Though prostate cancer is often indolent, it is nonetheless a leading cause of cancer death. Defining the underlying molecular genetic alterations may lead to new strategies for prevention or treatment. Towards this goal, we performed array-based comparative genomic hybridization (CGH) on 86 primary
prostate tumors. Among the most frequent alterations not associated with a known cancer gene, we identified focal deletions within 5q21 in 15 out of 86 (17%) cases. By high-resolution tiling array CGH, the smallest common deletion targeted just one gene, the chromatin remodeler chromodomain helicase DNA-binding protein 1 (CHD1). Expression of CHD1 was significantly reduced in tumors with deletion (P=0.03), and compared with normal prostate (P=0.04). Exon sequencing analysis also uncovered nonsynonymous mutations in 1 out of 7 (14%) cell lines (LAPC4) and in 1 out of 24 (4%) prostate tumors surveyed. RNA interference-mediated knockdown of CHD1 in two nontumorigenic prostate epithelial cell lines, OPCN2 and RWPE-1, did not alter cell growth, but promoted cell invasiveness, and in OPCN2-enhanced cell clonogenicity. Taken together, our findings suggest that CHD1 deletion may underlie cell invasiveness in a subset of prostate cancers, and indicate a possible novel role of altered chromatin remodeling in prostate tumorigenesis.
Marcos-Villar L, etal., J Virol. 2016 Jan 20;90(7):3694-707. doi: 10.1128/JVI.00053-16.
Influenza A virus requires ongoing cellular transcription to carry out the cap-snatching process. Chromatin remodelers modify chromatin structure to produce an active or inactive conformation, which enables or prevents the recruitment of transcriptional complexes to specific genes; viral transcript
ion thus depends on chromatin dynamics. Influenza virus polymerase associates with chromatin components of the infected cell, such as RNA polymerase II (RNAP II) or the CHD6 chromatin remodeler. Here we show that another CHD family member, CHD1 protein, also interacts with the influenza virus polymerase complex. CHD1 recognizes the H3K4me3 (histone 3 with a trimethyl group in lysine 4) histone modification, a hallmark of active chromatin. Downregulation of CHD1 causes a reduction in viral polymerase activity, viral RNA transcription, and the production of infectious particles. Despite the dependence of influenza virus on cellular transcription, RNAP II is degraded when viral transcription is complete, and recombinant viruses unable to degrade RNAP II show decreased pathogenicity in the murine model. We describe the CHD1-RNAP II association, as well as the parallel degradation of both proteins during infection with viruses showing full or reduced induction of degradation. The H3K4me3 histone mark also decreased during influenza virus infection, whereas a histone mark of inactive chromatin, H3K27me3, remained unchanged. Our results indicate that CHD1 is a positive regulator of influenza virus multiplication and suggest a role for chromatin remodeling in the control of the influenza virus life cycle. IMPORTANCE: Although influenza virus is not integrated into the genome of the infected cell, it needs continuous cellular transcription to synthesize viral mRNA. This mechanism implies functional association with host genome expression and thus depends on chromatin dynamics. Influenza virus polymerase associates with transcription-related factors, such as RNA polymerase II, and with chromatin remodelers, such as CHD6. We identified the association of viral polymerase with another chromatin remodeler, the CHD1 protein, which positively modulated viral polymerase activity, viral RNA transcription, and virus multiplication. Once viral transcription is complete, RNAP II is degraded in infected cells, probably as a virus-induced mechanism to reduce the antiviral response. CHD1 associated with RNAP II and paralleled its degradation during infection with viruses that induce full or reduced degradation. These findings suggest that RNAP II degradation and CHD1 degradation cooperate to reduce the antiviral response.
Metzger E, etal., Nat Struct Mol Biol. 2016 Feb;23(2):132-9. doi: 10.1038/nsmb.3153. Epub 2016 Jan 11.
Prostate cancer evolution is driven by a combination of epigenetic and genetic alterations such as coordinated chromosomal rearrangements, termed chromoplexy. TMPRSS2-ERG gene fusions found in human prostate tumors are a hallmark of chromoplexy. TMPRSS2-ERG fusions have been linked to androgen signa
ling and depend on androgen receptor (AR)-coupled gene transcription. Here, we show that dimethylation of KDM1A at K114 (to form K114me2) by the histone methyltransferase EHMT2 is a key event controlling androgen-dependent gene transcription and TMPRSS2-ERG fusion. We identified CHD1 as a KDM1A K114me2 reader and characterized the KDM1A K114me2-CHD1 recognition mode by solving the cocrystal structure. Genome-wide analyses revealed chromatin colocalization of KDM1A K114me2, CHD1 and AR in prostate tumor cells. Together, our data link the assembly of methylated KDM1A and CHD1 with AR-dependent transcription and genomic translocations, thereby providing mechanistic insight into the formation of TMPRSS2-ERG gene fusions during prostate-tumor evolution.
