Hmx1 regulates urfh1 expression in the craniofacial region in zebrafish

Fersioui, Younes El; Pinton, Gaëtan; Allaman-Pillet, Nathalie

doi:10.1371/journal.pone.0245239

Cited by 4 publications

(8 citation statements)

References 38 publications

(63 reference statements)

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“…Previously, we identified uhrf1 as an hmx1 target gene, and it has been implicated in the regulation of several developmental and homeostatic processes related to zebrafish development. In situ hybridization in hmx1 transgenic and mutant zebrafish showed that uhrf1 expression is modulated in the hindbrain, eye region, and branchial arches [ 33 ]. Potentially, uhrf1 could change the methylation pattern of bmp2b and bmp4 and, therefore, induce gene transcription.…”

Section: Discussionmentioning

confidence: 99%

“…All embryos at desired stages were kept in Danieau’s solution with 0.003% 1-phenyl-2-thiourea (Sigma, Buchs, Switzerland) to suppress pigmentation. The zebrafish mutant lines hmx1 mut10 and hmx1 mut150 were previously generated and described [ 33 ]. Briefly, hmx1 mut10 zebrafish have a frameshift mutation that generates a termination codon in the SD1 domain, while mutant hmx1 mut150 has an indel mutation that replaces the HD domain; dimerization of SD1 and HD is necessary for the proper function of hmx1 .…”

Section: Methodsmentioning

confidence: 99%

“…HMX1 binds preferentially to the consensus sequence 5′-CAAGTG-3′ located in the promoter region of target genes, and acts as a transcriptional regulator [ 31 ]. We previously designed a predictive promoter model [ 32 ] and generated two zebrafish models— hmx1 mut10 and hmx1 mut150 mutant lines—to screen and identify potential hmx1 target genes [ 33 ]. The hmx1 mut10 and hmx1 mut150 mutant lines carry mutations in the SD1 and homeodomain domains, which are implicated in the dimerization and activity of hmx1 [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

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Premature Vertebral Mineralization in hmx1-Mutant Zebrafish

Fersioui

Pinton

Allaman-Pillet

2022

Cells

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H6 family homeobox 1 (HMX1) regulates multiple aspects of craniofacial development, and mutations in HMX1 are linked to an ocular defect termed oculoauricular syndrome of Schorderet–Munier–Franceschetti (OAS) (MIM #612109). Recently, additional altered orofacial features have been reported, including short mandibular rami, asymmetry of the jaws, and altered premaxilla. We found that in two mutant zebrafish lines termed hmx1mut10 and hmx1mut150, precocious mineralization of the proximal vertebrae occurred. Zebrafish hmx1mut10 and hmx1mut150 report mutations in the SD1 and HD domains, which are essential for dimerization and activity of hmx1. In hmx1mut10, the bone morphogenetic protein (BMP) antagonists chordin and noggin1 were downregulated, while bmp2b and bmp4 were highly expressed and specifically localized to the dorsal region prior to the initiation of the osteogenic process. The osteogenic promoters runx2b and spp1 were also upregulated. Supplementation with DMH1—an inhibitor of the BMP signaling pathway—at the specific stage in which bmp2b and bmp4 are highly expressed resulted in reduced vertebral mineralization, resembling the wildtype mineralization progress of the axial skeleton. These results point to a possible role of hmx1 as part of a complex gene network that inhibits bmp2b and bmp4 in the dorsal region, thus regulating early axial skeleton development.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Premature Vertebral Mineralization in hmx1-Mutant Zebrafish

Fersioui

Pinton

Allaman-Pillet

2022

Cells

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“…The expression of UHRF1 is also regulated by several proteins, including E2F1 (E2F transcription factor 1), E2F8 (E2F transcription factor 8), FOXM1 (forkhead box protein M1), SP1 (specificity protein 1), SHMT2 (serine hydroxymethyltransferase-2), Setd1a (SET domain containing 1A, histone lysine methyltransferase), and Hmx1 (H6 family homeobox 1). Moreover, the activity of CD47 (cluster of differentiation 47) integrins increases UHRF1 expression in different cancers and represses the activity of many tumor-suppressor proteins [ 58 , 59 , 60 , 61 , 62 , 63 ]. Finally, the downregulation of various regulatory mi-RNAs leads to a high-level expression of UHRF1 proteins in cancers [ 64 , 65 ].…”

