MLL4 regulates postnatal palate growth and midpalatal suture development
MLL4, also known as KMT2D, is a histone methyltransferase that acts as an important epigenetic regulator in various organogenesis programs. Mutations in the MLL4 gene are the major cause of Kabuki syndrome, a human developmental disorder that involves craniofacial birth defects, including anomalies...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2025.1466948/full |
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| author | Jung-Mi Lee Hunmin Jung Bruno de Paula Machado Pasqua Yungki Park Qinghuang Tang Shin Jeon Shin Jeon Soo-Kyung Lee Jae W. Lee Hyuk-Jae Edward Kwon |
| author_facet | Jung-Mi Lee Hunmin Jung Bruno de Paula Machado Pasqua Yungki Park Qinghuang Tang Shin Jeon Shin Jeon Soo-Kyung Lee Jae W. Lee Hyuk-Jae Edward Kwon |
| author_sort | Jung-Mi Lee |
| collection | DOAJ |
| description | MLL4, also known as KMT2D, is a histone methyltransferase that acts as an important epigenetic regulator in various organogenesis programs. Mutations in the MLL4 gene are the major cause of Kabuki syndrome, a human developmental disorder that involves craniofacial birth defects, including anomalies in the palate. This study aimed to investigate the role of MLL4 and the underlying mechanisms in the development and growth of the palate. We generated a novel conditional knockout (cKO) mouse model with tissue-specific deletion of Mll4 in the palatal mesenchyme. Using micro-computed tomography (CT), histological analysis, cell mechanism assays, and gene expression profiling, we examined palate development and growth in the Mll4-cKO mice. Gross craniofacial examination at adult stages revealed mild midfacial hypoplasia and midline defects of the palate in Mll4-cKO mice, including a widened midpalatal suture and disrupted midline rugae pattern. Micro-CT-based time-course skeletal analysis during postnatal palatogenesis through adulthood demonstrated a transverse growth deficit in overall palate width in Mll4-cKO mice. Whole-mount and histological staining at perinatal stages identified that the midline defects in the Mll4-cKO mice emerged as early as 1 day prior to birth, presenting as a widened midpalatal suture, accompanied by increased cell apoptosis in the suture mesenchyme. Genome-wide mRNA expression analysis of the midpalatal suture tissue revealed that MLL4 is essential for the timely expression of major cartilage development genes, such as Col2a1 and Acan, at birth. Immunofluorescence staining for osteochondral differentiation markers demonstrated a marked decrease in the chondrogenic marker COL2A1, while the expression of the osteogenic marker RUNX2 remained unchanged, in the Mll4-cKO midpalatal suture. Additionally, SOX9, a master regulator of chondrogenesis, exhibited a significant decrease in protein expression. Indeed, time-course histological analysis during postnatal palate growth revealed retardation in the development of the suture cartilage in Mll4-cKO mice. Taken together, our results demonstrate that MLL4 is essential for orchestrating key cellular and molecular events that ensure proper midpalatal suture development and palate growth. |
| format | Article |
| id | doaj-art-a9d6cecc8c7b4b29b2ccb0df79d8dfcb |
| institution | Kabale University |
| issn | 2296-634X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj-art-a9d6cecc8c7b4b29b2ccb0df79d8dfcb2025-01-24T08:57:43ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-01-011310.3389/fcell.2025.14669481466948MLL4 regulates postnatal palate growth and midpalatal suture developmentJung-Mi Lee0Hunmin Jung1Bruno de Paula Machado Pasqua2Yungki Park3Qinghuang Tang4Shin Jeon5Shin Jeon6Soo-Kyung Lee7Jae W. Lee8Hyuk-Jae Edward Kwon9Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, NY, United StatesDepartment of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, NY, United StatesDepartment of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, NY, United StatesDepartment of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, University at Buffalo, The State University of New York, Buffalo, NY, United StatesDepartment of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, NY, United StatesDepartment of Biological Sciences, College of Arts and Sciences, FOXG1 Research Center, University at