BACKGROUND: The list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncoveri
ng the genetic aetiology of autism. OBJECTIVES: To explore whether variants in CHD1 are associated with a human phenotype. METHODS: We used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts. RESULTS: Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1. CONCLUSIONS: Our results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.
The packaging of eukaryotic DNA into nucleosomes, and the organisation of these nucleosomes into chromatin, plays a critical role in regulating all DNA-associated processes. Chromodomainhelicase DNA-binding protein 1 (CHD1) is an ATP-dependent chromatin remodell
ing protein that is conserved throughout eukaryotes and has an ability to assemble and organise nucleosomes both in vitro and in vivo. This activity is involved in the regulation of transcription and is implicated in mammalian development and stem cell biology. CHD1 is classically depicted as possessing a pair of tandem chromodomains that directly precede a core catalytic helicase-like domain that is then followed by a SANT-SLIDE DNA-binding domain. Here, we have identified an additional conserved domain C-terminal to the SANT-SLIDE domain and determined its structure by multidimensional heteronuclear NMR spectroscopy. We have termed this domain the CHD1helical C-terminal (CHCT) domain as it is composed of five alpha-helices arranged in a variant helical bundle topology. CHCT has a conserved, positively charged surface and is able to bind DNA and nucleosomes. In addition, we have identified another group of proteins, the as yet uncharacterised C17orf64 proteins, as also containing a conserved CHCT domain. Our data provide new structural insights into the CHD1 enzyme family.
Yao H, etal., Mol Cancer. 2015 Apr 11;14:81. doi: 10.1186/s12943-015-0353-x.
BACKGROUND: RUNX1/AML1, which is a Runt family transcription factor critical for normal hematopoiesis, is frequently mutated or translocated in a broad spectrum of hematopoietic malignancies. FINDINGS: We describe here the case of a 54-year-old female developed acute myeloid leukemia with a t(5;21)
(q21;q22). Transcriptome sequencing identified the chromodomain-helicase-DNA-binding protein 1 gene, CHD1, as a novel partner gene of RUNX1. Furthermore, the patient was found to harbor FLT3-ITD mutation, which might collaborated with CHD1-RUNX1 in the development of acute myeloid leukemia. CONCLUSIONS: We have identified CHD1 as the RUNX1 fusion partner in acute myeloid leukemia with t(5;21)(q21;q22).
Liu M, etal., Hepatology. 2016 May;63(5):1544-59. doi: 10.1002/hep.28437. Epub 2016 Mar 4.
High-grade tumors with poor differentiation usually show phenotypic resemblance to their developmental ancestral cells. Cancer cells that gain lineage precursor cell properties usually hijack developmental signaling pathways to promote tumor malignant progression. However, the molecular mechanisms
underlying this process remain unclear. In this study, the chromatin remodeler chromodomain-helicase-DNA-binding-protein 1-like (CHD1L) was found closely associated with liver development and hepatocellular carcinoma (HCC) tumor differentiation. Expression of CHD1L decreased during hepatocyte maturation and increased progressively from well-differentiated HCCs to poorly differentiated HCCs. Chromatin immunoprecipitation followed by high-throughput deep sequencing found that CHD1L could bind to the genomic sequences of genes related to development. Bioinformatics-aided network analysis indicated that CHD1L-binding targets might form networks associated with developmental transcription factor activation and histone modification. Overexpression of CHD1L conferred ancestral precursor-like properties of HCC cells both in vitro and in vivo. Inhibition of CHD1L reversed tumor differentiation and sensitized HCC cells to sorafenib treatment. Mechanism studies revealed that overexpression of CHD1L could maintain an active "open chromatin" configuration at promoter regions of estrogen-related receptor-beta and transcription factor 4, both of which are important regulators of HCC self-renewal and differentiation. In addition, we found a significant correlation of CHD1L with developmental transcriptional factors and lineage differentiation markers in clinical HCC patients. CONCLUSION: Genomic amplification of chromatin remodeler CHD1L might drive dedifferentiation of HCC toward an ancestral lineage through opening chromatin for key developmental transcriptional factors; further inhibition of CHD1L might "downgrade" poorly differentiated HCCs and provide novel therapeutic strategies.
