Publications by authors named "Erik Engelen"

11 Publications

  • Page 1 of 1

CHD7 regulates cardiovascular development through ATP-dependent and -independent activities.

Proc Natl Acad Sci U S A 2020 11 30;117(46):28847-28858. Epub 2020 Oct 30.

Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294;

encodes an ATP-dependent chromatin remodeling factor. Mutation of this gene causes multiple developmental disorders, including CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth/development, Genital abnormalities, and Ear anomalies) syndrome, in which conotruncal anomalies are the most prevalent form of heart defects. How CHD7 regulates conotruncal development remains unclear. In this study, we establish that deletion of in neural crest cells (NCCs) causes severe conotruncal defects and perinatal lethality, thus providing mouse genetic evidence demonstrating that CHD7 cell-autonomously regulates cardiac NCC development, thereby clarifying a long-standing controversy in the literature. Using transcriptomic analyses, we show that CHD7 fine-tunes the expression of a gene network that is critical for cardiac NCC development. To gain further molecular insights into gene regulation by CHD7, we performed a protein-protein interaction screen by incubating recombinant CHD7 on a protein array. We find that CHD7 directly interacts with several developmental disorder-mutated proteins including WDR5, a core component of H3K4 methyltransferase complexes. This direct interaction suggested that CHD7 may recruit histone-modifying enzymes to target loci independently of its remodeling functions. We therefore generated a mouse model that harbors an ATPase-deficient allele and demonstrates that mutant CHD7 retains the ability to recruit H3K4 methyltransferase activity to its targets. Thus, our data uncover that CHD7 regulates cardiovascular development through ATP-dependent and -independent activities, shedding light on the etiology of CHD7-related congenital disorders. Importantly, our data also imply that patients carrying a premature stop codon versus missense mutations will likely display different molecular alterations; these patients might therefore require personalized therapeutic interventions.
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http://dx.doi.org/10.1073/pnas.2005222117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682373PMC
November 2020

Zoonotic risks of pathogens from sheep and their milk borne transmission.

Small Rumin Res 2020 Aug 15;189:106123. Epub 2020 May 15.

Royal GD, Department of Small Ruminant Health, Deventer, The Netherlands.

Sheep were domesticated around 9000 BC in the Middle East, and since then milk from sheep gradually became very popular, not only for drinking but also for making cheeses and other dairy products. Nowadays, these dairy products are also important for people with an allergy to cow milk, and these products are an essential part of the local daily diet in regions of the world that are not suitable for cows and goats. Consumption of raw milk and raw milk products has a zoonotic risk, and with regard to sheep, the main pathogens associated with such dairy products are: , spp., spp., spp., Shiga-toxin producing , , tick borne encephalitis virus, and . Especially, young children, elderly people, pregnant women and immunocompromised (YOPI) persons, and those suffering from disease should be aware of the risk of consuming raw milk and raw milk products. This latter risk can be reduced by proper flock health management, prevention of contamination during milking, adequate milk processing, transport, and refrigerated storage. Only processes equaling pasteurization sufficiently reduce zoonotic risks from milk and milk products, but proper cooling is essential and recontamination must be prevented. Therefore, strict hygiene practices throughout the production process and supply chain especially for raw milk and raw dairy products, should be applied. Small scale production systems pose a greater risk compared to industrialized production systems because of a less protocolized and controlled production process. This manuscript describes zoonotic risks of pathogens from sheep and their milk borne transmission. Additionally, routes of contamination, possibilities for multiplication, and prevention measures thereof are described. We summarize some major human outbreaks caused by consumption of sheep milk and products made thereof, and finally discuss their implications.
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http://dx.doi.org/10.1016/j.smallrumres.2020.106123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227596PMC
August 2020

EcR recruits dMi-2 and increases efficiency of dMi-2-mediated remodelling to constrain transcription of hormone-regulated genes.

Nat Commun 2017 04 5;8:14806. Epub 2017 Apr 5.

Institute of Molecular Biology and Tumour Research, Philipps University Marburg, Marburg 35037, Germany.

