Gene expression regulation by the Chromodomain Helicase DNA-binding protein 9 (CHD9) chromatin remodeler is dispensable for murine development
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ABSTRACT:
PROVIDER: PRJNA625751 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11557900_1.fastq.gz | Fastqsanger.gz | |||
| SRR11557900_2.fastq.gz | Fastqsanger.gz | |||
| SRR11557901_1.fastq.gz | Fastqsanger.gz | |||
| SRR11557901_2.fastq.gz | Fastqsanger.gz | |||
| SRR11557902_1.fastq.gz | Fastqsanger.gz |
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Project description:Chromodomain helicase DNA-binding (CHD) chromatin remodelers regulate transcription and DNA repair. They govern cell-fate decisions during embryonic development and are often deregulated in human pathologies. Chd1-8 show upon germline disruption pronounced, often developmental lethal phenotypes. Here we show that contrary to Chd1-8 disruption, Chd9-/-animals are viable, fertile and display no developmental defects or disease predisposition. Germline deletion of Chd9 only moderately affects gene expression in tissues and derived cells, whereas acute depletion in human cancer cells elicits more robust changes suggesting that CHD9 is a highly context-dependent chromatin regulator that, surprisingly, is dispensable for mouse development.
| S-EPMC7250415 | biostudies-literature
Project description:Purpose: Chromodomain helicase DNA-binding (CHD) chromatin remodelers regulate transcription and DNA repair. Chd1-8 show upon germline disruption pronounced, often developmental lethal phenotypes. Here we show that contrary to Chd1-8 disruption, Chd9–/– animals are viable, fertile and display no developmental defects or disease predisposition. Germline deletion of Chd9 only moderately affects gene expression in tissues and derived cells, whereas acute depletion in human cancer cells elicits more robust changes suggesting that CHD9 is a highly context-dependent chromatin regulator that, surprisingly, is dispensable for mouse development. Methods: The role of CHD9 in gene expression regulation during murine development and lymphomagenesis, as well as in human cancer cell lines was explored by RNA-seq analysis. Embryonic (E15) brain and liver were isolated from littermates and snap-frozen. Mouse embryonic fibroblasts (MEFs) were isolated from the Chd9+/-x Chd9+/- cross at day 13.5 post coitum and cultured using standard methods. Three wild-type control and four Chd9 knockout derived fibroblast lines were used. Embryonic stem cells (ESC) were derived from the Chd9+/-x Chd9+/- cross as described before (Huijbers IJ, et al, 2015). Three wild-type control and three Chd9 knockout derived ESC lines were used. For all the experiments early passage MEFs and ESCs were used. Enlarged lymph nodes from three moribund Emu-Myc control, Chd9+/- and Chd9-/- mice were isolated and snap-frozen. Human SNB19 and K562 cells bearing doxycycline-inducible short hairpin RNAs (shRNA) targeting CHD9 were induced with 1ug/ml doxycycline for 48 hours, harvested, and pellet was snap-frozen. Total RNA was extracted, prepared using TruSeq protocol, and standard sample preparation protocols and RNA-seq was performed on a Hiseq2000 machine (Illumina) at the NKI Genomics Core Facility. Results: Sequencing data were aligned to mm9 (MEFs, ESCs), mm10 (E15 brain and liver; Emu-Myc lymphomas), hg37 (K562 and SNB19 cells) using TopHat (v2.1.0 using bowtie 1.1.0). and number of reads per gene were measured with HTSeq count (v0.5.3). Statistical analysis of the differential expression of genes were performed using DESeq2. Results were considered statistically significant at an adjusted p < 0.05. Normalized expression values were obtained by correcting for differences in sequencing depth between samples using DESeqs median-of-ratios approach. Analysis of Chd9 knockout MEFs revealed only downregulation of Chd9 and upregulation of the Hmgb2 and pseudogene Gm13237, (adjusted p–value 0.05, log2FC ±1). Conversely, in derived Chd9–/– ESCs maintained in serum–free 2i media with leukemia inhibitory factor (LIF), 63 upregulated and 212 downregulated genes were observed (adjusted p–value 0.05, log2FC ±1). RNA–seq of Chd9 knockout embryonic (E15) liver and brain revealed only a handful of differentially expressed genes (DEGs) (adjusted p–value 0.05, log2FC ±1). Both liver and brain