Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis.

BACKGROUND AND AIMS: Besides well-defined genetic alterations, the dedifferentiation of mature acinar cells is an important prerequisite for pancreatic carcinogenesis. Acinar-specific genes controlling cell homeostasis are extensively downregulated during cancer development; however, the underlying mechanisms are poorly understood. Now, we devised a novel in vitro strategy to determine genome-wide dynamics in the epigenetic landscape in pancreatic carcinogenesis. DESIGN: With our in vitro carcinogenic sequence, we performed global gene expression analysis and ChIP sequencing for the histone modifications H3K4me3, H3K27me3 and H2AK119ub. Followed by a comprehensive bioinformatic approach, we captured gene clusters with extensive epigenetic and transcriptional remodelling. Relevance of Ring1b-catalysed H2AK119ub in acinar cell reprogramming was studied in an inducible Ring1b knockout mouse model. CRISPR/Cas9-mediated Ring1b ablation as well as drug-induced Ring1b inhibition were functionally characterised in pancreatic cancer cells. RESULTS: The epigenome is vigorously modified during pancreatic carcinogenesis, defining cellular identity. Particularly, regulatory acinar cell transcription factors are epigenetically silenced by the Ring1b-catalysed histone modification H2AK119ub in acinar-to-ductal metaplasia and pancreatic cancer cells. Ring1b knockout mice showed greatly impaired acinar cell dedifferentiation and pancreatic tumour formation due to a retained expression of acinar differentiation genes. Depletion or drug-induced inhibition of Ring1b promoted tumour cell reprogramming towards a less aggressive phenotype. CONCLUSIONS: Our data provide substantial evidence that the epigenetic silencing of acinar cell fate genes is a mandatory event in the development and progression of pancreatic cancer. Targeting the epigenetic repressor Ring1b could offer new therapeutic options.

Long-term left atrial remodeling after ablation of persistent atrial fibrillation: 7-year follow-up by cardiovascular magnetic resonance imaging.

PURPOSE: Restoration of sinus rhythm in patients with persistent atrial fibrillation (ps. AF) induces reverse atrial remodeling and improvement of left ventricular function. We evaluated the effect of ablative treatment on cardiac remodeling after a long follow-up period of 7 years by cardiovascular magnetic resonance (CMR). METHODS: Patients with symptomatic ps. AF underwent CMR within 7 days prior to the ablation procedure. Left atrial and ventricular volumes were measured. All patients underwent circumferential pulmonary vein isolation. At the end of follow-up (FU), a CMR and 7-day ECG registration were performed. RESULTS: Forty-two patients (67 ± 9 years) were included. After a FU of 86 ± 13 months, 23 patients had a successful outcome. In these patients, LVEF improved from 56 ± 5 to 62 ± 4% (p = 0.02), but left atrial volume and ejection fraction (LAV, LAEF) remained unchanged (105 ± 25 to 98 ± 34, p = 0.44; 34 ± 10 to 36 ± 11, p = 0.6, respectively). In 14 patients with a BMI < 30 and no left ventricular hypertrophy (LVH), LAV decreased (104 ± 30 to 82 ± 26 ml, p = 0.01) and LAEF improved (33 ± 12 to 40 ± 11%, p = 0.03). In 9 patients with successful outcome and either BMI ≥ 30 or LVH, LAV increased (110 ± 26 to 125 ± 30 ml, p = 0.03) and LAEF deteriorated (35 ± 11 to 31 ± 10%, p = 0.04). CONCLUSIONS: Successful ablative treatment of atrial fibrillation is associated with reverse left atrial remodeling and improvement of left atrial and ventricular function. In patients with a BMI ≥ 30 or left ventricular hypertrophy, further left atrial enlargement occurs despite successful outcome.