Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects

Patel, Shireen; Anand, Deepti; Motohashi, Hozumi; Katsuoka, Fumiki; Yamamoto, Masayuki; Lachke, Salil A.

doi:10.3389/fcell.2022.981893

Cited by 12 publications

(10 citation statements)

References 87 publications

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“…This unexpected result was our first clue about compensatory upregulation or deregulation in KO animals. In addition to our data, a recent work described marked downregulation of Epha5 transcripts in developing lenses with the disruption of the musculoaponeurotic fibrosarcoma ( MAF ) family of proteins [ 44 ]. The data from RNA-seq plates did not distinguish between the 14 variants of Epha5 .…”

Section: Discussionsupporting

confidence: 70%

“…The data from RNA-seq plates did not distinguish between the 14 variants of Epha5 . MAFs encode basic leucine zipper transcription factors that are known to be important for lens development and to be involved cataractogenesis [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. There may be other insights that can be gleaned from the microarray data between the control, EphA2 −/− , and ephrin-A5 −/− lens samples.…”

Section: Discussionmentioning

confidence: 99%

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Mapping the Universe of Eph Receptor and Ephrin Ligand Transcripts in Epithelial and Fiber Cells of the Eye Lens

Cheng

2022

Cells

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The eye lens is a transparent, ellipsoid organ in the anterior chamber of the eye that is required for fine focusing of light onto the retina to transmit a clear image. Cataracts, defined as any opacity in the lens, remains the leading cause of blindness in the world. Recent studies in humans and mice indicate that Eph–ephrin bidirectional signaling is important for maintaining lens transparency. Specifically, mutations and polymorphisms in the EphA2 receptor and the ephrin-A5 ligand have been linked to congenital and age-related cataracts. It is unclear what other variants of Ephs and ephrins are expressed in the lens or whether there is preferential expression in epithelial vs. fiber cells. We performed a detailed analysis of Eph receptor and ephrin ligand mRNA transcripts in whole mouse lenses, epithelial cell fractions, and fiber cell fractions using a new RNA isolation method. We compared control samples with EphA2 knockout (KO) and ephrin-A5 KO samples. Our results revealed the presence of transcripts for 12 out of 14 Eph receptors and 8 out of 8 ephrin ligands in various fractions of lens cells. Using specific primer sets, RT-PCR, and sequencing, we verified the variant of each gene that is expressed, and we found two epithelial-cell-specific genes. Surprisingly, we also identified one Eph receptor variant that is expressed in KO lens fibers but is absent from control lens fibers. We also identified one low expression ephrin variant that is only expressed in ephrin-A5 control samples. These results indicate that the lens expresses almost all Ephs and ephrins, and there may be many receptor–ligand pairs that play a role in lens homeostasis.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Mapping the Universe of Eph Receptor and Ephrin Ligand Transcripts in Epithelial and Fiber Cells of the Eye Lens

Cheng

2022

Cells

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“…For the full result of the motif analysis, see Additional file 9 . Importantly, previous studies have shown major roles of c-Maf [ 99 – 101 ], Hif1α [ 102 – 104 ], MafG and MafK [ 105 , 106 ], and RAR/RXR [ 107 – 109 ] in control of lens-specific transcription. The NF1 and TEAD motifs were also previously identified using open chromatin analysis [ 44 ]; nevertheless, no data are available for individual transcription factors recognizing these motifs from previous lens studies.…”

Section: Resultsmentioning

confidence: 99%

Dynamic changes in whole genome DNA methylation, chromatin and gene expression during mouse lens differentiation

