Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract

Abstract

S100A4, a member of the S100 family of multifunctional calcium-binding proteins, participates in several physiological and pathological processes. In this study, we demonstrate that S100A4 expression is robustly induced in differentiating fiber cells of the ocular lens and that S100A4(−/−) knockout mice develop late-onset cortical cataracts. Transcriptome profiling of lenses from S100A4(−/−) mice revealed a robust increase in the expression of multiple photoreceptor- and Müller glia-specific genes, as well as the olfactory sensory neuron-specific gene, S100A5. This aberrant transcriptional profile is characterized by corresponding increases in the levels of proteins encoded by the aberrantly upregulated genes. Ingenuity pathway network and curated pathway analyses of differentially expressed genes in S100A4(−/−) lenses identified Crx and Nrl transcription factors as the most significant upstream regulators, and revealed that many of the upregulated genes possess promoters containing a high-density of CpG islands bearing trimethylation marks at histone H3K27 and/or H3K4, respectively. In support of this finding, we further documented that S100A4(−/−) knockout lenses have altered levels of trimethylated H3K27 and H3K4. Taken together, our findings suggest that S100A4 suppresses the expression of retinal genes during lens differentiation plausibly via a mechanism involving changes in histone methylation.

miR-26 deficiency causes alterations in lens transcriptome and results in adult-onset cataract

“…Some of these neural characteristics may be driven by molecular regulators of alternative splicing that are shared in both lens and neurons, including several members of the ELAV/Hu proteins 48,49 . Despite this, several recent studies have suggested that the suppression of neural gene expression in lens cells may be an important component of normal lens development and function 50,51 .…”

miR-26 Deficiency Causes Alterations in Lens Transcriptome and Results in Adult-Onset Cataract

“…56 , 57 Despite this, several recent studies have suggested that the suppression of neural gene expression in lens cells may be an important component of normal lens development and function. 58 , 59…”

Integrated single-cell multiomics uncovers foundational regulatory mechanisms of lens development and pathology

“…For example, retinal genes such as ASCL1, RAX, SIX6, VSX2, among others, exhibit a high degree of PRC2 binding and H3K27me3 localization signal, pointing toward their active suppression by PRC2 in lens cells. Indeed, other studies have suggested that lens cells may have a predisposition for acquiring aberrant retinal-like transcript profiles, and documented perturbed H3K27 trimethylation levels linked to this phenotype 96 . Our data now show that a PRC2mediated regulatory mechanism may be involved in suppression of retinal cell fates in the lens.…”