Gene regulation by steroid hormones plays important roles in health and disease. In Drosophila, the hormone ecdysone governs transitions between key developmental stages. Ecdysone-regulated genes are bound by a heterodimer of ecdysone receptor (EcR) and Ultraspiracle. According to the bimodal switch model, steroid hormone receptors recruit corepressors in the absence of hormone and coactivators in its presence. Here we show that the nucleosome remodeller dMi-2 is recruited to ecdysone-regulated genes to limit transcription. Contrary to the prevalent model, recruitment of the dMi-2 corepressor increases upon hormone addition to constrain gene activation through chromatin remodelling. Furthermore, EcR and dMi-2 form a complex that is devoid of Ultraspiracle. Unexpectedly, EcR contacts the dMi-2 ATPase domain and increases the efficiency of dMi-2-mediated nucleosome remodelling. This study identifies a non-canonical EcR-corepressor complex with the potential for a direct regulation of ATP-dependent nucleosome remodelling by a nuclear hormone receptor.
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http://dx.doi.org/10.1038/ncomms14806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382322PMC
April 2017

An intra-laboratory cultural and real-time PCR method comparison and evaluation for the detection of subclinical paratuberculosis in dairy herds.

Folia Microbiol (Praha) 2017 May 17;62(3):197-205. Epub 2016 Dec 17.

Dairy Sciences, Institute of Veterinary Food Science, Justus Liebig University Giessen, Ludwigstr. 21, 35390, Giessen, Germany.

Mycobacterium avium subsp. paratuberculosis (MAP) is a vigorous microorganism which causes incurable chronic enteritis, Johne's disease (JD) in cattle. A target of control programmes for JD is to accurately detect MAP-infected cattle early to reduce disease transmission. The present study evaluated the efficacy of two different cultural procedures and a TaqMan real-time PCR assay for detection of subclinical paratuberculosis in dairy herds. Therefore, sixty-one faecal samples were collected from two Dutch dairy herds (n = 40 and n = 21, respectively) which were known to be MAP-ELISA positive. All individual samples were assessed using two different cultural protocols in two different laboratories. The first cultural protocol (first laboratory) included a decontamination step with 0.75% hexadecylpyridinium chloride (HPC) followed by inoculation on Herrold's egg yolk media (HEYM). The second protocol (second laboratory) comprised of a decontamination step using 4% NaOH and malachite green-oxalic acid followed by inoculation on two media, HEYM and in parallel on modified Löwenstein-Jensen media (mLJ). For the TaqMan real-time PCR assay, all faecal samples were tested in two different laboratories using TaqMan® MAP (Johne's) reagents (Life Technologies). The cultural procedures revealed positive reactions in 1.64% of the samples for cultivation protocol 1 and 6.56 and 8.20% of the samples for cultivation protocol 2, respectively. The results of the TaqMan real-time PCR performed in two different laboratories yielded 13.11 and 19.76% positive reaction. The kappa test showed proportional agreement 0.54 between the mLJ media (second laboratory) and TaqMan® real-time PCR method (second laboratory). In conclusion, the TaqMan real-time PCR could be a strongly useful and efficient assay for the detection of subclinical paratuberculosis in dairy cattle leading to an improvement in the efficiency of MAP control strategies.
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http://dx.doi.org/10.1007/s12223-016-0488-1DOI Listing
May 2017

Proteins that bind regulatory regions identified by histone modification chromatin immunoprecipitations and mass spectrometry.

Nat Commun 2015 May 20;6:7155. Epub 2015 May 20.

Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.

The locations of transcriptional enhancers and promoters were recently mapped in many mammalian cell types. Proteins that bind those regulatory regions can determine cell identity but have not been systematically identified. Here we purify native enhancers, promoters or heterochromatin from embryonic stem cells by chromatin immunoprecipitations (ChIP) for characteristic histone modifications and identify associated proteins using mass spectrometry (MS). 239 factors are identified and predicted to bind enhancers or promoters with different levels of activity, or heterochromatin. Published genome-wide data indicate a high accuracy of location prediction by ChIP-MS. A quarter of the identified factors are important for pluripotency and includes Oct4, Esrrb, Klf5, Mycn and Dppa2, factors that drive reprogramming to pluripotent stem cells. We determined the genome-wide binding sites of Dppa2 and find that Dppa2 operates outside the classical pluripotency network. Our ChIP-MS method provides a detailed read-out of the transcriptional landscape representative of the investigated cell type.
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http://dx.doi.org/10.1038/ncomms8155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455091PMC
May 2015

Pneumonia associated with Acinetobacter baumannii in a group of minks (Neovison vison).