Buffalo, The State University of New York, Buffalo, NY, United StatesDepartment of Systems Pharmacology and Translational Therapeutics, Institute for Immunology, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Biological Sciences, College of Arts and Sciences, FOXG1 Research Center, University at Buffalo, The State University of New York, Buffalo, NY, United StatesDepartment of Biological Sciences, College of Arts and Sciences, FOXG1 Research Center, University at Buffalo, The State University of New York, Buffalo, NY, United StatesDepartment of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, NY, United StatesMLL4, also known as KMT2D, is a histone methyltransferase that acts as an important epigenetic regulator in various organogenesis programs. Mutations in the MLL4 gene are the major cause of Kabuki syndrome, a human developmental disorder that involves craniofacial birth defects, including anomalies in the palate. This study aimed to investigate the role of MLL4 and the underlying mechanisms in the development and growth of the palate. We generated a novel conditional knockout (cKO) mouse model with tissue-specific deletion of Mll4 in the palatal mesenchyme. Using micro-computed tomography (CT), histological analysis, cell mechanism assays, and gene expression profiling, we examined palate development and growth in the Mll4-cKO mice. Gross craniofacial examination at adult stages revealed mild midfacial hypoplasia and midline defects of the palate in Mll4-cKO mice, including a widened midpalatal suture and disrupted midline rugae pattern. Micro-CT-based time-course skeletal analysis during postnatal palatogenesis through adulthood demonstrated a transverse growth deficit in overall palate width in Mll4-cKO mice. Whole-mount and histological staining at perinatal stages identified that the midline defects in the Mll4-cKO mice emerged as early as 1 day prior to birth, presenting as a widened midpalatal suture, accompanied by increased cell apoptosis in the suture mesenchyme. Genome-wide mRNA expression analysis of the midpalatal suture tissue revealed that MLL4 is essential for the timely expression of major cartilage development genes, such as Col2a1 and Acan, at birth. Immunofluorescence staining for osteochondral differentiation markers demonstrated a marked decrease in the chondrogenic marker COL2A1, while the expression of the osteogenic marker RUNX2 remained unchanged, in the Mll4-cKO midpalatal suture. Additionally, SOX9, a master regulator of chondrogenesis, exhibited a significant decrease in protein expression. Indeed, time-course histological analysis during postnatal palate growth revealed retardation in the development of the suture cartilage in Mll4-cKO mice. Taken together, our results demonstrate that MLL4 is essential for orchestrating key cellular and molecular events that ensure proper midpalatal suture development and palate growth.https://www.frontiersin.org/articles/10.3389/fcell.2025.1466948/fullpalatogenesisgene regulatory mechanismendochondral ossificationchondrogenesismidpalatal sutureepigenetic regulation |
| spellingShingle | Jung-Mi Lee Hunmin Jung Bruno de Paula Machado Pasqua Yungki Park Qinghuang Tang Shin Jeon Shin Jeon Soo-Kyung Lee Jae W. Lee Hyuk-Jae Edward Kwon MLL4 regulates postnatal palate growth and midpalatal suture development Frontiers in Cell and Developmental Biology palatogenesis gene regulatory mechanism endochondral ossification chondrogenesis midpalatal suture epigenetic regulation |
| title | MLL4 regulates postnatal palate growth and midpalatal suture development |
| title_full | MLL4 regulates postnatal palate growth and midpalatal suture development |
| title_fullStr | MLL4 regulates postnatal palate growth and midpalatal suture development |
| title_full_unstemmed | MLL4 regulates postnatal palate growth and midpalatal suture development |
| title_short | MLL4 regulates postnatal palate growth and midpalatal suture development |
| title_sort | mll4 regulates postnatal palate growth and midpalatal suture development |
| topic | palatogenesis gene regulatory mechanism endochondral ossification chondrogenesis midpalatal suture epigenetic regulation |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2025.1466948/full |
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