show concordant upregulation of an uncharacterized pseudogene Gm4322. Despite high Chd9 expression in the developing brain, only marginal upregulation of the Hoxa (a7), Hoxb (b6, b7, b9) and Hoxc (c5, c6) homeotic gene clusters was observed. Analysis of lymphomas from Emu-Myc Chd9 wildtype, heterozygous and knockout mice revealed that in heterozygous tumours 20 genes were upregulated, and only Lrnn4 was downregulated. In the knockout tumours 28 genes were up– and 8 down–regulated. The presence of a shared six upregulated genes in both CHD9 heterozygous and knockout lymphomas suggests that they might be direct target genes. RNA-seq analysis of human cancer cell lines revealed profound gene expression changes 48 hours upon CHD9 depletion. In K562 cells, CHD9 knockdown resulted in 215 down- and 635 upregulated genes, whereas in SNB19 cells, 121 down- and 113 up–regulated genes were observed. Notably, a number of deregulated genes in CHD9-depleted K562 cells – such as PBX1, APLNR, and BIN1– are implicated in neuronal development and pathology. This suggests a more widespread role for CHD9 in regulation of neuronal-specific genes, which even shows up in the context of malignant hematopoietic K562 cells. We did not find any significant overlap in DEGs between both human cancer cell lines. Conclusions: Our study represents the first analysis of the role of CHD9 in gene expression regulation during murine development and lymphomagenesis, as well as in human cancer cells. The very modest effects on gene expression seen upon germline deletion of Chd9, as compared to the substantial change in gene expression upon acute depletion in two human cell lines, point to compensatory me chanisms mitigating the effects of germline deletion of Chd9. Our gene expression analysis failed to reveal any compensatory transcriptional deregulation of CHD enzymes or other chromatin regulators. Our results reveal that, despite ubiquitous expression, Chd9 is dispensable for embryonic development. Furthermore, knockout animals are viable, fertile, display no overt phenotypes and have a normal lifespan.
2020-04-17 | GSE148803 | GEO
Project description:Integrative analysis of colorectal cancer (CRC) whole genomes and matched transcriptomes revealed that somatic promoter mutations are associated with increased Chromodomain helicase DNA-binding protein 2 (CHD2) levels. In both primary and metastatic CRC patients, elevated CHD2 levels are associated with worse prognosis and overall survival. We find that CHD2 increases promoter-transcription start site-chromatin accessibility and transcriptional upregulation of multiple oncogenes. In vitro, elevated CHD2 promoted CRC cell proliferation, migration and growth. In orthotopic xenografts, CHD2 promoted higher tumor burden and abdominal metastases, most prominently to the liver. FTD/TPI is an FDA approved chemotherapy for advanced chemo-refractory CRC. In orthotopic CRC models, FTD/TPI was highly effective in reducing metastases and prolonging survival for CHD2 high expressing CRCs. Thus, high CHD2 expression may be a potential CRC chemopredictive biomarker for FTD/TPI. Overall, these results provide new insights into the role of non-coding mutations and CHD2 levels to promote CRC growth and metastasis.
2021-02-12 | GSE146398 | GEO
Project description:B cell specification and identity are controlled by transcription factors and cytokine receptors that drive the expression of stage-specific transcriptomes during lineage progression. A key feature of these mechanisms is the repression of inappropriate transcription. Here, we utilized RNA-seq to demonstrate that chromodomain helicase DNA-binding protein 4 (CHD4), an ATPase/helicase subunit of Mi-2/NuRD chromatin remodeling complexes, is essential for B cell identity. In mice that lack CHD4 selectively in the B lineage, defects include developmental arrest at the early pro-B cell stage. While many pro-B-specific genes are expressed in the mutant cells, transcripts that are normally restricted to other tissues including pancreas and bone are expressed out of context. Moreover, CHD4-deficient pro-B cells do not proliferate in response to IL-7, exhibit greatly decreased utilization of distal VH segments and accumulate DNA damage. Together, our data confirm the importance of CHD4 and NuRD complexes for the generation of functional B cells.
