Epigenetic Regulation by Suv4-20h1 in Cardiopulmonary Progenitor Cells Is Required to Prevent Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease

Abstract

Background: The etiology of life-threatening cardiopulmonary diseases such as Pulmonary Hypertension (PH) and Chronic Obstructive Pulmonary Disease (COPD) originates from a complex interplay of environmental factors and genetic predispositions, which is not fully understood. Likewise, little is known about developmental abnormalities or epigenetic dysregulations that might predispose for PH or COPD in adult individuals. Methods: To identify pathology-associated epigenetic alteration in diseased lung tissues, we screened a cohort of human PH and COPD patients for changes of histone modifications by immunofluorescence staining. To analyze the function of H4K20me2/3 in lung pathogenesis, we developed a series of Suv4-20h1 knockout mouse lines targeting cardiopulmonary progenitor cells (CPPs) and different heart and lung cell types, followed by hemodynamic studies and morphometric assessment of tissue samples. Molecular, cellular and biochemical techniques were applied to analyze the function of Suv4-20h1-dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives. Results: We discovered a strong reduction of the histone modifications H4K20me2/3 in human COPD but not PH patients, which depend on the activity of the H4K20 di-methyltransferase SUV4-20H1. Loss of Suv4-20h1 in CPPs caused a COPD-like/PH phenotype in mice including formation of perivascular tertiary lymphoid tissue and goblet cell hyperplasia, hyper-proliferation of smooth muscle cells/myofibroblasts, impaired alveolarization and maturation defects of the microvasculature leading to massive right ventricular dilatation and premature death. Mechanistically, SUV4-20H1 binds directly to the 5'-upstream regulatory element of superoxide dismutase 3 ( Sod3 ) gene to repress its expression. Increased levels of the extracellular SOD3 enzyme in Suv4-20h1 mutants increases hydrogen peroxide (H2O2) concentrations, causing vascular defects and impairing alveolarization. Conclusions: Our findings reveal a pivotal role of the histone modifier SUV4-20H1 in cardiopulmonary co-development and uncover developmental origins of cardiopulmonary diseases. We assume that the study will facilitate the understanding of pathogenic events causing PH and COPD, and aid the development of epigenetic drugs for treatment of cardiopulmonary diseases.

Cardiopulmonary progenitors facilitate cardiac repair via exosomal transfer of miR‐27b‐3p targeting the SIK1‐CREB1 axis

“…First, we isolated CPPs from E9.5 murine embryos, maintained CPPs stemness while expanding them with ABC medium, and confirmed that CPPs harbour the unique potential to differentiate into two lineages of cells, which is in line with the latest publication showing that Isl1+ CPPs give rise to SMC, EC, EpiC, and alveolar myofibroblasts. 19 Data from scRNA-seq demonstrated that CPPs we obtained were a population mainly composed of heterogenic stem cells expressing CPPs marker Isl1, and exhibited a hybrid fibroblastic and endothelial state, which is similar to another study that found that pituitary stem cells are in a hybrid epithelial and mesenchymal state. 38 Additional analysis is needed to demonstrate the membrane markers for our CPPs, and verification experiment should be performed.…”

“…Nonetheless, there is no reported research on whether CPPs have the ability to repair the heart. Articles on CPPs are few and focus mainly on the regulation of heart or lung development 19 . The roles of CPPs in repairing damaged hearts need to be investigated.…”

“…Articles on CPPs are few and focus mainly on the regulation of heart or lung development. 19 The roles of CPPs in repairing damaged hearts need to be investigated.…”

Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine

“…Human asthma samples were received from the BioMaterialBank Nord, Clinical and Experimental Pathology Medicine, Research Center Borstel. Human donor samples, human COPD samples and human cystic fibrosis samples were provided by the DZL Biobank were obtained during lung transplantation of human COPD and cystic fibrosis patients 36 . Donor lung material was obtained as a result of atypical resections undertaken to adjust the donor organ to the recipient’s thoracal cavity.…”

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

“…However, a detailed time course of KMT5B expression in model systems is lacking. Loss of KMT5B results in altered development of both the brain and cardiopulmonary system ( 23 , 24 ). Evidence of KMT5B’s role in neurogenesis is available for many models [zebrafish ( 25 , 26 ), amphibian ( 27 ), rodent ( 28 ), and primate ( 29 ) model systems].…”