Vet Q 2015 13;35(3):174-6. Epub 2015 Apr 13.

a GD Animal Health , Arnsbergstraat 7, 7418 EZ Deventer , The Netherlands.

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http://dx.doi.org/10.1080/01652176.2015.1030714DOI Listing
May 2016

Mammalian TIMELESS is involved in period determination and DNA damage-dependent phase advancing of the circadian clock.

PLoS One 2013 13;8(2):e56623. Epub 2013 Feb 13.

Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

The transcription/translation feedback loop-based molecular oscillator underlying the generation of circadian gene expression is preserved in almost all organisms. Interestingly, the animal circadian clock proteins CRYPTOCHROME (CRY), PERIOD (PER) and TIMELESS (TIM) are strongly conserved at the amino acid level through evolution. Within this evolutionary frame, TIM represents a fascinating puzzle. While Drosophila contains two paralogs, dTIM and dTIM2, acting in clock/photoreception and chromosome integrity/photoreception respectively, mammals contain only one TIM homolog. Whereas TIM has been shown to regulate replication termination and cell cycle progression, its functional link to the circadian clock is under debate. Here we show that RNAi-mediated knockdown of TIM in NIH3T3 and U2OS cells shortens the period by 1 hour and diminishes DNA damage-dependent phase advancing. Furthermore, we reveal that the N-terminus of TIM is sufficient for interaction with CRY1 and CHK1 as well for homodimerization, and the C-terminus is necessary for nuclear localization. Interestingly, the long TIM isoform (l-TIM), but not the short (s-TIM), interacts with CRY1 and both proteins can reciprocally regulate their nuclear translocation in transiently transfected COS7 cells. Finally, we demonstrate that co-expression of PER2 abolishes the formation of the TIM/CRY1 complex through affinity binding competition to the C-terminal tail of CRY1. Notably, the presence of the latter protein region evolutionarily and structurally distinguishes mammalian from insect CRYs. We propose that the dynamic interaction between these three proteins could represent a post-translational aspect of the mammalian circadian clock that is important for its pace and adaption to external stimuli, such as DNA damage and/or light.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056623PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572085PMC
August 2013

RTTN mutations link primary cilia function to organization of the human cerebral cortex.

Am J Hum Genet 2012 Sep 30;91(3):533-40. Epub 2012 Aug 30.

Department of Clinical Genetics, Erasmus University Medical Center (Erasmus MC), P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

Polymicrogyria is a malformation of the developing cerebral cortex caused by abnormal organization and characterized by many small gyri and fusion of the outer molecular layer. We have identified autosomal-recessive mutations in RTTN, encoding Rotatin, in individuals with bilateral diffuse polymicrogyria from two separate families. Rotatin determines early embryonic axial rotation, as well as anteroposterior and dorsoventral patterning in the mouse. Human Rotatin has recently been identified as a centrosome-associated protein. The Drosophila melanogaster homolog of Rotatin, Ana3, is needed for structural integrity of centrioles and basal bodies and maintenance of sensory neurons. We show that Rotatin colocalizes with the basal bodies at the primary cilium. Cultured fibroblasts from affected individuals have structural abnormalities of the cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B, which are key regulators of cortical patterning and are expressed at the cortical hem, the cortex-organizing center that gives rise to Cajal-Retzius (CR) neurons. Interestingly, we have shown that in mouse embryos, Rotatin colocalizes with CR neurons at the subpial marginal zone. Knockdown experiments in human fibroblasts and neural stem cells confirm a role for RTTN in cilia structure and function. RTTN mutations therefore link aberrant ciliary function to abnormal development and organization of the cortex in human individuals.
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http://dx.doi.org/10.1016/j.ajhg.2012.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511998PMC
September 2012

Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes.