Chang

Zhao

Rayêe

et al. 2023

Epigenetics & Chromatin

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Background Cellular differentiation is marked by temporally and spatially coordinated gene expression regulated at multiple levels. DNA methylation represents a universal mechanism to control chromatin organization and its accessibility. Cytosine methylation of CpG dinucleotides regulates binding of methylation-sensitive DNA-binding transcription factors within regulatory regions of transcription, including promoters and distal enhancers. Ocular lens differentiation represents an advantageous model system to examine these processes as lens comprises only two cell types, the proliferating lens epithelium and postmitotic lens fiber cells all originating from the epithelium. Results Using whole genome bisulfite sequencing (WGBS) and microdissected lenses, we investigated dynamics of DNA methylation and chromatin changes during mouse lens fiber and epithelium differentiation between embryos (E14.5) and newborns (P0.5). Histone H3.3 variant chromatin landscapes were also generated for both P0.5 lens epithelium and fibers by chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq). Tissue-specific features of DNA methylation patterns are demonstrated via comparative studies with embryonic stem (ES) cells and neural progenitor cells (NPCs) at Nanog, Pou5f1, Sox2, Pax6 and Six3 loci. Comparisons with ATAC-seq and RNA-seq data demonstrate that reduced methylation is associated with increased expression of fiber cell abundant genes, including crystallins, intermediate filament (Bfsp1 and Bfsp2) and gap junction proteins (Gja3 and Gja8), marked by high levels of histone H3.3 within their transcribed regions. Interestingly, Pax6-binding sites exhibited predominantly DNA hypomethylation in lens chromatin. In vitro binding of Pax6 proteins showed Pax6’s ability to interact with sites containing one or two methylated CpG dinucleotides. Conclusions Our study has generated the first data on methylation changes between two different stages of mammalian lens development and linked these data with chromatin accessibility maps, presence of histone H3.3 and gene expression. Reduced DNA methylation correlates with expression of important genes involved in lens morphogenesis and lens fiber cell differentiation.

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“…Similarly, the 2019 study by Zhao et al in E14.5 and P0.5 mice identified FOXO3, several Maf family members (Mafa, Mafg, Mafk), CTCF, Pax6, Hsf4, and Sox1 as the predicted factors ( Table 3 ). The transcription factors Pax6 [ 46 , 144 , 145 ], Hsf4 [ 55 , 56 , 57 ], Sox1 [ 161 ], and Mafg/Mafk [ 72 , 73 ] have established functions while others have functions that have yet to be investigated in the lens. Pax6 is expressed in the anterior pre-placodal region that gives rise to the adenohypophyseal, olfactory, and lens placodes [ 162 ].…”

Section: Analysis Of Chromatin Landscape In Lens Tissues With Atac-seqmentioning

confidence: 99%

Multiomics Analysis Reveals Novel Genetic Determinants for Lens Differentiation, Structure, and Transparency

et al. 2023

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Recent advances in next-generation sequencing and data analysis have provided new gateways for identification of novel genome-wide genetic determinants governing tissue development and disease. These advances have revolutionized our understanding of cellular differentiation, homeostasis, and specialized function in multiple tissues. Bioinformatic and functional analysis of these genetic determinants and the pathways they regulate have provided a novel basis for the design of functional experiments to answer a wide range of long-sought biological questions. A well-characterized model for the application of these emerging technologies is the development and differentiation of the ocular lens and how individual pathways regulate lens morphogenesis, gene expression, transparency, and refraction. Recent applications of next-generation sequencing analysis on well-characterized chicken and mouse lens differentiation models using a variety of omics techniques including RNA-seq, ATAC-seq, whole-genome bisulfite sequencing (WGBS), chip-seq, and CUT&RUN have revealed a wide range of essential biological pathways and chromatin features governing lens structure and function. Multiomics integration of these data has established new gene functions and cellular processes essential for lens formation, homeostasis, and transparency including the identification of novel transcription control pathways, autophagy remodeling pathways, and signal transduction pathways, among others. This review summarizes recent omics technologies applied to the lens, methods for integrating multiomics data, and how these recent technologies have advanced our understanding ocular biology and function. The approach and analysis are relevant to identifying the features and functional requirements of more complex tissues and disease states.

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Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects

Cited by 12 publications

References 87 publications

Mapping the Universe of Eph Receptor and Ephrin Ligand Transcripts in Epithelial and Fiber Cells of the Eye Lens

Mapping the Universe of Eph Receptor and Ephrin Ligand Transcripts in Epithelial and Fiber Cells of the Eye Lens

Dynamic changes in whole genome DNA methylation, chromatin and gene expression during mouse lens differentiation

Multiomics Analysis Reveals Novel Genetic Determinants for Lens Differentiation, Structure, and Transparency

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