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Regulation of human ZNF687, a gene associated with Paget's disease of bone

2023-01Journal article Open access
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dc.contributor.authorVarela, Débora
dc.contributor.authorVarela, Tatiana
dc.contributor.authorConceição, Natércia
dc.contributor.authorCancela, M. Leonor
dc.date.accessioned2023-02-09T13:27:24Z
dc.date.available2023-02-09T13:27:24Z
dc.date.issued2023-01
dc.description.abstractMutations in Zinc finger 687 (ZNF687) were associated with Paget's disease of bone (PDB), a disease charac-terized by increased bone resorption and excessive bone formation. It was suggested that ZNF687 plays a role in bone differentiation and development. However, the mechanisms involved in ZNF687 regulation remain un-known. This study aimed to obtain novel knowledge regarding ZNF687 transcriptional and epigenetic regulation. Through in silico analysis, we hypothesized three ZNF687 promoter regions located upstream exon 1 A, 1B, and 1 C and denominated promoter regions 1, 2, and 3, respectively. Their functionality was confirmed by luciferase activity assays and positive/negative regulatory regions were identified using promoter deletions constructs. In silico analysis revealed a high density of CpG islands in these promoter regions and in vitro methylation sup-pressed promoters' activity. Using bioinformatic approaches, bone-associated transcription factor binding sites containing CpG dinucleotides were identified, including those for NF kappa B, PU.1, DLX5, and SOX9. By co-transfection in HEK293 and hFOB cells, we found that DLX5 specifically activated ZNF687 promoter region 1, and its methylation impaired DLX5-driven promoter stimulation. NF kappa B repressed and activated promoter regions 1 and 2, respectively, and these activities were affected by methylation. PU.1 induced ZNF687 promoter region 1 which was affected by methylation. SOX9 differentially regulated ZNF687 promoters in HEK293 and hFOB cells that were impaired after methylation. In conclusion, this study provides novel insights into ZNF687 regulation by demonstrating that NF kappa B, PU.1, DLX5, and SOX9 are regulators of ZNF687 promoters, and DNA methylation influences their activity. The contribution of the dysregulation of these mechanisms in PDB should be further elucidated.pt_PT
dc.description.sponsorshipLA/P/0101/2020
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1016/j.biocel.2022.106332pt_PT
dc.identifier.eissn1878-5875
dc.identifier.urihttp://hdl.handle.net/10400.1/19032
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPergamon - Elsevierpt_PT
dc.relationAlgarve Centre for Marine Sciences
dc.relationAlgarve Centre for Marine Sciences
dc.relationEpigenetic regulation of ZNF687 in bone cells: elucidation of its role in the progression of Paget’s disease towards giant cell tumor of bone
dc.relationIdentification of novel CDKL5 molecular targets/pathways associated with skeletal defects present in CDKL5 associated disorders
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectZNF687pt_PT
dc.subjectPromoterspt_PT
dc.subjectRegulationpt_PT
dc.subjectTranscription factorspt_PT
dc.subjectMethylationPaget?s disease of bonept_PT
dc.titleRegulation of human ZNF687, a gene associated with Paget's disease of bonept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleAlgarve Centre for Marine Sciences
oaire.awardTitleAlgarve Centre for Marine Sciences
oaire.awardTitleEpigenetic regulation of ZNF687 in bone cells: elucidation of its role in the progression of Paget’s disease towards giant cell tumor of bone
oaire.awardTitleIdentification of novel CDKL5 molecular targets/pathways associated with skeletal defects present in CDKL5 associated disorders
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04326%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04326%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F141918%2F2018/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F144230%2F2019/PT
oaire.citation.startPage106332pt_PT
oaire.citation.titleThe International Journal of Biochemistry & Cell Biologypt_PT
oaire.citation.volume154pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamOE
person.familyNameDomingos Varela
person.familyNameDomingos Varela
person.familyNameConceição
person.familyNameCancela
person.givenNameDébora Cristina
person.givenNameTatiana da Conceição
person.givenNameNatércia
person.givenNameM. Leonor
person.identifier.ciencia-id9A1C-DFE4-98C9
person.identifier.ciencia-idF613-7482-6731
person.identifier.ciencia-id7C11-760D-F425
person.identifier.orcid0000-0002-5057-0912
person.identifier.orcid0000-0003-3114-6662
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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