2019-05-22 | GSE84806 | GEO
Project description:Although autism spectrum disorders (ASDs) share a core set of nosological features, they exhibit substantial genetic heterogeneity. A parsimonious hypothesis posits that dysregulated epigenetic mechanisms represent common pathways in the etiology of ASDs. To investigate this hypothesis, we generated a novel mouse model resulting from brain-specific deletion of chromodomain helicase DNA-binding 5 (Chd5), a chromatin remodeling protein known to regulate neuronal differentiation and a member of a gene family strongly implicated in ASDs. RNA sequencing of Chd5-/- mouse forebrain tissue revealed a preponderance of changes in expression of genes important in cellular development and signaling, sociocommunicative behavior and ASDs. Pyramidal neurons cultured from Chd5-/- cortex displayed alterations in dendritic morphology. Paralleling ASD nosology, Chd5-/- mice exhibited abnormal sociocommunicative behavior and a strong preference for familiarity. Chd5-/- mice further showed deficits in responding to the distress of a conspecific, a mouse homolog of empathy. Thus, dysregulated chromatin remodeling produces a pattern of transcriptional, neuronal and behavioral effects consistent with the presentation of ASDs.
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Project description:Gene expression profiling on heads of Drosophila chromodomain helicase DNA binding protein 1 (CHD1) deletion mutants
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Project description:Paramutations represent directed and meiotically-heritable changes in gene regulation leading to apparent violations of Mendelian inheritance. Although the mechanism and evolutionary importance of paramutation behaviors remain largely unknown, genetic screens in maize (Zea mays) identify five components affecting 24 nucleotide RNA biogenesis as required to maintain repression of a paramutant purple plant1 (pl1) allele. Currently, the RNA polymerase IV largest subunit represents the only component also specifying proper development. Here we identify a chromodomain helicase DNA-binding 3 (CHD3) protein orthologous to Arabidopsis (Arabidopsis thaliana) PICKLE as a second component maintaining both pl1 paramutation, and normal somatic development. In addition, genetic tests show this protein contributes to proper male gametophyte function. The similar mutant phenotypes documented in Arabidopsis and maize implicate some evolutionarily-conserved gene regulation while developmental defects associated with the two paramutation mutants are largely distinct. Our results show that a CHD3 protein responsible for normal plant ontogeny and sperm transmission also maintains meiotically-heritable epigenetic regulatory variation for specific alleles. This finding implicates an intersection of RNA polymerase IV function and nucleosome positioning in the paramutation process.
2020-11-24 | GSE158990 | GEO
Project description:Mutations in CHD8, an ATP-dependent chromodomain-helicase-DNA-binding protein 8, are known to cause a set of Autism Spectrum Disorders (ASD). We found that CHD8 is highly expressed in myelinating oligodendrocytes (OL) and their progenitors in the developing central nervous system (CNS). We performed CHD8 chIP-seq analysis in cultured oligodendrocytes.
2018-06-20 | GSE107919 | GEO
Project description:Herein we characterize an apparently balanced de novo translocation, t(X;15)(p22.2;q26.1)dn, in a female patient with scoliosis, hirsutism, learning problems, and developmental delay (DGAP025). Other clinical findings include a high-arched palate, 2-3 syndactyly of the toes, and mildly elevated serum testosterone. No known or predicted genes are disrupted by the Xp22.2 breakpoint. The 15q26.1 breakpoint disrupts chromodomain helicase DNA binding protein 2 (CHD2). Another member of the chromatin-remodeling gene family, CHD7, has been associated with a defined constellation of congenital anomalies known as coloboma, heart anomaly, choanal atresia, mental retardation, genital and ear anomalies syndrome (CHARGE) and idiopathic scoliosis. Monosomy of 15q26 also has been associated with a spectrum of congenital abnormalities and growth retardation that overlaps with those of DGAP025. To provide a biological correlate, we characterized a mutant mouse model with Chd2 disruption that is associated with embryonic and perinatal lethality. Expression analysis indicated that Chd2 is expressed in the heart, forebrain, extremities, facial and dorsal regions during specific times of embryonic development. Chd2(+/m) mice showed pronounced lordokyphosis, reduced body fat, postnatal runting, and growth retardation. These data suggest that haploinsufficiency for CHD2 could result in a complex of abnormal human phenotypes that includes scoliosis and possibly features similar to CHARGE syndrome.
| S-EPMC2834558 | biostudies-literature