Section: Uhrf1 Expression and Its Regulationmentioning

confidence: 99%

Natural and Synthetic Anticancer Epidrugs Targeting the Epigenetic Integrator UHRF1

et al. 2023

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Cancer is one of the leading causes of death worldwide, and its incidence and mortality are increasing each year. Improved therapeutic strategies against cancer have progressed, but remain insufficient to invert this trend. Along with several other risk factors, abnormal genetic and epigenetic regulations play a critical role in the initiation of cellular transformation, as well as tumorigenesis. The epigenetic regulator UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is a multidomain protein with oncogenic abilities overexpressed in most cancers. Through the coordination of its multiple domains and other epigenetic key players, UHRF1 regulates DNA methylation and histone modifications. This well-coordinated dialogue leads to the silencing of tumor-suppressor genes (TSGs) and facilitates tumor cells’ resistance toward anticancer drugs, ultimately promoting apoptosis escape and uncontrolled proliferation. Several studies have shown that the downregulation of UHRF1 with natural compounds in tumor cells induces the reactivation of various TSGs, inhibits cell growth, and promotes apoptosis. In this review, we discuss the underlying mechanisms and the potential of various natural and synthetic compounds that can inhibit/minimize UHRF1’s oncogenic activities and/or its expression.

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“…It is characterized by complex ophthalmological and external ear anomalies as well as aberrant orofacial development with underdeveloped and asymmetric jaws [37]. OAS is caused by homozygous pathogenic variants in HMX1 (H6 Family Homeobox 1), encoding a homeobox transcription factor with high affinity toward a consensus HMX-binding site harboring a 5 -CAAGTG-3 element required for sensory organ development [65][66][67][68]. HMX1 is highly conserved across orthologs and contains three essential domains: a homeobox domain (HD) and conserved domains SD1 and SD2 [37,65,66].…”

Section: Schorderet-munier-franceschetti Syndromementioning

confidence: 99%

Significance of Premature Vertebral Mineralization in Zebrafish Models in Mechanistic and Pharmaceutical Research on Hereditary Multisystem Diseases

Van Wynsberghe,

Vanakker

2023

Biomolecules

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Zebrafish are increasingly becoming an important model organism for studying the pathophysiological mechanisms of human diseases and investigating how these mechanisms can be effectively targeted using compounds that may open avenues to novel treatments for patients. The zebrafish skeleton has been particularly instrumental in modeling bone diseases as—contrary to other model organisms—the lower load on the skeleton of an aquatic animal enables mutants to survive to early adulthood. In this respect, the axial skeletons of zebrafish have been a good read-out for congenital spinal deformities such as scoliosis and degenerative disorders such as osteoporosis and osteoarthritis, in which aberrant mineralization in humans is reflected in the respective zebrafish models. Interestingly, there have been several reports of hereditary multisystemic diseases that do not affect the vertebral column in human patients, while the corresponding zebrafish models systematically show anomalies in mineralization and morphology of the spine as their leading or, in some cases, only phenotype. In this review, we describe such examples, highlighting the underlying mechanisms, the already-used or potential power of these models to help us understand and amend the mineralization process, and the outstanding questions on how and why this specific axial type of aberrant mineralization occurs in these disease models.

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Hmx1 regulates urfh1 expression in the craniofacial region in zebrafish

Cited by 4 publications

References 38 publications

Premature Vertebral Mineralization in hmx1-Mutant Zebrafish

Premature Vertebral Mineralization in hmx1-Mutant Zebrafish

Natural and Synthetic Anticancer Epidrugs Targeting the Epigenetic Integrator UHRF1

Significance of Premature Vertebral Mineralization in Zebrafish Models in Mechanistic and Pharmaceutical Research on Hereditary Multisystem Diseases

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