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Genetic ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema.

ABSTRACT: Histone deacetylase 2 (HDAC2), a critical determinant of chromatin remodeling, is reduced as a consequence of oxidative stress-mediated DNA damage and impaired repair. Cigarette smoke (CS) exposure causes DNA damage and cellular senescence. However, no information is available on the role of HDAC2 in CS-induced DNA damage, stress-induced premature senescence (SIPS), and senescence-associated secretory phenotype (SASP) during the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. We hypothesized that CS causes persistent DNA damage and cellular senescence via HDAC2-dependent mechanisms. We used HDAC2 global knockout (KO) and HDAC2 lung epithelial cell-specific KO [Clara cell-specific HDAC2 deletion (HDAC2 CreCC10)] mice to determine whether HDAC2 is a major player in CS-induced oxidative stress, SIPS, and SASP. HDAC2 KO mice exposed to CS show exaggerated DNA damage, inflammatory response, and decline in lung function leading to airspace enlargement. Chronic CS exposure augments lung senescence-associated ?-galactosidase activity in HDAC2 KO, but not in HDAC2 CreCC10 mice. HDAC2 lung epithelial cell-specific KO did not further augment CS-induced inflammatory response and airspace enlargement but instead caused an increase in lymphoid aggregate formation. Our study reveals that HDAC2 is a key player regulating CS-induced DNA damage, inflammatory response, and cellular senescence leading to COPD/emphysema.-Sundar, I. K., Rashid, K., Gerloff, J., Rangel-Moreno, J., Li, D., Rahman, I. Genetic ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema.

SUBMITTER: Sundar IK

PROVIDER: S-EPMC6103175 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Genetic ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema.

Sundar Isaac K IK Rashid Kahkashan K Gerloff Janice J Rangel-Moreno Javier J Li Dongmei D Rahman Irfan I

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20180409 9

Histone deacetylase 2 (HDAC2), a critical determinant of chromatin remodeling, is reduced as a consequence of oxidative stress-mediated DNA damage and impaired repair. Cigarette smoke (CS) exposure causes DNA damage and cellular senescence. However, no information is available on the role of HDAC2 in CS-induced DNA damage, stress-induced premature senescence (SIPS), and senescence-associated secretory phenotype (SASP) during the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphys ...[more]

PMID: 29630406

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Project description:BackgroundPanobinostat (PB), a histone deacetylase (HDAC) inhibitor drug, is clinically used in the treatment of cancers. We investigated the effects of PB on murine ovarian functions in embryos and adult animals.MethodsC57BL/6J mice were treated with 5 mg/kg PB on alternate days from embryonic day (E) 6.5 to E15.5. We analysed the effects of PB on the ovaries by using immunofluorescence, gene expression analysis and DNA methylation analysis techniques.ResultsAt E15.5, we observed increases in histone H3K9Ac, H4Ac and H3K4me3 marks, while the level of the silencing H3K9me3 mark decreased. Synaptonemal complex examination at E15.5, E17.5 and E18.5 showed a delay in meiotic progression characterized by the absence of synaptonemal complexes at E15.5 and the persistence of double-strand breaks (DSBs) at E17.5 and E18.5 in PB-exposed oocytes. We found that exposure to PB led to changes in the expression of 1169 transcripts at E15.5. Genes regulated by the male-specific factors SRY-Box Transcription Factor 9 (SOX9) and Doublesex and Mab-3-related Transcription factor 1 (DMRT1) were among the most upregulated genes in the ovaries of PB-exposed mice. In contrast, PB treatment led to decreases in the expression of genes regulated by the WNT4 pathway. Notably, we observed 119 deregulated genes encoding Zn-finger proteins. The observed alterations in epigenetic marks and gene expression correlated with decreases in the numbers of germ cells at E15.5. After birth, PB-exposed ovaries showed increased proliferation of primary and secondary follicles. We also observed decreases in the numbers of primordial, primary and secondary follicles in adult ovaries from mice that were exposed to PB in utero. Finally, epigenetic alterations such as decreased H3K4me3 and increased H4 acetylation levels were also detected in somatic cells surrounding fully grown oocytes.ConclusionOur data suggest that inhibition of histone deacetylase by PB during a critical developmental window affects reprogramming and germ cell specification via alteration of epigenetic marks.

Project description:PurposeCorneal myofibroblasts differentiated from activated corneal stromal cells are the major cellular sources of extracellular matrix synthesis for the repair of corneal injury. In this study, the effects of histone deacetylase (HDAC) inhibitors on the activation, proliferation, migration and senescence of corneal stromal cells were evaluated.MethodsPrimary human and mouse corneal stromal cells were harvested by sequential digestion with dispase and collagenase, and cultured in DMEM/F-12 media under serum-free (keratocytes), serum- (corneal fibroblasts) and TGFbeta1-supplemented (corneal myofibroblasts) conditions. The responses of corneal stromal cells to HDAC inhibitors were characterized by cDNA microarray, real time PCR, immunocytochemistry and western blot analysis. The effects of HDAC inhibitors on corneal fibroblast proliferation, cell cycle distribution, migration and senescence were also assessed in vitro.ResultsFetal bovine serum and TGFbeta1 activated the transdifferentiation of corneal stromal cells into fibroblasts and myofibroblasts, indicated by cell spreading, renewed assembly of actin filaments and enhanced expression of extracellular matrix components, all of which were suppressed by the addition of HDAC inhibitors. HDAC inhibitors inhibited the proliferation of corneal fibroblasts by decreasing the proportion in the S-phase and increasing the proportion in the G0/G1 and G2/M cell cycle checkpoints. HDAC inhibitors showed a dose-dependent inhibitory effects on the migration of corneal fibroblasts. In addition, HDAC inhibitors induced the senescence of corneal myofibroblasts as shown by enhanced staining of beta-galactosidase and upregulated expression of p16(ink4a).ConclusionsHDAC inhibitors may affect corneal stromal cells by inhibiting myofibroblastic differentiation, cell proliferation, migration and by inducing cell senescence. Thus, this has implications for future studies in the development of promising drugs in the prevention or treatment of corneal haze and scar formation.

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Genetic ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema.

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Genetic ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema.

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