TY - JOUR
T1 - Histone deficiency and hypoacetylation in the aging retinal pigment epithelium
AU - Dubey, Sushil K.
AU - Dubey, Rashmi
AU - Prajapati, Subhash C.
AU - Jung, Kyungsik
AU - Mohan, Kabhilan
AU - Liu, Xinan
AU - Roney, Jacob
AU - Tian, Wenjian
AU - Abney, Jennifer
AU - Giarmarco, Michelle M.
AU - Hernandez, Alvaro G.
AU - Liu, Jinze
AU - Kleinman, Mark E.
N1 - We thank Anita Hendrickson, Ph.D. (University of Washington, Vision Science Center, Dec. 2017) and NDRI for generously providing human retinal sections; and Johanna Preiszner (East Tennessee State University) for scanning IHC slides.
This work was supported by grants from NIH NEI R01EY028206 (Mark E. Kleinman), NIH NEI K08EY021757 (Mark E. Kleinman), BrightFocus Macular Degeneration Research Award (Mark E. Kleinman), American Federation for Aging Research (Mark E. Kleinman), International Retinal Research Foundation (Sushil K. Dubey) and NEI Center Core Grant for Vision Research (NIH NEI P30EY001730; Maureen Neitz).
PY - 2024/5
Y1 - 2024/5
N2 - Histones serve as a major carrier of epigenetic information in the form of post-translational modifications which are vital for controlling gene expression, maintaining cell identity, and ensuring proper cellular function. Loss of histones in the aging genome can drastically impact the epigenetic landscape of the cell leading to altered chromatin structure and changes in gene expression profiles. In this study, we investigated the impact of age-related changes on histone levels and histone acetylation in the retinal pigment epithelium (RPE) and retina of mice. We observed a global reduction of histones H1, H2A, H2B, H3, and H4 in aged RPE/choroid but not in the neural retina. Transcriptomic analyses revealed significant downregulation of histones in aged RPE/choroid including crucial elements of the histone locus body (HLB) complex involved in histone pre-mRNA processing. Knockdown of HINFP, a key HLB component, in human RPE cells induced histone loss, senescence, and the upregulation of senescence-associated secretory phenotype (SASP) markers. Replicative senescence and chronological aging in human RPE cells similarly resulted in progressive histone loss and acquisition of the SASP. Immunostaining of human retina sections revealed histone loss in RPE with age. Acetyl-histone profiling in aged mouse RPE/choroid revealed a specific molecular signature with loss of global acetyl-histone levels, including H3K14ac, H3K56ac, and H4K16ac marks. These findings strongly demonstrate histone loss as a unique feature of RPE aging and provide critical insights into the potential mechanisms linking histone dynamics, cellular senescence, and aging.
AB - Histones serve as a major carrier of epigenetic information in the form of post-translational modifications which are vital for controlling gene expression, maintaining cell identity, and ensuring proper cellular function. Loss of histones in the aging genome can drastically impact the epigenetic landscape of the cell leading to altered chromatin structure and changes in gene expression profiles. In this study, we investigated the impact of age-related changes on histone levels and histone acetylation in the retinal pigment epithelium (RPE) and retina of mice. We observed a global reduction of histones H1, H2A, H2B, H3, and H4 in aged RPE/choroid but not in the neural retina. Transcriptomic analyses revealed significant downregulation of histones in aged RPE/choroid including crucial elements of the histone locus body (HLB) complex involved in histone pre-mRNA processing. Knockdown of HINFP, a key HLB component, in human RPE cells induced histone loss, senescence, and the upregulation of senescence-associated secretory phenotype (SASP) markers. Replicative senescence and chronological aging in human RPE cells similarly resulted in progressive histone loss and acquisition of the SASP. Immunostaining of human retina sections revealed histone loss in RPE with age. Acetyl-histone profiling in aged mouse RPE/choroid revealed a specific molecular signature with loss of global acetyl-histone levels, including H3K14ac, H3K56ac, and H4K16ac marks. These findings strongly demonstrate histone loss as a unique feature of RPE aging and provide critical insights into the potential mechanisms linking histone dynamics, cellular senescence, and aging.
KW - HINFP
KW - aging
KW - epigenetics
KW - histone acetylation
KW - histones
KW - replicative senescence
KW - retinal pigment epithelium
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U2 - 10.1111/acel.14108
DO - 10.1111/acel.14108
M3 - Article
C2 - 38408164
AN - SCOPUS:85186572743
SN - 1474-9718
VL - 23
JO - Aging Cell
JF - Aging Cell
IS - 5
M1 - e14108
ER -