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 β-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.

Age-Dependent Assessment of Genes Involved in Cellular Senescence, Telomere, and Mitochondrial Pathways in Human Lung Tissue of Smokers, COPD, and IPF: Associations With SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 Axis

“…NanoString has several advantages in simultaneous estimation of the several gene levels in a single sample with low amounts of sample input (Eastel et al, 2019;Goytain and Ng, 2020). We have successfully used this platform to report changes in gene expression using different gene set panels in our earlier studies (Rashid et al, 2018;Sundar et al, 2018). In the current study, the custom designed panel included genes from three different pathways addressing the mitochondrial biogenesis and function, telomere function, and cellular senescence, which play a major role in the lung inflammation and COPD development.…”

“…The Benjamini-Hochberg procedure was used to adjust the p values to control the false discovery rates at 5%. The analyzed data was represented in the graphs as y-axis showing the negative log10 P-value and x-axis representing log2 fold change across each pairwise comparisons as described previously (Sundar et al, 2018). The significantly altered gene data were shown as dot plot representation.…”

p16-3MR: a novel model to study cellular senescence in cigarette smoke-induced lung injuries during aging

“…18S rRNA was used as housekeeping control. Fold-Change (2^(- Delta Delta Ct)) is the normalized gene expression (2^(- Delta Ct)) in the CS exposed group (Treated) divided by the normalized gene expression (2^(- Delta Ct)) in the Air group (Control) 39,40 . The sequence of the primers used for amplification is provided in Supplementary file Table 1.…”

Age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, COPD and IPF: Associations with SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 axis

“…The Benjamini-Hochberg procedure was used to adjust the p values to control the false discovery rates at 5%. The analyzed data was represented in the graphs as y-axis showing the negative log10 P-value and x-axis representing log2 fold change across each pairwise comparisons as described previously 42 . The significantly altered gene data were shown as dot plot representation in supplementary Figures S1-9 .…”