Liver Injury and Regeneration: Current Understanding, New Approaches, and Future Perspectives.

The liver is a complex organ with the ability to regenerate itself in response to injury. However, several factors can contribute to liver damage beyond repair. Liver injury can be caused by viral infections, alcoholic liver disease, non-alcoholic steatohepatitis, and drug-induced liver injury. Understanding the cellular and molecular mechanisms involved in liver injury and regeneration is critical to developing effective therapies for liver diseases. Liver regeneration is a complex process that involves the interplay of various signaling pathways, cell types, and extracellular matrix components. The activation of quiescent hepatocytes that proliferate and restore the liver mass by upregulating genes involved in cell-cycle progression, DNA repair, and mitochondrial function; the proliferation and differentiation of progenitor cells, also known as oval cells, into hepatocytes that contribute to liver regeneration; and the recruitment of immune cells to release cytokines and angiogenic factors that promote or inhibit cell proliferation are some examples of the regenerative processes. Recent advances in the fields of gene editing, tissue engineering, stem cell differentiation, small interfering RNA-based therapies, and single-cell transcriptomics have paved a roadmap for future research into liver regeneration as well as for the identification of previously unknown cell types and gene expression patterns. In summary, liver injury and regeneration is a complex and dynamic process. A better understanding of the cellular and molecular mechanisms driving this phenomenon could lead to the development of new therapies for liver diseases and improve patient outcomes.

TIP60 represses activation of endogenous retroviral elements.

TIP60 is a lysine acetyltransferase and is known to be a haplo-insufficient tumor suppressor. TIP60 downregulation is an early event in tumorigenesis which has been observed in several cancer types including breast and colorectal cancers. However, the mechanism by which it regulates tumor progression is not well understood. In this study, we identified the role of TIP60 in the silencing of endogenous retroviral elements (ERVs). TIP60-mediated silencing of ERVs is dependent on BRD4. TIP60 and BRD4 positively regulate the expression of enzymes, SUV39H1 and SETDB1 and thereby, the global H3K9 trimethylation (H3K9me3) level. In colorectal cancer, we found that the loss of TIP60 de-represses retrotransposon elements genome-wide, which in turn activate the cellular response to pathogens, mediated by STING, culminating in an induction of Interferon Regulatory Factor 7 (IRF7) and associated inflammatory response. In summary, this study has identified a unique mechanism of ERV regulation in cancer cells mediated by TIP60 and BRD4 through regulation of histone H3 K9 trimethylation, and a new tumor suppressive role of TIP60 in vivo.

Stressing the (Epi)Genome: Dealing with Reactive Oxygen Species in Cancer.

SIGNIFICANCE: Growing evidence indicates cross-talk between reactive oxygen species (ROS) and several key epigenetic processes such as DNA methylation, histone modifications, and miRNAs in normal physiology and human pathologies including cancer. This review focuses on how ROS-induced oxidative stress, metabolic intermediates, and epigenetic processes influence each other in various cancers. Recent Advances: ROS alter chromatin structure and metabolism that impact the epigenetic landscape in cancer cells. Several site-specific DNA methylation changes have been identified in different cancers and are discussed in the review. We also discuss the interplay of epigenetic enzymes and miRNAs in influencing malignant transformation in an ROS-dependent manner. CRITICAL ISSUES: Loss of ROS-mediated signaling mostly by epigenetic regulation may promote tumorigenesis. In contrast, augmented oxidative stress because of high ROS levels may precipitate epigenetic alterations to effect various phases of carcinogenesis. We address both aspects in the review. FUTURE DIRECTIONS: Several drugs targeting ROS are under various stages of clinical development. Recent analysis of human cancers has revealed pervasive deregulation of the epigenetic machinery. Thus, a better understanding of the cross-talk between ROS and epigenetic alterations in cancer could lead to the identification of new drug targets and more effective treatment modalities.

TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter.

HIV1-TAT interactive protein (TIP60) is a haploinsufficient tumor suppressor. However, the potential mechanisms endowing its tumor suppressor ability remain incompletely understood. It plays a vital role in virus-induced cancers where TIP60 down-regulates the expression of human papillomavirus (HPV) oncoprotein E6 which in turn destabilizes TIP60. This intrigued us to identify the role of TIP60, in the context of a viral infection, where it is targeted by oncoproteins. Through an array of molecular biology techniques such as Chromatin immunoprecipitation, expression analysis and mass spectrometry, we establish the hitherto unknown role of TIP60 in repressing the expression of the catalytic subunit of the human telomerase complex, TERT, a key driver for immortalization. TIP60 acetylates Sp1 at K639, thus inhibiting Sp1 binding to the TERT promoter. We identified that TIP60-mediated growth suppression of HPV-induced cervical cancer is mediated in part due to TERT repression through Sp1 acetylation. In summary, our study has identified a novel substrate for TIP60 catalytic activity and a unique repressive mechanism acting at the TERT promoter in virus-induced malignancies.