TY - JOUR
T1 - Histone HIST1H1C/H1.2 regulates autophagy in the development of diabetic retinopathy
AU - Wang, Wenjun
AU - Wang, Qing
AU - Wan, Danyang
AU - Sun, Yue
AU - Wang, Lin
AU - Chen, Hong
AU - Liu, Chengyu
AU - Petersen, Robert B.
AU - Li, Jianshuang
AU - Xue, Weili
AU - Zheng, Ling
AU - Huang, Kun
N1 - Publisher Copyright:
© 2017 Taylor & Francis.
PY - 2017/5/4
Y1 - 2017/5/4
N2 - Autophagy plays critical and complex roles in many human diseases, including diabetes and its complications. However, the role of autophagy in the development of diabetic retinopathy remains uncertain. Core histone modifications have been reported involved in the development of diabetic retinopathy, but little is known about the histone variants. Here, we observed increased autophagy and histone HIST1H1C/H1.2, an important variant of the linker histone H1, in the retinas of type 1 diabetic rodents. Overexpression of histone HIST1H1C upregulates SIRT1 and HDAC1 to maintain the deacetylation status of H4K16, leads to upregulation of ATG proteins, then promotes autophagy in cultured retinal cell line. Histone HIST1H1C overexpression also promotes inflammation and cell toxicity in vitro. Knockdown of histone HIST1H1C reduces both the basal and stresses (including high glucose)-induced autophagy, and inhibits high glucose induced inflammation and cell toxicity. Importantly, AAV-mediated histone HIST1H1C overexpression in the retinas leads to increased autophagy, inflammation, glial activation and neuron loss, similar to the pathological changes identified in the early stage of diabetic retinopathy. Furthermore, knockdown of histone Hist1h1c by siRNA in the retinas of diabetic mice significantly attenuated the diabetes-induced autophagy, inflammation, glial activation and neuron loss. These results indicate that histone HIST1H1C may offer a novel therapeutic target for preventing diabetic retinopathy.
AB - Autophagy plays critical and complex roles in many human diseases, including diabetes and its complications. However, the role of autophagy in the development of diabetic retinopathy remains uncertain. Core histone modifications have been reported involved in the development of diabetic retinopathy, but little is known about the histone variants. Here, we observed increased autophagy and histone HIST1H1C/H1.2, an important variant of the linker histone H1, in the retinas of type 1 diabetic rodents. Overexpression of histone HIST1H1C upregulates SIRT1 and HDAC1 to maintain the deacetylation status of H4K16, leads to upregulation of ATG proteins, then promotes autophagy in cultured retinal cell line. Histone HIST1H1C overexpression also promotes inflammation and cell toxicity in vitro. Knockdown of histone HIST1H1C reduces both the basal and stresses (including high glucose)-induced autophagy, and inhibits high glucose induced inflammation and cell toxicity. Importantly, AAV-mediated histone HIST1H1C overexpression in the retinas leads to increased autophagy, inflammation, glial activation and neuron loss, similar to the pathological changes identified in the early stage of diabetic retinopathy. Furthermore, knockdown of histone Hist1h1c by siRNA in the retinas of diabetic mice significantly attenuated the diabetes-induced autophagy, inflammation, glial activation and neuron loss. These results indicate that histone HIST1H1C may offer a novel therapeutic target for preventing diabetic retinopathy.
KW - H4K16Ac
KW - autophagy
KW - cell toxicity
KW - diabetic retinopathy
KW - histone HIST1H1C
KW - inflammation
UR - http://www.scopus.com/inward/record.url?scp=85017439300&partnerID=8YFLogxK
U2 - 10.1080/15548627.2017.1293768
DO - 10.1080/15548627.2017.1293768
M3 - Article
C2 - 28409999
AN - SCOPUS:85017439300
VL - 13
SP - 941
EP - 954
JO - Autophagy
JF - Autophagy
SN - 1554-8627
IS - 5
ER -