Chd4

Chromatin remodellers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), however, their functions during brain development are not fully understood. Here, we focused on Sifrim-Hitz-Weiss Syndrome (SIHIWES)-an intellectual disability disorder caused by mutations in the CHD4 chromodomain helicase gene. We utilized mouse genetics to excise the Chd4 ATPase/helicase domain-either constitutively, or conditionally in the developing telencephalon. Conditional heterozygotes exhibited no change in cortical size and cellular composition and had only subtle behavioral phenotypes...

The nucleosome remodeling and histone deacetylase (NuRD) complex physically associates with BCL11B to regulate murine T-cell development. However, the function of NuRD complex in mature T cells remains unclear. Here, we characterize the fate and metabolism of human T cells in which key subunits of the NuRD complex or BCL11B are ablated. BCL11B and the NuRD complex bind to each other and repress natural killer (NK)-cell fate in T cells. In addition, T cells upregulate the NK cell-associated receptors and transcription factors, lyse NK-cell targets, and are reprogrammed into NK-like cells (ITNKs) upon deletion of MTA2, MBD2, CHD4, or BCL11B...

BACKGROUND: It is generally recognized that genetic metabolic disorders can result in neurological symptoms such as seizures, developmental delay, and intellectual disability. Heterogeneous clinical presentations make the diagnosis challenging. CASE PRESENTATION: In this case report, we present a unique and complex genetic disorder observed in a female patient who exhibited three pathogenic gene variants in the KCNT1, ACADM , and CHD4 genes. The convergence of these variants resulted in a multifaceted clinical presentation characterized by severe seizures of combined focal and generalized onset, metabolic dysfunction, and neurodevelopmental abnormalities...

PURPOSE: To evaluate the molecular features of clear cell adenocarcinoma (CCA) of the urinary tract and investigate its pathogenic pathways and possible actionable targets. MATERIALS AND METHODS: We retrospectively collected the data of patients with CCA between January 1999 and December 2016; the data were independently reviewed by two pathologists. We selected five cases of urinary CCA, based on the clinicopathological features. We analyzed these five cases by whole-exome sequencing (WES) and subsequent bioinformatics analyses to determine the mutational spectrum and possible pathogenic pathways...

The chromatin remodeler Chromodomain-helicase-DNA-binding protein 4 (CHD4) is crucial for the development of multiple organ systems. Functional mutations of CHD4 have recently been described in a developmental disorder, namely Siffrim-Hitz-Weiss syndrome (SIHIWES). Herein, we have generated a homozygous CHD4G1003D hESC line (WAe025-A-1) using CRISPR/eCas9-based gene editing in the WA-25 hESC line. The edited hESC line maintains normal karyotype, pluripotency, and ability to differentiate into three germ layers...

Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 ( MECP2 ) cause classical forms of Rett syndrome (RTT) in girls. A subset of patients who are recognized to have an overlapping neurological phenotype with RTT but are lacking a mutation in a gene that causes classical or atypical RTT can be described as having a 'Rett-syndrome-like phenotype (RTT-L). Here, we report eight patients from our cohort diagnosed as having RTT-L who carry mutations in genes unrelated to RTT. We annotated the list of genes associated with RTT-L from our patient cohort, considered them in the light of peer-reviewed articles on the genetics of RTT-L, and constructed an integrated protein-protein interaction network (PPIN) consisting of 2871 interactions connecting 2192 neighboring proteins among RTT- and RTT-L-associated genes...

Osteoarthritis (OA) is a common degenerative joint disorder that adversely affects the quality of life of patients. Identification of novel diagnostic biomarkers is pivotal for the early detection and prevention of OA. Dataset GSE185059 was selected from Gene Expression Omnibus database to obtain differentially expressed lncRNAs (DE-lncRNAs), mRNAs (DE-mRNAs), and circRNAs (DE-circRNAs) between OA and normal samples. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses as well as protein-protein interaction (PPI) network construction of DE-mRNAs were conducted...

Loss of spiral ganglion neurons (SGNs) in the cochlea causes hearing loss. Understanding the mechanisms of cell fate transition accelerates efforts that employ directed differentiation and lineage conversion to repopulate lost SGNs. Proposed strategies to regenerate SGNs rely on altering cell fate by activating transcriptional regulatory networks, but repressing networks for alternative cell lineages is also essential. Epigenomic changes during cell fate transitions suggest that CHD4 represses gene expression by altering the chromatin status...

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Type 2 immune responses are critical in tissue homeostasis, anti-helminth immunity, and allergy. T helper 2 (Th2) cells produce interleukin-4 (IL-4), IL-5, and IL-13 from the type 2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand transcriptional regulation of Th2 cell differentiation, we performed CRISPR-Cas9 screens targeting 1,131 TFs. We discovered that activity-dependent neuroprotector homeobox protein (ADNP) was indispensable for immune reactions to allergen...

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) can be described as a debilitating lung disease that is characterized by the complex interactions between various immune cell types and signaling pathways. Chromatin-modifying enzymes are significantly involved in regulating gene expression during immune cell development, yet their role in IPF is not well understood. METHODS: In this study, differential gene expression analysis and chromatin-modifying enzyme-related gene data were conducted to identify hub genes, common pathways, immune cell infiltration, and potential drug targets for IPF...

