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.

MicroRNAs in microglia: deciphering their role in neurodegenerative diseases.

This review presents a comprehensive analysis of the role of microRNAs in microglia and their implications in the pathogenesis of neurodegenerative diseases. Microglia, as the resident immune cells of the central nervous system (CNS), are pivotal in maintaining neural homeostasis and responding to pathological changes. Recent studies have highlighted the significance of miRNAs, small non-coding RNA molecules, in regulating microglial functions. In neurodegenerative diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), dysregulated miRNA expression in microglia contributes to disease progression through various mechanisms such regulation of gene expression, as modulation of cytokine response and phagocytosis. This review synthesizes current knowledge on how miRNAs influence microglial activation, cytokine production, and phagocytic activity. Specific miRNAs, such as miR-155, are explored for their roles in modulating microglial responses in the context of neuroinflammation and neurodegeneration. The study also discusses the impact of miRNA dysregulation on the transition of microglia from a neuroprotective to a neurotoxic phenotype, a critical aspect in the progression of neurodegenerative diseases.

TIP60 inhibits metastasis by ablating DNMT1-SNAIL2-driven epithelial-mesenchymal transition program.

HIV-Tat-interacting protein of 60 kDa (TIP60) is a lysine acetyltransferase and known to be downregulated in multiple cancers. Among various signalling pathways, TIP60 is implicated in regulating epithelial-mesenchymal transition (EMT). Here, we show that TIP60 expression abrogates cell migration and metastatic potential of breast cancer cells using in vitro and in vivo models. Mechanistically, we show that this is through its ability to destabilize DNMT1 and inhibit SNAIL2 function (SNAIL2-mediated EMT/cell migration). Depletion of TIP60 stabilizes DNMT1 and increases SNAIL2 levels, resulting in EMT. Recruitment of DNMT1 to the SNAIL2 targets in the absence of TIP60 increases DNA methylation on their promoter region and further represses the expression of epithelial markers. In pathophysiological scenario, we find TIP60 to be significantly downregulated in breast cancer patients with poor overall survival and disease-free survival prognoses. These data suggest that levels of TIP60 can be a prognostic marker of breast cancer progression and stabilization of TIP60 could be a promising strategy to treat cancers.