Nat Genet 2011 Jun 1;43(6):607-11. Epub 2011 May 1.

Department of Cell Biology, Erasmus Medical Center (MC), Rotterdam, The Netherlands.

The HMG-box transcription factor Sox2 plays a role throughout neurogenesis and also acts at other stages of development, as illustrated by the multiple organs affected in the anophthalmia syndrome caused by SOX2 mutations. Here we combined proteomic and genomic approaches to characterize gene regulation by Sox2 in neural stem cells. Chd7, a chromatin remodeling ATPase associated with CHARGE syndrome, was identified as a Sox2 transcriptional cofactor. Sox2 and Chd7 physically interact, have overlapping genome-wide binding sites and regulate a set of common target genes including Jag1, Gli3 and Mycn, genes mutated in Alagille, Pallister-Hall and Feingold syndromes, which show malformations also associated with SOX2 anophthalmia syndrome or CHARGE syndrome. Regulation of disease-associated genes by a Sox2-Chd7 complex provides a plausible explanation for several malformations associated with SOX2 anophthalmia syndrome or CHARGE syndrome. Indeed, we found that Chd7-haploinsufficient embryos showed severely reduced expression of Jag1 in the developing inner ear.
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http://dx.doi.org/10.1038/ng.825DOI Listing
June 2011

Exportin 4 mediates a novel nuclear import pathway for Sox family transcription factors.

J Cell Biol 2009 Apr;185(1):27-34

Department of Pediatric Surgery, Erasmus Medical Center, Rotterdam, Netherlands.

SRY and other Sox-type transcription factors are important developmental regulators with various implications in human disease. In this study, we identified Exp4 (exportin 4) as an interaction partner of Sox2 in mouse embryonic stem cells and neural progenitors. We show that, besides its established function in nuclear export, Exp4 acts as a bona fide nuclear import receptor for Sox2 and SRY. Thus, Exp4 is an example of a nuclear transport receptor carrying distinct cargoes into different directions. In contrast to a published study, we observed that the import activity of Imp-alpha (importin-a) isoforms toward Sox2 is negligible. Instead, we found that Imp9 and the Imp-beta/7 heterodimer mediate nuclear import of Sox2 in parallel to Exp4. Import signals for the three pathways overlap and include conserved residues in the Sox2 high-mobility group (HMG) box domain that are also critical for DNA binding. This suggests that nuclear import of Sox proteins is facilitated by several parallel import pathways.
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http://dx.doi.org/10.1083/jcb.200810106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700522PMC
April 2009

Estrogen-related receptor beta interacts with Oct4 to positively regulate Nanog gene expression.

Mol Cell Biol 2008 Oct 28;28(19):5986-95. Epub 2008 Jul 28.

Department of Cell Biology, Erasmus MC, Dr. Molewaterplein 50, 3015GE Rotterdam, The Netherlands.

Embryonic stem (ES) cell self-renewal is regulated by transcription factors, including Oct4, Sox2, and Nanog. A number of additional transcriptional regulators of ES cell self-renewal have recently been identified, including the orphan nuclear receptor estrogen-related receptor beta (Esrrb). However, the mode of action of Esrrb in ES cells is unknown. Here, using an Oct4 affinity screen, we identify Esrrb as an Oct4 partner protein. Esrrb can interact with Oct4 independently of DNA. Esrrb is recruited near the Oct-Sox element in the Nanog proximal promoter, where it positively regulates Nanog expression. Esrrb recruitment to the Nanog promoter requires both the presence of Oct4 and a degenerate estrogen-related receptor DNA element. Consistent with its role in Nanog regulation, expression of the Esrrb protein within the Oct4-positive ES cell population is mosaic and correlates with the mosaic expression of the Nanog protein. Together with previous reports that Nanog may regulate Esrrb gene expression, our results suggest that Esrrb and Nanog act as part of a feedback regulatory circuit that modulates the fluctuating self-renewal capacity of ES cell populations.
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http://dx.doi.org/10.1128/MCB.00301-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2547019PMC
October 2008