergen. Mechanistically, ADNP performs a previously unappreciated role in gene activation forming a critical bridge in the transition from pioneer TFs to chromatin remodelling by recruiting CHD4 and BRG1. Although GATA3 and AP-1 bound the type-2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type-2 cytokine expression. Similar ADNP-dependent regulation was observed for the Maf and Il4ra genes which are known regulators of Th2 differentiation. Our results demonstrate an important role for ADNP in promoting immune cell specialization.

2023-06-06 | GSE218015 | GEO

Neuroprotective protein ADNP-dependent histone remodeling complex promotes Th2 immune cell differentiation (ChIP-Seq)

2023-06-06 | GSE218014 | GEO

Neuroprotective protein ADNP-dependent histone remodeling complex promotes Th2 immune cell differentiation (RNA-Seq)

2023-06-06 | GSE218016 | GEO

Neuroprotective protein ADNP-dependent histone remodeling complex promotes Th2 immune cell differentiation (scRNA-Seq)

2023-06-06 | GSE231522 | GEO

Transcription profiling of mouse ADNP knockout vs wild type

Project description:The putative transcription factor, activity-dependent neuroprotective protein (ADNP) is a zinc finger and homeodomain - like profile containing protein. ADNP knockout mice die at day 9 of gestation. To reveal ADNP-associated pathways, a 22,690- Affymetrix probe array was used on ADNP knockout and control embryos. References:; Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem. 1999 Mar;72(3):1283-93. PMID: 10037502 [PubMed - indexed for MEDLINE]; Cloning and characterization of the human activity-dependent neuroprotective protein. J Biol Chem. 2001 Jan 5;276(1):708-14. PMID: 11013255 [PubMed - indexed for MEDLINE]; Activity-dependent neuroprotective protein: a novel gene essential for brain formation. Brain Res Dev Brain Res. 2003 Aug 12;144(1):83-90. PMID: 12888219 [PubMed - indexed for MEDLINE] Experiment Overall Design: To identify downstream target genes of ADNP, we examined global gene expression profiles of whole E9 knockout embryos (KO - ADNP -l-), their wild-type (WT - ADNP +l+ ) and their heterozygous (H - ADNP âl+ ) littermates, using the Affymetrix Murine Genome 430A oligonucleotide microarrays. Gestation day 9 was chosen as it is the period at which embryos lacking ADNP exhibit distinct morphological and developmental changes prior to degeneration and in uterus absorption. Total RNA was extracted from four ADNP knockout embryos, four normal embryos and six heterozygous embryos. A pool of two genotype identical littermates was used on seven different arrays (pooling of two embryos was necessary to obtain enough RNA on each of the gene microarrays).

2008-06-12 | E-GEOD-4068 | biostudies-arrayexpress

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