PARP1 and poly(ADP-ribosyl)ation (PARylation) have been shown to be essential for the initial steps of cellular reprogramming. However, the mechanism underlying PARP1/PARylation-regulated activation of pluripotency loci remains undetermined. Here, we demonstrate that CHD1
CHD1L, a DNA helicase, possesses chromatin remodeling activity and interacts with PARP1/PARylation in regulating pluripotency during reprogramming. We found that this interaction is mediated through the interplay of the CHD1L macro-domain and the PAR moiety of PARylated-PARP1. Chromatin immunoprecipitation assays demonstrated the co-occupancy of CHD1L and PARP1 at Pou5f1, Nanog, and Esrrb pluripotency loci. Knockdown of CHD1L significantly blocked the binding activity of PARP1 at pluripotency loci and inhibited the efficiency of PARP1-driven reprogramming. Notably, we found that CHD1L-promoted reprogramming requires both a PARP1-interacting domain and DNA helicase activity, partly contributing to the chromatin-remodeling states of pluripotency loci. Taken together, these results identify CHD1L as a key chromatin remodeler involved in PARP1/PARylation-regulated early-stage reprogramming and pluripotency in stem cells.
Mu QJ, etal., PLoS One. 2015 Nov 23;10(11):e0143030. doi: 10.1371/journal.pone.0143030. eCollection 2015.
BACKGROUND: Chromodomain helicase/ATPase DNA-binding protein 1-like gene (CHD1L), also known as ALC1 (amplified in liver cancer 1 gene), is a new oncogene amplified in many solid tumors. Whether this gene plays a role in invasion and metastasis of breast cancer
is unknown. METHODS: Immunohistochemistry was performed to detect the expression of CHD1L in patients with invasive ductal carcinoma and normal mammary glands. Chemotaxis, wound healing, and Transwell invasion assays were also performed to examine cell migration and invasion. Western blot analysis was conducted to detect the expression of CHD1L, MMP-2, MMP-9, pAkt/Akt, pARK5/ARK5, and pmTOR/mTOR. Moreover, ELISA was carried out to detect the expression levels of MMP-2 and MMP-9. Nude mice xenograft model was used to detect the invasion and metastasis of breast cancer cell lines. RESULTS: CHD1L overexpression was observed in 112 of 268 patients (41.8%). This overexpression was associated with lymph node metastasis (P = 0.008), tumor differentiation (P = 0.020), distant metastasis (P = 0.026), MMP-2 (P = 0.035), and MMP-9 expression (P = 0.022). In the cell experiment, reduction of CHD1L inhibited the invasion and metastasis of breast cancer cells by mediating MMP-2 and MMP-9 expression. CHD1L knockdown via siRNA suppressed EGF-induced pAkt, pARK5, and pmTOR. This knockdown inhibited the metastasis of breast cancer cells into the lungs of SCID mice. CONCLUSIONS: CHD1L promoted the invasion and metastasis of breast cancer cells via the PI3K/Akt/ARK5/mTOR/MMP signaling pathway. This study identified CHD1L as a potential anti-metastasis target for therapeutic intervention in breast cancer.
He LR, etal., Oncotarget. 2015 Oct 13;6(31):31181-90. doi: 10.18632/oncotarget.5070.
CHD1L (chromodomain helicase/ATPase DNA binding protein 1-like gene) has been demonstrated as an oncogene in hepatocellular carcinoma (HCC), however, the role of CHD1L in non-small-cell lung cancer (NSCLC) tumorigenesis has
n't been elucidated. In this study, the expression and amplification status of CHD1L were examined by immunohistochemistry and fluorescence in situ hybridization respectively in 248 surgically resected NSCLCs. The associations between CHD1L expression and clinicopathologic features and the prognostic value of CHD1L were analyzed. Overexpression and amplification of CHD1L was found in 42.1% and 17.7% of NSCLCs, respectively. The frequency of CHD1L overexpression (53.2% vs. 28.1%, P = 0.002) and amplification (25.2% vs. 8.2%, P = 0.020) in adenocarcinoma (ADC), was much higher than that in squamous cell carcinoma (SCC). CHD1L overexpression was associated closely with ascending pN status (P < 0.001), advanced clinical stage (P = 0.001) and tumor distant metastasis (P = 0.001) in ADCs, but not in SCCs. For the whole cohort and ADC patients, univariate survival analysis demonstrated a significant association of CHD1L overexpression with shortened survival; and in multivariate analysis, CHD1L overexpression was evaluated as a independent predictor for overall survival and distant metastasis free survival. These results suggested that overexpression of CHD1L is positively associated with tumor metastasis of lung ADC, and might serve as a novel prognostic biomarker and potential therapeutic target for lung ADC patients.
