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Age-related histone loss and altered histone acetylation in mouse retinal pigment epithelium. [Total RNA]

ABSTRACT: Histones are pivotal carriers of epigenetic information through post-translational modifications (PTMs), crucial for regulating gene expression, proper cellular function and maintaining cell identity. Perturbations in histone levels within the aging genome can profoundly impact chromatin structure and gene expression profiles. In this study, we examined the effects of age-related changes on histone levels and histone acetylation in the retinal pigment epithelium (RPE) and retina of mice. Our findings revealed a global reduction in histones H1, H2A, H2B, H3, and H4 within the aged RPE/choroid, while the neural retina remained unaffected. Transcriptome analysis unveiled a significant downregulation of histone genes in the aged RPE/choroid, including key components of the histone locus body (HLB) complex involved in histone pre-mRNA processing. Knockdown of HINFP, a critical HLB component, in human RPE cells resulted in histone loss, induction of senescence, and upregulation of senescence-associated secretory phenotype (SASP) markers. Replicative aging of human RPE cells exhibited progressive histone loss and acquisition of the SASP phenotype. Immunostaining of human retina sections demonstrated a gradual decline in histones within the aging RPE. Additionally, aging in mice RPE/choroid led to diminished global histone acetylation levels, particularly H3K14ac, H3K56ac, and H4K16ac marks. These alterations in histone acetylation were metabolically driven and correlated with changes in acetyl-CoA abundance. Collectively, our findings highlight the characteristic loss of histones as a hallmark of aging in the RPE/choroid, shedding light on potential mechanisms linking histone dynamics, cellular senescence, and age-related functional changes in RPE cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE236220 | GEO | 2023/07/15

REPOSITORIES: GEO

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Project description:Proper spatial differentiation of retinal cell types is necessary for normal human vision. Many retinal diseases, such as Best disease and male germ cell associated kinase (MAK)-associated retinitis pigmentosa, preferentially affect distinct topographic regions of the retina. While much is known about the distribution of cell types in the retina, the distribution of molecular components across the posterior pole of the eye has not been well-studied. To investigate regional difference in molecular composition of ocular tissues, we assessed differential gene expression across the temporal, macular, and nasal retina and retinal pigment epithelium (RPE)/choroid of human eyes using RNA-Seq. RNA from temporal, macular, and nasal retina and RPE/choroid from four human donor eyes was extracted, poly-A selected, fragmented, and sequenced as 100 bp read pairs. Digital read files were mapped to the human genome and analyzed for differential expression using the Tuxedo software suite. Retina and RPE/choroid samples were clearly distinguishable at the transcriptome level. Numerous transcription factors were differentially expressed between regions of the retina and RPE/choroid. Photoreceptor-specific genes were enriched in the peripheral samples, while ganglion cell and amacrine cell genes were enriched in the macula. Within the RPE/choroid, RPE-specific genes were upregulated at the periphery while endothelium associated genes were upregulated in the macula. Consistent with previous studies, BEST1 expression was lower in macular than extramacular regions. The MAK gene was expressed at lower levels in macula than in extramacular regions, but did not exhibit a significant difference between nasal and temporal retina. The regional molecular distinction is greatest between macula and periphery and decreases between different peripheral regions within a tissue. Datasets such as these can be used to prioritize candidate genes for possible involvement in retinal diseases with regional phenotypes. Reprinted from <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=25446321">Whitmore, S.S., Wagner, A.H., DeLuca, A.P., Drack, A.V., Stone, E.M., Tucker, B.A., Zeng, S., Braun, T.A., Mullins, R.F., Scheetz, T.E., 2014. Transcriptomic analysis across nasal, temporal, and macular regions of human neural retina and RPE/choroid by RNA-Seq. Experimental Eye Research</a>. Used under <a href="http://creativecommons.org/licenses/by-nc-sa/3.0/">Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported </a>license. Additional RNA sequencing was performed on temporal, macular, nasal, inferior, and superior retina from a fifth subject and is included in this dataset. See original publication for details.

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Age-related histone loss and altered histone acetylation in mouse retinal pigment epithelium. [Total RNA]

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