Aberrant Modulation of the BRCA1 and G1/S Cell Cycle Pathways in Alcoholic Hepatitis Patients with Mallory Denk Bodies Present Revealed by RNA Sequencing

Abstract

Mallory‐Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. Liver injury from alcohol administration causes balloon hepatocytes and MDB formation impeding liver regeneration. By comparing AH livers where MDBs had formed with normal liver transcriptomes obtained by RNA sequencing (RNA‐Seq), there was significant up regulation of BRCA1‐mediated signaling and G1/S cell cycle checkpoint pathways. The transcriptional architecture of differentially expressed genes from AH patients reflected step‐wise transcriptional changes progressing to AH. Key molecules such as BRCA1, p15 and p21 involved in BRCA1 signaling and G1/S cell cycle checkpoints were significantly up regulated both in patients’ livers and in the livers of the DDC re‐fed mice model where MDBs had formed. MiR‐483‐3p was down regulated in AH livers. The down regulation of miR‐483‐3p may be the mechanism for the up regulation of BRCA1 since miR‐483‐3p is an inhibitor of BRCA1 expression. The hyperactivation of G1/S cell cycle checkpoint inhibitors p15 and p21 results in cell cycle arrest and liver regeneration inhibition.ConclusionsProvided here for the first time is the RNA‐Seq data that represents the fully annotated catalogue of the expression of mRNAs. The most prominent alterations observed were the changes in BRCA1‐mediated signaling and G1/S cell cycle checkpoint pathways. These new findings expand previous and related knowledge in the search for gene changes that might be critical in the understanding of the underlying progression to the development of AH.Support or Funding InformationNIH (AAU01021898‐04).