Catalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1.

SUV420H1 di- and tri-methylates histone H4 lysine 20 (H4K20me2/H4K20me3) and plays crucial roles in DNA replication, repair, and heterochromatin formation. It is dysregulated in several cancers. Many of these processes were linked to its catalytic activity. However, deletion and inhibition of SUV420H1 have shown distinct phenotypes, suggesting that the enzyme likely has uncharacterized non-catalytic activities. Our cryoelectron microscopy (cryo-EM), biochemical, biophysical, and cellular analyses reveal how SUV420H1 recognizes its nucleosome substrates, and how histone variant H2A.Z stimulates its catalytic activity. SUV420H1 binding to nucleosomes causes a dramatic detachment of nucleosomal DNA from the histone octamer, which is a non-catalytic activity. We hypothesize that this regulates the accessibility of large macromolecular complexes to chromatin. We show that SUV420H1 can promote chromatin condensation, another non-catalytic activity that we speculate is needed for its heterochromatin functions. Together, our studies uncover and characterize the catalytic and non-catalytic mechanisms of SUV420H1, a key histone methyltransferase that plays an essential role in genomic stability.

Histone deacetylases as targets in autoimmune and autoinflammatory diseases.

Reversible lysine acetylation of histones is a key epigenetic regulatory process controlling gene expression. Reversible histone acetylation is mediated by two opposing enzyme families: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Moreover, many non-histone targets of HATs and HDACs are known, suggesting a crucial role for lysine acetylation as a posttranslational modification on the cellular proteome and protein function far beyond chromatin-mediated gene regulation. The HDAC family consists of 18 members and pan-HDAC inhibitors (HDACi) are clinically used for the treatment of certain types of cancer. HDACi or individual HDAC member-deficient (cell lineage-specific) mice have also been tested in a large number of preclinical mouse models for several autoimmune and autoinflammatory diseases and in most cases HDACi treatment results in an attenuation of clinical disease severity. A reduction of disease severity has also been observed in mice lacking certain HDAC members. This indicates a high therapeutic potential of isoform-selective HDACi for immune-mediated diseases. Isoform-selective HDACi and thus targeted inactivation of HDAC isoforms might also overcome the adverse effects of current clinically approved pan-HDACi. This review provides a brief overview about the fundamental function of HDACs as epigenetic regulators, highlights the roles of HDACs beyond chromatin-mediated control of gene expression and summarizes the studies showing the impact of HDAC inhibitors and genetic deficiencies of HDAC members for the outcome of autoimmune and autoinflammatory diseases with a focus on rheumatoid arthritis, inflammatory bowel disease and experimental autoimmune encephalomyelitis (EAE) as an animal model of multiple sclerosis.

BMI1 and PTEN are key determinants of breast cancer therapy: A plausible therapeutic target in breast cancer.

BMI-1 (B-lymphoma Mo-MLV insertion region 1) is a key protein partner in polycomb repressive complex 1 (PRC1) that helps in maintaining the integrity of the complex. It is also a key player in ubiquitination of histone H2A which affects gene expression pattern involved in various cellular processes such as cell proliferation, growth, DNA repair, apoptosis and senescence. In many cancers, Overexpression of BMI1correlates with advanced stages of disease, aggressive clinicopathological behavior, poor prognosis resistance to radiation and chemotherapy. BMI1 is emerging as a key player in EMT, chemo-resistance and cancer stemness. Overexpression is observed in various cancer types such as breast, primary hepatocellular carcinoma (HCC), gastric, ovarian, head and neck, pancreatic and lung cancer. Studies have shown that experimental reduction of BMI protein level in tumor cells results in inhibition of cell proliferation, induction of apoptosis and/or senescence, and increases susceptibility to cytotoxic agents and radiation therapy. Thus, inhibition of BMI1 expression particularly in breast cancer stem cells can be used as a potential strategy for the complete elimination of tumor and to prevent disease relapse. On other hand PTEN is known to be an important tumor suppressor next to p53. In many cancers particularly in breast cancer, p53 and PTEN undergo mutations. Studies have indicated the functional and mechanistic link between the BMI-1oncoprotein and tumor suppressor PTEN in the development and progression of cancer. The current review focuses on recent findings of how oncogenicity and chemo-resistance are caused by BMI1. It also highlights the transcriptional regulation between BMI1 and PTEN that dictates the therapeutic outcome in cancers where the functional p53 is absent. Herein, we have clearly demonstrated the regulation of transcription at genomic loci of BMI1 and PTEN in cancerous tissue or cells and the possible epigenetic regulation by histone deacetylase inhibitors (HDACi) at BMI1 and PTEN loci that may provide some clue for the possible therapy against TNBC in near future.

What is the role of histone H1 heterogeneity? A functional model emerges from a 50 year mystery.

For the past 50 years, understanding the function of histone H1 heterogeneity has been mired in confusion and contradiction. Part of the reason for this is the lack of a working model that tries to explain the large body of data that has been collected about the H1 subtypes so far. In this review, a global model is described largely based on published data from the author and other researchers over the past 20 years. The intrinsic disorder built into H1 protein structure is discussed to help the reader understand that these histones are multi-conformational and adaptable to interactions with different targets. We discuss the role of each structural section of H1 (as we currently understand it), but we focus on the H1's C-terminal domain and its effect on each subtype's affinity, mobility and compaction of chromatin. We review the multiple ways these characteristics have been measured from circular dichroism to FRAP analysis, which has added to the sometimes contradictory assumptions made about each subtype. Based on a tabulation of these measurements, we then organize the H1 variants according to their ability to condense chromatin and produce nucleosome repeat lengths amenable to that compaction. This subtype variation generates a continuum of different chromatin states allowing for fine regulatory control and some overlap in the event one or two subtypes are lost to mutation. We also review the myriad of disparate observations made about each subtype, both somatic and germline specific ones, that lend support to the proposed model. Finally, to demonstrate its adaptability as new data further refines our understanding of H1 subtypes, we show how the model can be applied to experimental observations of telomeric heterochromatin in aging cells.