BACKGROUND: Left ventricular noncompaction (LVNC) is a prevalent cardiomyopathy associated with excessive trabeculation and thin compact myocardium. Patients with LVNC are vulnerable to cardiac dysfunction and at high risk of sudden death. Although sporadic and inherited mutations in cardiac genes are implicated in LVNC, understanding of the mechanisms responsible for human LVNC is limited. METHODS: We screened the complete exome sequence database of the Pediatrics Cardiac Genomics Consortium and identified a cohort with a de novo CHD4 (chromodomain helicase DNA-binding protein 4) proband, CHD4M202I , with congenital heart defects...

The Nucleosome Remodelling and Deacetylase (NuRD) complex represents one of the major chromatin remodelling complexes in mammalian cells, uniquely coupling the ability to "open" the chromatin by inducing nucleosome sliding with histone deacetylase activity. At the core of the NuRD complex are a family of ATPases named CHDs that utilise the energy produced by the hydrolysis of the ATP to induce chromatin structural changes. Recent studies have highlighted the prominent role played by the NuRD in regulating gene expression during brain development and in maintaining neuronal circuitry in the adult cerebellum...

BACKGROUND: Single recurrence in the sub-frontal region after cerebellar medulloblastoma (MB) resection is rare and the underlying molecular characteristics have not been specifically addressed. METHODS: We summarized two such cases in our center. All five samples were molecularly profiled for their genome and transcriptome signatures. RESULTS: The recurrent tumors displayed genomic and transcriptomic divergence. Pathway analysis of recurrent tumors showed functional convergence in metabolism, cancer, neuroactive ligand-receptor interaction, and PI3K-AKT signaling pathways...

GATA zinc finger domain containing 2A (GATAD2A) is a subunit of the nucleosome remodeling and deacetylase (NuRD) complex. NuRD is known to regulate gene expression during neural development and other processes. The NuRD complex modulates chromatin status through histone deacetylation and ATP-dependent chromatin remodeling activities. Several neurodevelopmental disorders (NDDs) have been previously linked to variants in other components of NuRD's chromatin remodeling subcomplex (NuRDopathies). We identified five individuals with features of an NDD that possessed de novo autosomal dominant variants in GATAD2A ...

BACKGROUND: Brain tumours are the leading cause of cancer-related death in children, and there is no effective treatment. A growing body of evidence points to deregulated epigenetics as a tumour driver, particularly in paediatric cancers as they have relatively few genomic alterations, and key driver mutations have been identified in histone 3 (H3). Cancer stem cells (CSC) are implicated in tumour development, relapse and therapy resistance and thus particularly important to target. We therefore aimed to identify novel epigenetic treatment targets in CSC derived from H3-mutated high-grade glioma (HGG) through a CRISPR-Cas9 knockout screen...

OBJECTIVES: Myositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), antisynthetase syndrome (AS) and inclusion body myositis (IBM). Myositis-specific autoantibodies define different subtypes of myositis. For example, patients with anti-Mi2 autoantibodies targeting the chromodomain helicase DNA-binding protein 4 (CHD4)/NuRD complex (a transcriptional repressor) have more severe muscle disease than other DM patients. This study aimed to define the transcriptional profile of muscle biopsies from anti-Mi2-positive DM patients...

Combined hepatocellular-cholangiocarcinoma with a ductal plate malformation pattern is an extremely rare entity with unelucidated pathogenesis. We present the case of a 60-year-old male patient who underwent a sectionectomy for pre-operative diagnosis of hepatocellular carcinoma based on clinical and image findings. Gross examination of the specimen revealed a well-defined tumor with cystic change measuring 6.7 × 6.2 cm. Microscopically, the lesion had classical features of hepatocellular carcinoma and intrahepatic cholangiocarcinoma exhibited neoplastic glands with irregular-sized dilated lumens, resembling a ductal plate malformation...

Cellular totipotency is critical for whole-organism generation, yet how totipotency is established remains poorly illustrated. Abundant transposable elements (TEs) are activated in totipotent cells, which is critical for embryonic totipotency. Here, we show that the histone chaperone RBBP4, but not its homolog RBBP7, is indispensable for maintaining the identity of mouse embryonic stem cells (mESCs). Auxin-induced degradation of RBBP4, but not RBBP7, reprograms mESCs to the totipotent 2C-like cells. Also, loss of RBBP4 enhances transition from mESCs to trophoblast cells...

Dermatomyositis (DM) is an idiopathic inflammatory myopathy belonging to the spectrum of autoimmune connective tissue diseases. DM patients present with antinuclear antibodies against Mi-2, also known as Chromodomain-helicase-DNA-binding protein 4 (CHD4). CHD4 is upregulated in DM skin biopsies and could potentially affect DM pathophysiology as it binds endogenous DNA with a high affinity (KD = 0.2 nM ± 0.076 nM) and forms CHD4-DNA complexes. The complexes are localized in the cytoplasm of UV-radiated and transfected HaCaTs and amplify the expression of interferon (IFN) regulated genes and the amount of functional CXCL10 protein stronger than DNA alone...