Transcriptomic analysis and novel insights into lens fibre cell differentiation regulated by Gata3

Abstract

Gata3 is a DNA-binding transcription factor involved in cellular differentiation in a variety of tissues including inner ear, hair follicle, kidney, mammary gland and T-cells. In a previous study in 2009, Maeda et al. (Dev. Dyn. 238, 2280–2291; doi:10.1002/dvdy.2203510.1002/dvdy.22035) found that Gata3 mutants could be rescued from midgestational lethality by the expression of a Gata3 transgene in sympathoadrenal neuroendocrine cells. The rescued embryos clearly showed multiple defects in lens fibre cell differentiation. To determine whether these defects were truly due to the loss of Gata3 expression in the lens, we generated a lens-specific Gata3 loss-of-function model. Analogous to the previous findings, our Gata3 null embryos showed abnormal regulation of cell cycle exit during lens fibre cell differentiation, marked by reduction in the expression of the cyclin-dependent kinase inhibitors Cdkn1b/p27 and Cdkn1c/p57, and the retention of nuclei accompanied by downregulation of Dnase IIβ. Comparisons of transcriptomes between control and mutated lenses by RNA-Seq revealed dysregulation of lens-specific crystallin genes and intermediate filament protein Bfsp2. Both Cdkn1b/p27 and Cdkn1c/p57 loci are occupied in vivo by Gata3, as well as Prox1 and c-Jun, in lens chromatin. Collectively, our studies suggest that Gata3 regulates lens differentiation through the direct regulation of the Cdkn1b/p27and Cdkn1c/p57 expression, and the direct/or indirect transcriptional control of Bfsp2 and Dnase IIβ.

A Functional Map of Genomic HIF1α-DNA Complexes in The Eye Lens Revealed Through Multiomics Analysis

“…The HIF1α-activated ENO1 gene (tau crystallin) is both a lens structural protein and a glycolytic enzyme [63]. BNIP3L, BMP4, GATA3, CDKN1B, HES5, JAG1, and VEGFA all play important roles in lens cell development and differentiation (Table S3) [23,56,60,67,[84][85][86][87][88][89][90][91].…”

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

“…These studies can reveal genes, transcription factors, and molecular pathways that underlie lens differentiation during the transition from epithelial cells to fiber cells as well as those mechanisms critical for maintaining lens structure and transparency. By contrast, RNA-seq studies comparing wild-type versus mutant lens transcriptomes aim to identify the molecular changes that occur due to genetic mutations that affect lens differentiation [ 53 , 60 , 75 , 114 , 115 , 116 , 117 , 118 , 119 ]. By identifying the genes and pathways that are dysregulated in these mutant lenses, researchers can gain a better understanding of the molecular mechanisms underlying lens development and the genetic factors that contribute to cataract formation.…”

“…These pathways include but are not limited to Wnt [ 10 , 11 , 12 , 13 , 14 , 15 ], Notch [ 16 , 17 , 18 , 19 , 20 , 21 ], BMP [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], FGF-MAPK [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ], and Hippo pathways [ 43 , 44 ]. Key transcription factors include Pax6 [ 45 , 46 , 47 , 48 , 49 , 50 ], Prox1 [ 49 , 51 , 52 , 53 , 54 ], Hsf4 [ 55 , 56 , 57 ], Gata3 [ 58 , 59 , 60 ], FoxE3 […”

Cell fate decisions, transcription factors and signaling during early retinal development

“…Another pioneering factor RBPJ ( Fernandez Garcia et al, 2019 ) regulates retinal development after optic cup formation ( Rowan et al, 2008 ). The pioneering activity of Gata3 ( Tanaka et al, 2020 ) and TFAP2A ( Fernandez Garcia et al, 2019 ) established in other systems could play roles in lens development; however, loss-of-functions of these genes do not affect the earliest formation of lens precursor cells ( Maeda et al, 2009 ; Martynova et al, 2019 ; Pontoriero et al, 2008 ). Thus, additional data are needed to determine occupancy of pioneering transcription factors within the chromatin landscape together with visualization of accessible domains using cells from midstage embryos.…”